Neoadjuvant durvalumab improves survival in early triple-negative breast cancer independent of pathological complete response - Loibl, S.; Schneeweiss, A.; Huober, J.; Braun, M.; Rey, J.; Blohmer, J. U.; Furlanetto, J.; Zahm, D. M.; Hanusch, C.; Thomalla, J.; Jackisch, C.; Staib, P.; et al. (Annals of Oncology, 2022)
BACKGROUND: Addition of immune checkpoint inhibitors to neoadjuvant chemotherapy (NACT) is a promising strategy in early breast cancer, but the optimal duration of therapy is currently unknown. In the GeparNuevo (NCT02685059) trial, addition of durvalumab to NACT as previously reported led to a moderate increase in pathological complete response (pCR) rate by an absolute 9% (P = 0.287). PATIENTS AND METHODS: Patients with cT1b-cT4a-d triple-negative breast cancer (TNBC) received durvalumab 1.5 g or placebo every 4 weeks added to nab-paclitaxel 125 mg/m2 weekly for 12 weeks, followed by durvalumab/placebo every 4 weeks plus epirubicin/cyclophosphamide every 2 weeks followed by surgery. Durvalumab was not continued after surgery. The primary objective was pCR. Secondary endpoints included invasive disease-free survival (iDFS), distant disease-free survival (DDFS) and overall survival (OS). RESULTS: A total of 174 patients were randomised between June 2016 and October 2017. After a median follow-up of 43.7 months, 34 events had occurred. Despite a non-significant increase in the pCR rate, significant differences were observed for 3-year iDFS, DDFS and OS: iDFS was 85.6% with durvalumab versus 77.2% with placebo [hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.24-0.97, stratified log-rank P = 0.036]; DDFS 91.7% versus 78.4% (HR 0.31, 95% CI 0.13-0.74, P = 0.005); OS 95.2% versus 83.5% (HR 0.24, 95% CI 0.08-0.72, P = 0.006). pCR patients had 3-year iDFS of 95.5% with durvalumab and 86.1% without (HR 0.22, 95% CI 0.05-1.06). In the non-pCR cohort 3-year iDFS was 76.3% versus 69.7% (HR 0.67, 95% CI 0.29-1.54). Multivariable analysis confirmed a durvalumab effect independent of the pCR effect. No new safety signals occurred. CONCLUSIONS: Durvalumab added to NACT in TNBC significantly improved survival despite a modest pCR increase and no adjuvant component of durvalumab. Additional studies are needed to clarify the optimal duration and sequence of checkpoint inhibitors in the treatment of early TNBC.
CRIS-Team Scopus Importer:2022-11-11
Keywords: checkpoint inhibitor; durvalumab; early triple-negative breast cancer; neoadjuvant chemotherapy; survival

Neoadjuvante Therapiekonzepte beim Zervixkarzinom - Stübs, Frederik A.; Koch, Martin; Beckmann, Matthias (Gynäkologe, 2019)
Background: The neoadjuvant treatment concept is nowadays the standard of care for many different organ entities. The neoadjuvant treatment also seems to be of interest in special situations for cervical cancer. Objective: This article gives an overview of the currently discussed fields of application of neoadjuvant therapy in treating patients with cervical cancer and the various options are discussed. Material and methods: This article is based on the national S3 guidelines for diagnostics, treatment and follow-up of patients with cervical cancer of the Association of the Scientific Medical Societies of Germany (AWMF, register number 032/033OL in the version from 2014). Additionally, this was extended by the literature for the update research of the new version of the guidelines. Results: The response rate to neoadjuvant therapy is 84%. The 5‑year progression-free survival and overall survival are 61.9% and 72.8%, respectively. Women responding to neoadjuvant therapy have a better long-term survival than non-responders. In a Cochrane meta-analysis from 2012 neoadjuvant chemotherapy before the planned operation improved the progression-free survival (hazard ratio, HR 0.75, 95% confidence interval, CI 0.61–0.93, P = 0.008) and the overall survival (HR 0.77, 95% CI 0.62–0.96, P = 0.02). The results were no longer significant when the random effects model was used (odds ratio, OR 0.60, 95% CI 0.32–1.12, P = 0.11). In macroinvasive cervical cancer during pregnancy neoadjuvant therapy is an established component of treatment. Discussion: The data on the use of neoadjuvant therapy in treating cervical cancer is unclear. The neoadjuvant therapy is currently not a standard of care in the treatment of cervical cancer. The roles of operative staging and positive lymph nodes after neoadjuvant therapy are also unresolved. Various meta-analyses could show that neoadjuvant therapy improves progression-free and overall survival. This is especially true for women who respond to this treatment.
CRIS-Team Scopus Importer:2019-05-21
Keywords: Disease progression; Disease progression; Disease-free survival; Pregnancy; Standard of care

Neoadjuvant giredestrant (GDC-9545) + palbociclib (palbo) vs anastrozole (A) plus palbo in post-menopausal women with oestrogen receptor-positive, HER2-negative, untreated early breast cancer (ER+/HER2-eBC): Interim analysis of the randomised, open-label, phase II coopERA BC study - Hurvitz, S. A.; Park, Y. H.; Bardia, A.; Quiroga, V.; Lopez-Valverde, V.; Steinseifer, J.; Moore, H. M.; Spera, G.; Xue, C.; Fasching, Peter (ANNALS OF ONCOLOGY, 2021)
CRIS-Team WoS Importer:2021-10-15

Neoadjuvant immunotherapy and chemotherapy regimens for the treatment of high-risk, early-stage triple-negative breast cancer: a systematic review and network meta-analysis - Cortes, Javier; Haiderali, Amin; Huang, Min; Pan, Wilbur; Schmid, Peter; Akers, Katherine G.; Park, Julie E.; Frederickson, Andrew M.; Fasching, Peter; O’Shaughnessy, Joyce (BMC Cancer, 2023)
Background: Patients with triple-negative breast cancer (TNBC) are generally younger and more likely to experience disease recurrence and have the shortest survival among all breast cancer patients. Recently, neoadjuvant delivery of the programmed cell death protein-1 inhibitor pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab was approved for patients with high-risk, early-stage TNBC, but this treatment regimen has not been evaluated in head-to-head trials with other neoadjuvant treatment regimens. Therefore, the objective of this study was to estimate the relative efficacy of neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab versus other neoadjuvant treatments for early-stage TNBC through a systematic review and network meta-analysis (NMA). Methods: EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials, conference abstracts, and clinical trial registries were searched for randomized controlled trials evaluating neoadjuvant treatments for early-stage TNBC. NMA was performed to estimate relative treatment effects among evaluated interventions. Results: Five trials met the inclusion criteria and were included in the NMA. The relative efficacy of neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab was favorable to paclitaxel followed by anthracycline + cyclophosphamide in terms of pathologic complete response (pCR), event-free survival (EFS), and overall survival; paclitaxel + carboplatin followed by anthracycline + cyclophosphamide in terms of pCR and EFS; paclitaxel + bevacizumab followed by anthracycline + cyclophosphamide + bevacizumab in terms of pCR; and paclitaxel + carboplatin + veliparib followed by anthracycline + cyclophosphamide in terms of EFS. Conclusions: Neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab confers benefits in response and survival outcomes versus alternative neoadjuvant treatments for early-stage TNBC.
CRIS-Team Scopus Importer:2023-09-01
Keywords: Chemotherapy; Immunotherapy; Neoadjuvant therapy; Network meta-analysis; PD-1; PD-L1; Triple-negative breast cancer

Neoadjuvant Paclitaxel/Olaparib in Comparison to Paclitaxel/Carboplatin in Patients with HER2-Negative Breast Cancer and HRD-Long-term Survival of the GeparOLA Study - Fasching, Peter; Schmatloch, Sabine; Hauke, Jan; Rey, Julia; Jackisch, Christian; Klare, Peter; Link, Theresa; Hanusch, Claus; Huober, Jens; Stefek, Andrea; Holtschmidt, Johannes; Schneeweiss, Andreas; et al. (Clinical Cancer Research, 2025)
PURPOSE: The GeparOLA study evaluated paclitaxel plus olaparib (PO) in neoadjuvant chemotherapy for patients with HER2-negative early breast cancer with homologous recombination deficiency (HRD). HRD was defined by high HRD score or germline (g)/tumor (t) BRCA1/2 mutations (g/tBRCA1/2mut). In this study, we report long-term outcome data. PATIENTS AND METHODS: GeparOLA (NCT02789332) was a randomized, multicenter, prospective, open-label, phase II trial. Patients with HER2-negative early breast cancer with HRD with an indication for chemotherapy (cT2-cT4a-d or cT1c and cN+ or cT1c and pNSLN+ or cT1c and triple-negative breast cancer, or cT1c and Ki-67 >20%) were randomly assigned to PO or paclitaxel + carboplatin (PCb), both followed by epirubicin + cyclophosphamide. Long-term efficacy endpoints were secondary endpoints and included invasive disease-free survival (iDFS), distant disease-free survival (DDFS), and overall survival, with a planned median follow-up of >4 years. RESULTS: Between September 2016 and July 2018, 107 patients were randomized and 106 (PO N = 69 and PCb N = 37) started treatment. The median age was 47.0 years; of all patients, 35.8% had cT1 tumors, 31.4% were cN+, 86.8% had G3 tumors, 89.6% had Ki-67 >20%, and 72.6% were triple negative. After a median follow-up of 49.8 months, 18 (15 in PO and three in PCb) iDFS events and seven (six in PO and one in PCb) deaths were reported. The 4-year iDFS (76.0% PO vs. 88.5% PCb, hazard ratio = 2.86; 95% CI, 0.83-9.90; log-rank P = 0.081), DDFS (81.2% PO vs. 93.4% PCb, hazard ratio = 3.03; 95% CI, 0.67-13.67; log-rank P = 0.129), and overall survival (89.2% PO vs. 96.9% PCb, hazard ratio = 3.27; 95% CI, 0.39-27.20; log-rank P = 0.244) tended to be inferior with olaparib. Patients without g/tBRCA1/2mut benefited from Cb (seven of 30 patients had iDFS/DDFS events in PO vs. 0/16 in PCb; log-rank P = 0.037), whereas no difference for patients with g/tBRCA1/2mut was observed (hazard ratio = 1.16, log-rank P = 0.83). CONCLUSIONS: For HER2-negative early breast cancer with HRD, olaparib showed a tendency for inferior outcomes compared with Cb, particularly in patients without g/tBRCA1/2mut. In patients with g/tBRCA1/2mut, olaparib may replace Cb.
CRIS-Team Scopus Importer:2025-05-23

Neoadjuvant paclitaxel/olaparib in comparison to paclitaxel/carboplatinum in patients with HER2-negative breast cancer and homologous recombination deficiency (GeparOLA study) - Fasching, Peter; Link, T.; Hauke, J.; Seither, F.; Jackisch, C.; Klare, P.; Schmatloch, S.; Hanusch, C.; Huober, J.; Stefek, A.; Seiler, S.; Schmitt, W. D.; et al. (Annals of Oncology, 2020)
Background: The efficacy and toxicity of olaparib as combination therapy in early breast cancer (BC) patients with homologous recombinant deficiency (HRD) [score high and/or germline (g) or tumour (t) BRCA1/2 mutation] is not well described. GeparOLA (ClinicalTrials.gov, NCT02789332) investigated olaparib in combination with paclitaxel in HER2-negative early BC with HRD. Patients and methods: Patients with untreated primary HER2-negative cT2-cT4a-d or cT1c with either cN+ or pNSLN+ or cT1c and triple-negative breast cancer (TNBC) or cT1c and Ki-67>20% BC with HRD were randomised either to paclitaxel (P) 80 mg/m2 weekly plus olaparib (O) 100 mg twice daily for 12 weeks or P plus carboplatinum (Cb) area under the curve 2 weekly for 12 weeks, both followed by epirubicin/cyclophosphamide (EC). Stratification factors were hormone receptor (HR) status (HR+ versus HR−) and age (<40 versus ≥40 years). The primary endpoint was pathological complete response (pCR; ypT0/is ypN0). A two-sided one-group χ2-test was planned to exclude a pCR rate of ≤55% in the PO-EC arm. Secondary end points were other pCR definitions, breast conservation rate, clinical/imaging response, tolerability and safety. Results: A total of 107 patients were randomised between September 2016 and July 2018; 106 (PO N = 69; PCb N = 37) started treatment. Median age was 47.0 years (range 25.0-71.0); 36.2% had cT1, 61.0% cT2, 2.9% cT3, and 31.8% cN-positive tumours; grade 3 tumours: 86.8%; Ki-67>20%: 89.6%; TNBC: 72.6%; confirmed gBRCA1/2 mutation: 56.2%. The pCR rate with PO was 55.1% [90% confidence interval (CI) 44.5% to 65.3%] versus PCb 48.6% (90% CI 34.3% to 63.2%). Analysis for the stratified subgroups showed higher pCR rates with PO in the cohorts of patients <40 years and HR+ patients. Conclusion: GeparOLA could not exclude a pCR rate of ≤55% in the PO arm. PO was significantly better tolerated and the combination merits further evaluation.
CRIS-Team Scopus Importer:2020-11-27
Keywords: carboplatinum; HER2-negative breast cancer; HRD; neoadjuvant therapy; olaparib; PARP inhibitor

Neoadjuvant palbociclib plus either giredestrant or anastrozole in oestrogen receptor-positive, HER2-negative, early breast cancer (coopERA Breast Cancer): an open-label, randomised, controlled, phase 2 study - Hurvitz, Sara A.; Bardia, Aditya; Quiroga, Vanesa; Park, Yeon Hee; Blancas, Isabel; Alonso-Romero, José Luis; Vasiliev, Aleksandr; Adamchuk, Hryhoriy; Salgado, Marcelo; Yardley, Denise A.; Berzoy, Oleksandr; Zamora-Auñón, Pilar; et al. (Lancet Oncology, 2023)
BACKGROUND: The development of more potent selective oestrogen receptor antagonists and degraders (SERDs) that can be orally administered could help to address the limitations of current endocrine therapies. We report the primary and final analyses of the coopERA Breast Cancer study, designed to test whether giredestrant, a highly potent, non-steroidal, oral SERD, would show a stronger anti-proliferative effect than anastrozole after 2 weeks for oestrogen receptor-positive, HER2-negative, untreated early breast cancer. METHODS: In this open-label, randomised, controlled, phase 2 study, postmenopausal women were eligible if they were aged 18 years or older; had clinical T stage (cT)1c to cT4a-c (≥1·5 cm within cT1c) oestrogen receptor-positive, HER2-negative, untreated early breast cancer; an Eastern Cooperative Oncology Group performance status of 0-1; and baseline Ki67 score of at least 5%. The study was conducted at 59 hospital or clinic sites in 11 countries globally. Participants were randomly assigned (1:1) to giredestrant 30 mg oral daily or anastrozole 1 mg oral daily on days 1-14 (window-of-opportunity phase) via an interactive web-based system with permuted-block randomisation with block size of four. Randomisation was stratified by cT stage, baseline Ki67 score, and progesterone receptor status. A 16-week neoadjuvant phase comprised the same regimen plus palbociclib 125 mg oral daily on days 1-21 of a 28-day cycle, for four cycles. The primary endpoint was geometric mean relative Ki67 score change from baseline to week 2 in patients with complete central Ki67 scores at baseline and week 2 (window-of-opportunity phase). Safety was assessed in all patients who received at least one dose of study drug. The study is registered with ClinicalTrials.gov (NCT04436744) and is complete. FINDINGS: Between Sept 4, 2020, and June 22, 2021, 221 patients were enrolled and randomly assigned to the giredestrant plus palbociclib group (n=112; median age 62·0 years [IQR 57·0-68·5]) or anastrozole plus palbociclib group (n=109; median age 62·0 [57·0-67·0] years). 15 (7%) of 221 patients were Asian, three (1%) were Black or African American, 194 (88%) were White, and nine (4%) were unknown races. At data cutoff for the primary analysis (July 19, 2021), the geometric mean relative reduction of Ki67 from baseline to week 2 was -75% (95% CI -80 to -70) with giredestrant and -67% (-73 to -59) with anastrozole (p=0·043), meeting the primary endpoint. At the final analysis (data cutoff Nov 24, 2021), the most common grade 3-4 adverse events were neutropenia (29 [26%] of 112 in the giredestrant plus palbociclib group vs 29 [27%] of 109 in the anastrozole plus palbociclib group) and decreased neutrophil count (17 [15%] vs 16 [15%]). Serious adverse events occurred in five (4%) patients in the giredestrant plus palbociclib group and in two (2%) patients in the anastrozole plus palbociclib group. There were no treatment-related deaths. One patient died due to an adverse event in the giredestrant plus palbociclib group (myocardial infarction). INTERPRETATION: Giredestrant offers encouraging anti-proliferative and anti-tumour activity and was well tolerated, both as a single agent and in combination with palbociclib. Results justify further investigation in ongoing trials. FUNDING: F Hoffmann-La Roche.
CRIS-Team Scopus Importer:2023-09-08

Neoadjuvant pembrolizumab plus chemotherapy/adjuvant pembrolizumab for early-stage triple-negative breast cancer: Quality-of-life results from the randomized KEYNOTE-522 study - Dent, Rebecca; Cortés, Javier; Pusztai, Lajos; McArthur, Heather; Kümmel, Sherko; Bergh, Jonas; Denkert, Carsten; Park, Yeon Hee; Hui, Rina; Harbeck, Nadia; Takahashi, Masato; Untch, Michael; et al. (Journal of the National Cancer Institute, 2024)
Background: In KEYNOTE-522 (NCT03036488), neoadjuvant pembrolizumab plus chemotherapy and then adjuvant pembrolizumab significantly improved pathological complete response and event-free survival vs neoadjuvant chemotherapy in early-stage triple-negative breast cancer (TNBC). We report patient-reported outcomes (PROs) from KEYNOTE-522. Methods: Patients were randomized 2:1 to neoadjuvant pembrolizumab 200 mg or placebo every 3 weeks, plus 4 cycles of paclitaxel plus carboplatin and then 4 cycles of doxorubicin (or epirubicin) plus cyclophosphamide. After surgery, patients received adjuvant pembrolizumab or placebo for up to 9 cycles. European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and EORTC Breast Cancer-Specific Quality of Life Questionnaire (EORTC QLQ-BR23) were prespecified secondary objectives. Between-group differences in least squares (LS) mean change from baseline (day 1 of cycle 1 in both neoadjuvant and adjuvant phases) to the prespecified latest time point with at least 60% completion and at least 80% compliance were assessed using a longitudinal model (no alpha error assigned). Results: Week 21 (neoadjuvant phase) and week 24 (adjuvant phase) were the latest time points at which completion/compliance rates were ≥60%/80%. In the neoadjuvant phase, between-group differences (pembrolizumab plus chemotherapy [n = 762] vs placebo plus chemotherapy [n = 383]) in LS mean change from baseline to week 21 in QLQ-C30 global health status/quality of life (GHS/QoL), emotional functioning, and physical functioning were -1.04 (95% confidence interval = -3.46 to 1.38), -0.69 (95% CI = -3.13 to 1.75), and -2.85 (95% CI = -5.11 to -0.60), respectively. In the adjuvant phase, between-group differences (pembrolizumab [n = 539] vs placebo [n = 308]) in LS mean change from baseline to week 24 were -0.41 (95% CI = -2.60 to 1.77), -0.60 (95% CI = -2.99 to 1.79), and -1.57 (95% CI = -3.36 to 0.21). Conclusions: No substantial differences in PRO assessments were observed between neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab vs neoadjuvant placebo plus chemotherapy in early-stage TNBC.
CRIS-Team Scopus Importer:2024-11-01
Keywords: cancer; chemotherapy regimen; emotions; immunologic adjuvants; pharmaceutical adjuvants; neoadjuvant therapy; organizations; european continental ancestry group; world health; quality of life; european organization for research and treatment of cancer; triple-negative breast cancer; patient self-report; chemotherapy; neoadjuvant; physical function; pembrolizumab; pik3ca-related overgrowth spectrum

Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab for treatment of high-risk, early-stage triple-negative breast cancer: A network meta-analysis - Cortes, J.; Haiderali, A.; Huang, M.; Pan, W.; Fox, G. E.; Park, J.; Frederickson, A. M.; Fasching, Peter; O'Shaughnessy, J. (ANNALS OF ONCOLOGY, 2022)
CRIS-Team WoS Importer:2022-12-23

Neoadjuvant pembrolizumab plus chemotherapy versus placebo plus chemotherapy, followed by adjuvant pembrolizumab versus placebo for early-stage TNBC: Event-free survival sensitivity and subgroup analyses from KEYNOTE-522 - Schmid, Peter; Cortes, Javier; Dent, Rebecca; Pusztai, Lajos; Mcarthur, Heather; Kuemmel, Sherko; Bergh, Jonas; Denkert, Carsten; Park, Yeon Hee; Hui, Rina; Harbeck, Nadia; Takahashi, Masato; et al. (ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY, 2022)
CRIS-Team WoS Importer:2022-11-11

Neoadjuvant trastuzumab emtansine and pertuzumab in human epidermal growth factor receptor 2–positive breast cancer: Three-year outcomes from the phase III KristinE study - Hurvitz, Sara A.; Martin, Miguel; Jung, Kyung Hae; Huang, Chiun Sheng; Harbeck, Nadia; Valero, Vicente; Stroyakovskiy, Daniil; Wildiers, Hans; Campone, Mario; Boileau, Jean François; Fasching, Peter; Afenjar, Karen; et al. (Journal of Clinical Oncology, 2019)
PURPOSE The KRISTINE study compared neoadjuvant trastuzumab emtansine plus pertuzumab (T-DM1+P) with docetaxel, carboplatin, trastuzumab plus P (TCH+P) for the treatment human epidermal growth factor receptor 2–positive stage II to III breast cancer. T-DM1+P led to a lower pathologic complete response rate (44.4% v 55.7%; P = .016), but fewer grade 3 or greater and serious adverse events (AEs). Here, we present 3-year outcomes from KRISTINE. METHODS Patients were randomly assigned to neoadjuvant T-DM1+P or TCH+P every 3 weeks for six cycles. Patients who received T-DM1+P continued adjuvant T-DM1+P, and patients who received TCH+P received adjuvant trastuzumab plus pertuzumab. Secondary end points included event-free survival (EFS), overall survival, patient-reported outcomes (measured from random assignment), and invasive disease-free survival (IDFS; measured from surgery). RESULTS Of patients, 444 were randomly assigned (T-DM1+P, n = 223; TCH+P, n = 221). Median follow-up was 37 months. Risk of an EFS event was higher with TDM-1+P (hazard ratio [HR], 2.61 [95% CI, 1.36 to 4.98]) with more locoregional progression events before surgery (15 [6.7%] v 0). Risk of an IDFS event after surgery was similar between arms (HR, 1.11 [95% CI, 0.52 to 2.40]). Pathologic complete response was associated with a reduced risk of an IDFS event (HR, 0.24 [95% CI, 0.09 to 0.60]) regardless of treatment arm. Overall, grade 3 or greater AEs (31.8% v 67.7%) were less common with T-DM1+P. During adjuvant treatment, grade 3 or greater AEs (24.5% v 9.9%) and AEs leading to treatment discontinuation (18.4% v 3.8%) were more common with T-DM1+P. Patient-reported outcomes favored T-DM1+P during neoadjuvant treatment and were similar to trastuzumab plus pertuzumab during adjuvant treatment. CONCLUSION Compared with TCH+P, T-DM1+P resulted in a higher risk of an EFS event owing to locoregional progression events before surgery, a similar risk of an IDFS event, fewer grade 3 or greater AEs during neoadjuvant treatment, and more AEs leading to treatment discontinuation during adjuvant treatment.
CRIS-Team Scopus Importer:2019-09-03

Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial - Hurvitz, Sara A.; Martin, Miguel; Symmans, W. Fraser; Jung, Kyung Hae; Huang, Chiun-Sheng; Thompson, Alastair M.; Harbeck, Nadia; Valero, Vicente; Stroyakovskiy, Daniil; Wildiers, Hans; Campone, Mario; Boileau, Jean-Francois; et al. (Lancet Oncology, 2018)
BACKGROUND: HER2-targeted treatments have improved outcomes in patients with HER2-positive breast cancer in the neoadjuvant, adjuvant, and metastatic settings; however, some patients remain at risk of relapse or death for many years after treatment of early-stage disease. Therefore, new strategies are needed. We did a phase 3 trial to assess a neoadjuvant regimen for HER2-positive breast cancer that replaces traditional systemic chemotherapy with targeted treatment. METHODS: We did a randomised, open-label phase 3 KRISTINE trial in 68 Translational Research In Oncology centres (hospitals and specialty cancer centres in Asia, Europe, USA, and Canada). Eligible participants were aged 18 years or older with centrally confirmed HER2-positive stage II-III operable breast cancer (>2 cm tumour size), an Eastern Cooperative Oncology Group performance status of 0-1, and a baseline left ventricular ejection fraction of at least 55% (by echocardiogram or multiple-gated acquisition scan). We randomly assigned participants (1:1) to receive either trastuzumab emtansine plus pertuzumab or docetaxel, carboplatin, and trastuzumab plus pertuzumab. We did the randomisation via an interactive response system under a permuted block randomisation scheme (block size of four), stratified by hormone receptor status, stage at diagnosis, and geographical location. Patients received six cycles (every 3 weeks) of neoadjuvant trastuzumab emtansine plus pertuzumab (trastuzumab emtansine 3·6 mg/kg; pertuzumab 840 mg loading dose, 420 mg maintenance doses) or docetaxel, carboplatin, and trastuzumab plus pertuzumab (docetaxel 75 mg/m2; carboplatin area under the concentration-time curve 6 mg/mL × min; trastuzumab 8 mg/kg loading dose, 6 mg/kg maintenance doses) plus pertuzumab [same dosing as in the other group]). All treatments were administered intravenously. The primary objective was to compare the number of patients who achieved a pathological complete response (ypT0/is, ypN0), between groups in the intention-to-treat population (two-sided assessment), based on local evaluation of tumour samples taken at breast cancer surgery done between 14 days and 6 weeks after completion of neoadjuvant therapy. Safety was analysed in patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02131064, and follow-up of the adjuvant phase is ongoing. FINDINGS: Between June 25, 2014, and June 15, 2015, we randomly assigned 444 patients to neoadjuvant treatment with trastuzumab emtansine plus pertuzumab (n=223) or docetaxel, carboplatin, and trastuzumab plus pertuzumab (n=221). A pathological complete response was achieved by 99 (44·4%) of 223 patients in the trastuzumab emtansine plus pertuzumab group and 123 (55·7%) of 221 patients in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group (absolute difference -11·3 percentage points, 95% CI -20·5 to -2·0; p=0·016). During neoadjuvant treatment, compared with patients receiving docetaxel, carboplatin, and trastuzumab plus pertuzumab, fewer patients receiving trastuzumab emtansine plus pertuzumab had a grade 3-4 adverse event (29 [13%] of 223 vs 141 [64%] of 219) or a serious adverse event (11 [5%] of 223 vs 63 [29%] of 219). The most common grade 3-4 adverse events in the trastuzumab emtansine plus pertuzumab group were decreased platelet count (three [1%] of 223 patients vs 11 [5%] of 219 with docetaxel, carboplatin, and trastuzumab plus pertuzumab), fatigue (three [1%] vs seven [3%]), alanine aminotransferase increase (three [1%] vs four [2%]), and hypokalaemia (three [1%] vs five [2%]). The most common grade 3-4 adverse events in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group were neutropenia (55 [25%] of 219 vs one [<1%] of 223 with trastuzumab emtansine plus pertuzumab), diarrhoea (33 [15%] vs 2 [<1%]), and febrile neutropenia (33 [15%] vs 0). No deaths were reported during neoadjuvant treatment. INTERPRETATION: Traditional neoadjuvant systemic chemotherapy plus dual HER2-targeted blockade (docetaxel, carboplatin, and trastuzumab plus pertuzumab) resulted in significantly more patients achieving a pathological complete response than HER2-targeted chemotherapy plus HER2-targeted blockade (trastuzumab emtansine plus pertuzumab); however, numerically more grade 3-4 and serious adverse events occurred in the chemotherapy plus trastuzumab and pertuzumab group. Further efforts to improve the efficacy of chemotherapy without imparting more toxicity are warranted. FUNDING: F Hoffmann-La Roche and Genentech.
EVALuna2:36439

Neoadjuvant Treatment of Breast Cancer - Advances and Limitations - Fasching, Peter; Gaß, Paul; Hein, Alexander (Breast Care, 2016)
EVALuna2:33102

Network-Based Integration of GWAS and Gene Expression Identifies a HOX-Centric Network Associated with Serous Ovarian Cancer Risk - Kar, Siddhartha P.; Tyrer, Jonathan P.; Li, Qiyuan; Lawrenson, Kate; Aben, Katja K. H.; Anton-Culver, Hoda; Antonenkova, Natalia; Chenevix-Trench, Georgia; Baker, Helen; Bandera, Elisa V.; Bean, Yukie T.; Beckmann, Matthias; et al. (Cancer Epidemiology Biomarkers & Prevention, 2015)
Genome-wide association studies (GWAS) have so far reported 12 loci associated with serous epithelial ovarian cancer (EOC) risk. We hypothesized that some of these loci function through nearby transcription factor (TF) genes and that putative target genes of these TFs as identified by coexpression may also be enriched for additional EOC risk associations.We selected TF genes within 1 Mb of the top signal at the 12 genome-wide significant risk loci. Mutual information, a form of correlation, was used to build networks of genes strongly coexpressed with each selected TF gene in the unified microarray dataset of 489 serous EOC tumors from The Cancer Genome Atlas. Genes represented in this dataset were subsequently ranked using a gene-level test based on results for germline SNPs from a serous EOC GWAS meta-analysis (2,196 cases/4,396 controls).Gene set enrichment analysis identified six networks centered on TF genes (HOXB2, HOXB5, HOXB6, HOXB7 at 17q21.32 and HOXD1, HOXD3 at 2q31) that were significantly enriched for genes from the risk-associated end of the ranked list (P < 0.05 and FDR < 0.05). These results were replicated (P < 0.05) using an independent association study (7,035 cases/21,693 controls). Genes underlying enrichment in the six networks were pooled into a combined network.We identified a HOX-centric network associated with serous EOC risk containing several genes with known or emerging roles in serous EOC development.Network analysis integrating large, context-specific datasets has the potential to offer mechanistic insights into cancer susceptibility and prioritize genes for experimental characterization. Cancer Epidemiol Biomarkers Prev; 24(10); 1574-84. ©2015 AACR.
EVALuna2:9287

Neurovascular compression of medulla oblongata - Association for gestation-induced hypertension - Tanrikulu, Levent; Naraghi, Ramin; Ernst, Veronika; Voigt, Franziska; Hastreiter, Peter; Dörfler, Arnd; Buchfelder, Michael; Beckmann, Matthias; Goecke, Tamme W. (Medical Hypotheses, 2015)
Patients with essential hypertension may show neurovascular compression (NVC) at the rostral ventrolateral medulla oblongata (RVLM). Ectatic loops of the vertebral artery (VA) or the inferior posterior cerebellar artery (PICA) cause NVC. This study aims to show the existence and morphology of NVC in patients with gestation-induced hypertension. 17 females were prospectively examined between 19. +. 0 and 35. +. 6. weeks of gestation. 3 patients with chronic hypertension (group A), 10 patients with preeclampsia (group B), 3 patients with superimposed preeclampsia (chronic hypertension with preeclampsia; group C) and one normotensive patient were included. Groups B and C represented patients with gestation-induced hypertension. All 17 patients underwent imaging by high resolution magnetic resonance imaging (MR-CISS, constructive interference in the steady state). Image processing was done with segmentation and three-dimensional (3D)-visualization was implemented with direct volume rendering of the individual neurovascular details of each patient. 9 of 17 patients (53%) showed NVC of the RVLM. Right-sided NVC was seen in 7 patients (41%). Left-sided NVC was seen in 6 patients (35%). Bilateral NVC was seen in 4 patients (24%). NVC was missing in 8 of the examined 17 patients (47%). The existence of NVC with high-resolution MRI was analyzed in gestation-induced hypertensive pregnant females for the first time. Neurovascular conflicts were seen in hypertensive pregnants. It is possible that NVC is potentially associated in patients with gestation-induced hypertension.
CRIS-Team Scopus Importer:2022-08-05

New Screening Proposals: the Federal Joint Commission Defines the Parameters for Cervical Cancer Screening from 2018 Statement of the Gynecology Oncology Working Group (AGO) - Hillemanns, P.; Mallmann, P.; Beckmann, Matthias (Geburtshilfe und Frauenheilkunde, 2016)
The Gynecology Oncology Working Group (AGO e.V.) unequivocally welcomes the decision taken by the German Federal Joint Commission (Gemeinsamer Bundesausschuss, G-BA) on March 19, 2015 regarding screening for cervical cancer. AGO is convinced that, in view of recent medical advances, this evidence-based decision will improve screening for cervical cancer.
EVALuna2:32998

New WHO Classification of Endometrial Hyperplasias - Emons, G.; Beckmann, Matthias; Schmidt, D.; Mallmann, P. (Geburtshilfe und Frauenheilkunde, 2015)
EVALuna2:17599

Next-generation DNA sequencing (NGS) results for tumours from phase II ABRAZO study of talazoparib after platinum or cytotoxic non-platinum regimens in patients (pts) with advanced breast cancer (ABC) and germline BRCA1/2 (gBRCA) mutations - Turner, N. C.; Laird, A. D.; Telli, M. L.; Rugo, H. S.; Mailliez, A.; Ettl, J.; Grischke, E. -M.; Mina, L. A.; Balmana, J.; Fasching, Peter; Hurvitz, S. A.; Albacker, L. A.; et al. (ANNALS OF ONCOLOGY, 2019)
CRIS-Team WoS Importer:2019-11-08

NGS zur Selektion innovativer Therapien – Was bringt das? - Schulmeyer, Carla; Bader, Simon; Hübner, Hanna; Rübner, Matthias; Fasching, Peter (Gynäkologe, 2021)
Next generation sequencing (NGS) describes a technology for sequencing the entire human genome, exome and transcriptome and has revolutionized genomic research. In comparison to Sanger sequencing NGS is able to sequence a whole human genome within 1 day. The results can be aligned with reference human genomes. Through DNA fragmentation, ligation of adaptors on the ends of fragments and amplification of the fragments a bioinformatics analysis is carried out, which is stored in the form of a chip and sequenced. The NGS can be used in multiple applications, especially in genetic, microbiological and oncologic research and has not yet become comprehensively established within the clinical routine. In obstetrics and gynecology, NGS is especially used in noninvasive prenatal testing (NIPT), reproductive medicine and oncology.
CRIS-Team Scopus Importer:2021-03-19
Keywords: Breast cancer; DNA fragmentation; Genome; human; Genomics; Prenatal diagnostics

Ninety-five orthotopic transplantations in 74 women of ovarian tissue after cytotoxic treatment in a fertility preservation network: tissue activity, pregnancy and delivery rates - Van Der Ven, H.; Liebenthron, J.; Beckmann, Matthias; Toth, B.; Korell, M.; Kruessel, J.; Frambach, T.; Kupka, M.; Hohl, M. K.; Winkler-Crepaz, K.; Seitz, S.; Dogan, A.; et al. (Human Reproduction, 2016)
STUDY QUESTION: What is the success rate in terms of ovarian activity (menstrual cycles) as well as pregnancy and delivery rates 1 year after orthotopic ovarian transplantations conducted in a three-country network? SUMMARY ANSWER: In 49 women with a follow-up >1 year after transplantation, the ovaries were active in 67% of cases and the pregnancy and delivery rates were 33 and 25%, respectively. WHAT IS KNOWN ALREADY: Cryopreservation of ovarian tissue in advance of cytotoxic therapies and later transplantation of the tissue is being performed increasingly often, and the total success rates in terms of pregnancy and delivery have been described in case series. However, published case series have not allowed either a more detailed analysis of patients with premature ovarian insufficiency (POI) or calculation of success rates based on the parameter 'tissue activity'. STUDY DESIGN, SIZE, DURATION: Retrospective analysis of 95 orthotopic transplantations in 74 patients who had been treated for cancer, performed in the FertiPROTEKT network from 2008 to June 2015. Of those 95 transplantations, a first subgroup (Subgroup 1) was defined for further analysis, including 49 women with a follow-up period >1 year after transplantation. Of those 49 women, a second subgroup (Subgroup 5) was further analysed, including 40 women who were transplanted for the first time and who were diagnosed with POI before transplantation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Transplantation was performed in 16 centres and data were transferred to the FertiPROTEKT registry. The transplantations were carried out after oncological treatment had been completed and after a remission period of at least 2 years. Tissue was transplanted orthotopically, either into or onto the residual ovaries or into a pelvic peritoneal pocket. The success rates were defined as tissue activity (menstrual cycles) after 1 year (primary outcome) and as pregnancies and deliveries achieved. MAIN RESULTS AND THE ROLE OF CHANCE: The average age of all transplanted 74 women was 31 ± 5.9 years at the time of cryopreservation and 35 ± 5.2 at the time of transplantation. Twenty-one pregnancies and 17 deliveries were recorded. In Subgroup 1, tissue was cryopreserved at the age of 30 ± 5.6 and transplanted at 34 ± 4.9 years. Ovaries remained active 1 year after transplantation in 67% of cases (n = 33/49), the pregnancy rate was 33% (n = 16/49) and the delivery rate was 25% (n = 12/49). In Subgroup 5, tissue was cryopreserved at the age 30 ± 5.9 years and transplanted at 34 ± 5.2 years. Ovaries remained active 1 year after transplantation in 63% of cases (n = 25/40), the pregnancy rate was 28% (n = 11/40) and the delivery rate was 23% (n = 9/40). The success rates were age dependant with higher success in women who cryopreserved at a younger age. In Subgroup 5, tissue was exclusively transplanted into the ovary in 10% (n = 4/40) of women and into a peritoneal pocket in 75% (n = 30/40), resulting in spontaneous conceptions in 91% of patients (n = 10/11). LIMITATIONS, REASONS FOR CAUTION: The data were drawn from a retrospective analysis. The cryopreservation and transplantation techniques used have changed during the study period. The tissue was stored in many tissue banks and many surgeons were involved, leading to heterogeneity of the procedures. However, this does reflect the realistic situation in many countries. Although patients with POI were evaluated before transplantation to allow specific analysis of the transplanted tissue itself, the possibility cannot be excluded that residual ovarian tissue was also reactivated. WIDER IMPLICATIONS OF THE FINDINGS: This is the largest case series worldwide to date and it confirms that cryopreservation and transplantation of ovarian tissue can be a successful option for preserving fertility. Persistent tissue activity 12 months after transplantation suggests that the pregnancy and delivery rates may increase further in the future. As transplantation into the peritoneum results in a high success rate, this approach may be an alternative to transplantation into the ovary. However, in order to establish the best transplantation site, a randomized study is required. STUDY FUNDING/COMPETING INTEREST: This study was in part funded from the Deutsche Forschungsgemeinschaft (# DI 1525) and the Wilhelm Sander Foundation (2012.127.1) and did not receive any funding from a commercial company. No competing interests. TRIAL REGISTRATION NUMBER: None.
EVALuna2:33464

No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer - Hollestelle, Antoinette; Van Der Baan, Frederieke H.; Berchuck, Andrew; Johnatty, Sharon E.; Aben, Katja K.; Agnarsson, Bjarni A.; Aittomaki, Kristiina; Alducci, Elisa; Andrulis, Irene L.; Anton-Culver, Hoda; Antonenkova, Natalia N.; Antoniou, Antonis C.; et al. (Gynecologic Oncology, 2016)
Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370.Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers).We found no association with risk of ovarian cancer (OR=0.99, 95% CI 0.94-1.04, p=0.74) or breast cancer (OR=0.98, 95% CI 0.94-1.01, p=0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR=1.09, 95% CI 0.97-1.23, p=0.14, breast cancer HR=1.04, 95% CI 0.97-1.12, p=0.27; BRCA2, ovarian cancer HR=0.89, 95% CI 0.71-1.13, p=0.34, breast cancer HR=1.06, 95% CI 0.94-1.19, p=0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR=0.94, 95% CI 0.83-1.07, p=0.38), breast cancer (HR=0.96, 95% CI 0.87-1.06, p=0.38), and all other previously-reported associations.rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
EVALuna2:9251

No Evidence That Genetic Variation in the Myeloid-Derived Suppressor Cell Pathway Influences Ovarian Cancer Survival - Sucheston-Campbell, Lara E.; Cannioto, Rikki; Clay, Alyssa I.; Etter, John Lewis; Eng, Kevin H.; Liu, Song; Battaglia, Sebastiano; Hu, Qiang; Szender, J. Brian; Minlikeeva, Albina; Joseph, Janine M.; Mayor, Paul; et al. (Cancer Epidemiology Biomarkers & Prevention, 2017)
Background: The precise mechanism by which the immune system is adversely affected in cancer patients remains poorly understood, but the accumulation of immunosuppressive/protumorigenic myeloid-derived suppressor cells (MDSCs) is thought to be a prominent mechanism contributing to immunologic tolerance of malignant cells in epithelial ovarian cancer (EOC). To this end, we hypothesized genetic variation in MDSC pathway genes would be associated with survival after EOC diagnoses.Methods: We measured the hazard of death due to EOC within 10 years of diagnosis, overall and by invasive subtype, attributable to SNPs in 24 genes relevant in the MDSC pathway in 10,751 women diagnosed with invasive EOC. Versatile Gene-based Association Study and the admixture likelihood method were used to test gene and pathway associations with survival.Results: We did not identify individual SNPs that were significantly associated with survival after correction for multiple testing (P < 3.5 × 10-5), nor did we identify significant associations between the MDSC pathway overall, or the 24 individual genes and EOC survival.Conclusions: In this well-powered analysis, we observed no evidence that inherited variations in MDSC-associated SNPs, individual genes, or the collective genetic pathway contributed to EOC survival outcomes.Impact: Common inherited variation in genes relevant to MDSCs was not associated with survival in women diagnosed with invasive EOC. Cancer Epidemiol Biomarkers Prev; 26(3); 420-4. ©2016 AACR.
EVALuna2:36152

No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing - Easton, Douglas F.; Lesueur, Fabienne; Decker, Brennan; Michailidou, Kyriaki; Li, Jun; Allen, Jamie; Luccarini, Craig; Pooley, Karen A.; Shah, Mitul; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; et al. (Journal of Medical Genetics, 2016)
BACKGROUND: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. METHODS: We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. RESULTS: The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). CONCLUSIONS: These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.
EVALuna2:33328

Non-embryo-destructive Extraction of Pluripotent Embryonic Stem Cells: Implications for Regenerative Medicine and Reproductive Medicine - Dittrich, Ralf; Beckmann, Matthias; Wuerfel, W. (Geburtshilfe und Frauenheilkunde, 2015)
On August 1, 2013, the German Patent and Trademark Office issued a patent for the "Non-embryo-destructive extraction of pluripotent embryonic stem cells, stem cells obtained by this process and their uses" (DE 10 2004 062 184 B4). The patent document describes a non-embryo-destructive process to harvest embryonic stem cells from the inner cell mass (ICM) during the blastocyst development stage. The patent application was filed with the German Patent Office in Munich on December 23, 2004 and the patent claim was published in 2006. The patent was granted on August 1, 2013. Processing the patent application was a lengthy affair due to the fact that, for a long time, the prevailing opinion in Germany was that genetic screening of embryos (preimplantation genetic diagnosis) was prohibited under the German Embryo Protection Act (ESchG). A ruling by the German Federal Court in 2010 proved this opinion to be false. Animal studies have provided the evidence that the described procedure is technically feasible; healthy offspring were born after stem cells were harvested from the blastocyst and stored. We report here on a technique for the non-embryo-destructive extraction of pluripotent embryonic stem cells together with potential future applications for stem cells harvested in this manner.
EVALuna2:17552

Novel approach for the assessment of ovarian follicles infiltration in polymeric electrospun patterned scaffolds - Raffel, Nathalie; Dittrich, Ralf; Bäuerle, Tobias; Seyler, Lisa; Amir, Fattahi; Hoffmann, Inge; Leal-Egaña, Aldo; Beckmann, Matthias; Boccaccini, Aldo R.; Liverani, Liliana (PLoS ONE, 2019)
Reproductive tissue engineering (REPROTEN) has been recently defined as the application of the tissue engineering approach targeting reproductive organs and several research works are focusing on this novel strategy. Being still an innovative field, most of the scaffold characterization techniques suitable for other tissue targets give inappropriate results, and there is the need to evaluate and investigate novel approaches. In particular the focus of this paper is the evaluation of the infiltration of ovarian follicles inside patterned electrospun scaffolds. Beyond the standard techniques, for the first time the use of magnetic resonance imaging (MRI) for this purpose is proposed and specific protocols for scaffold preparation are reported. Positive results in terms of evaluation of scaffolds incorporating follicles confirm this technique as highly effective for further applications in this field.
CRIS-Team Scopus Importer:2019-05-17

Novel Associations between Common Breast Cancer Susceptibility Variants and Risk-Predicting Mammographic Density Measures - Stone, Jennifer; Thompson, Deborah J.; Silva, Isabel Dos Santos; Scott, Christopher; Tamimi, Rulla M.; Lindstrom, Sara; Kraft, Peter; Hazra, Aditi; Li, Jingmei; Eriksson, Louise; Czene, Kamila; Hall, Per; et al. (Cancer Research, 2015)
Mammographic density measures adjusted for age and body mass index (BMI) are heritable predictors of breast cancer risk, but few mammographic density-associated genetic variants have been identified. Using data for 10,727 women from two international consortia, we estimated associations between 77 common breast cancer susceptibility variants and absolute dense area, percent dense area and absolute nondense area adjusted for study, age, and BMI using mixed linear modeling. We found strong support for established associations between rs10995190 (in the region of ZNF365), rs2046210 (ESR1), and rs3817198 (LSP1) and adjusted absolute and percent dense areas (all P < 10(-5)). Of 41 recently discovered breast cancer susceptibility variants, associations were found between rs1432679 (EBF1), rs17817449 (MIR1972-2: FTO), rs12710696 (2p24.1), and rs3757318 (ESR1) and adjusted absolute and percent dense areas, respectively. There were associations between rs6001930 (MKL1) and both adjusted absolute dense and nondense areas, and between rs17356907 (NTN4) and adjusted absolute nondense area. Trends in all but two associations were consistent with those for breast cancer risk. Results suggested that 18% of breast cancer susceptibility variants were associated with at least one mammographic density measure. Genetic variants at multiple loci were associated with both breast cancer risk and the mammographic density measures. Further understanding of the underlying mechanisms at these loci could help identify etiologic pathways implicated in how mammographic density predicts breast cancer risk.
EVALuna2:17571

Obesity and survival among women with ovarian cancer: results from the Ovarian Cancer Association Consortium - Nagle, C. M.; Dixon, S. C.; Jensen, A.; Kjaer, S. K.; Modugno, F.; Defazio, A.; Fereday, S.; Hung, J.; Johnatty, S. E.; Fasching, Peter; Beckmann, Matthias; Lambrechts, D.; et al. (British Journal of Cancer, 2015)
Observational studies have reported a modest association between obesity and risk of ovarian cancer; however, whether it is also associated with survival and whether this association varies for the different histologic subtypes are not clear. We undertook an international collaborative analysis to assess the association between body mass index (BMI), assessed shortly before diagnosis, progression-free survival (PFS), ovarian cancer-specific survival and overall survival (OS) among women with invasive ovarian cancer.We used original data from 21 studies, which included 12 390 women with ovarian carcinoma. We combined study-specific adjusted hazard ratios (HRs) using random-effects models to estimate pooled HRs (pHR). We further explored associations by histologic subtype.Overall, 6715 (54%) deaths occurred during follow-up. A significant OS disadvantage was observed for women who were obese (BMI: 30-34.9, pHR: 1.10 (95% confidence intervals (CIs): 0.99-1.23); BMI: ?35, pHR: 1.12 (95% CI: 1.01-1.25)). Results were similar for PFS and ovarian cancer-specific survival. In analyses stratified by histologic subtype, associations were strongest for women with low-grade serous (pHR: 1.12 per 5 kg m(-2)) and endometrioid subtypes (pHR: 1.08 per 5 kg m(-2)), and more modest for the high-grade serous (pHR: 1.04 per 5 kg m(-2)) subtype, but only the association with high-grade serous cancers was significant.Higher BMI is associated with adverse survival among the majority of women with ovarian cancer.
EVALuna2:17568

Occurrence and characteristics of patients with de novo advanced breast cancer according to patient and tumor characteristics – A retrospective analysis of a real world registry - Muller, Volkmar; Hein, Alexander; Hartkopf, Andreas D.; Fasching, Peter; Kolberg, Hans-Christian; Hadji, Peyman; Tesch, Hans; Häberle, Lothar; Ettl, Johannes; Luftner, Diana; Wallwiener, Markus; Beckmann, Matthias; et al. (European Journal of Cancer, 2022)
Background: Patients with de novo metastatic breast cancer (dnMBC) may have different clinical and pathological characteristics. In studies concerned with first-line metastatic patients, the proportion of these patients without secondary resistance mechanisms may have a large influence ont the study results. The aim of this study was to identify patient and tumor characteristics that are associated with dnMBC vs. recurrent MBC (rMBC). Methods: This is a retrospective analysis of data prospectively collected in the PRAEGNANT metastatic breast cancer registry (NCT02338167). Firs line treated patients were eligible. Patient and tumor characteristics were compared with common disease and tumor characteristics relative to de novo metastatic status, as well as early and late recurrences after primary disease without metastases. Results: Among the 947 patients identified, 355 were included with de novo metastatic disease (37.5%). Older age and HER2-positive disease were significantly associated with a higher frequency of dnMBC. Patients younger than 50, 50–69, or 70 years or older had dnMBC frequencies of 22.7%, 44.0%, and 57.6%, respectively. HER2-positive patients had dnMBC at initial presentation in 49.1% of cases, in comparison with 21.9%, 35.5%, and 37.6% in patients with triple-negative, luminal A–like and luminal B–like breast cancer, respectively. Conclusion: Age and breast cancer subtype are associated with the frequency of first-line MBC patients. Inclusion criteria concerning age or breast cancer subtype can influence the frequency of these patients in a selected patient population and can therefore modify the number of patients with secondary resistance to specific therapies in clinical trials.
CRIS-Team Scopus Importer:2022-07-08
Keywords: Advanced breast cancer; Clinical trials; de novo metastatic breast cancer; Recurrent breast cancer metastases

OLAPARIB IN GERMAN ROUTINE CLINICAL PRACTICE - INTERIM RESULTS OF THE NON-INTERVENTIONAL STUDY C-PATROL - Marme, F.; Sehouli, J.; Welslau, M.; Schinkoethe, T.; El-Balat, A.; Fasching, Peter; Glowik, R.; Hilpert, F. (2017)
EVALuna2:36181

Omics in Seminal Plasma: An Effective Strategy for Predicting Sperm Retrieval Outcome in Non-obstructive Azoospermia - Zarezadeh, Reza; Nikanfar, Saba; Oghbaei, Hajar; Rastgar Rezaei, Yeganeh; Jafari-Gharabaghlou, Davoud; Ahmadi, Yadollah; Nouri, Mohammad; Fattahi, Amir; Dittrich, Ralf (Molecular Diagnosis & Therapy, 2021)
Non-obstructive azoospermia (NOA) is a severe form of male factor infertility resulting from the impairment of sperm production. Surgical sperm retrieval followed by intracytoplasmic sperm injection (ICSI) is the only alternative for NOA patients to have their own genetic children. Nevertheless, due to an approximately 50% chance of success, harvesting sperm from these patients remains challenging. Thus, discovering noninvasive biomarkers, which are able to reliably predict the probability of sperm acquisition, not only can eliminate the risk of surgery but also can lower the costs of NOA diagnosis and treatment. Seminal plasma is the non-cellular and liquid portion of the ejaculate that consists of the secretions originating from testes and male accessory glands. In past years, a wide range of biomolecules including DNAs, RNAs, proteins, and metabolic intermediates have been identified by omics techniques in human seminal plasma. The current review aimed to briefly describe genomic, transcriptomic, proteomic, and metabolomic profiles of human seminal plasma in an attempt to introduce potential candidate noninvasive biomarkers for sperm-retrieval success in men with NOA.
CRIS-Team Scopus Importer:2021-06-11

Oncological heath care networks. The triangle formed by research, quality, and competition - Schrauder, Michael G.; Bamberg, Michael; Beckmann, Matthias (Onkologe, 2016)
The establishment of medical networks has recently gained momentum in health care policy. However, many questions regarding this topic still remain unanswered, including how exactly the terms "supply network" and "network" are defined, and the relevance of such structures in current oncological care in Germany is vague. This manuscript is based on selective literature research in different databases using the search term "networks of medical facilities in oncology". Searching the Internet with the term "supply network" mainly delivers hits related to supply of electricity. Searching for an exact definition of oncological supply networks is largely unfruitful, even when concrete search terms are used. If less vague statements on oncological networks are found, these vary greatly depending on the context. We present an extensive description of the adoption and significance of networking among oncological facilities in the German public health sector. Moreover, the legal requirements as well as future development opportunities of health care services within oncological networks are characterized.
EVALuna2:32990

On-treatment biopsies to predict response to neoadjuvant chemotherapy for breast cancer - Sinn, Bruno Valentin; Sychra, Katharina; Untch, Michael; Karn, Thomas; van Mackelenbergh, Marion; Huober, Jens; Schmitt, Wolfgang; Marmé, Frederik; Schem, Christian; Solbach, Christine; Stickeler, Elmar; Tesch, Hans; et al. (Breast Cancer Research, 2024)
Background: Patients with pathologic complete response (pCR) to neoadjuvant chemotherapy for invasive breast cancer (BC) have better outcomes, potentially warranting less extensive surgical and systemic treatments. Early prediction of treatment response could aid in adapting therapies. Methods: On-treatment biopsies from 297 patients with invasive BC in three randomized, prospective neoadjuvant trials were assessed (GeparQuattro, GeparQuinto, GeparSixto). BC quantity, tumor-infiltrating lymphocytes (TILs), and the proliferation marker Ki-67 were compared to pre-treatment samples. The study investigated the correlation between residual cancer, changes in Ki-67 and TILs, and their impact on pathologic complete response (pCR) and disease-free survival (DFS). Results: Among the 297 samples, 138 (46%) were hormone receptor-positive (HR+)/human epidermal growth factor 2-negative (HER2−), 87 (29%) were triple-negative (TNBC), and 72 (24%) were HER2+. Invasive tumor cells were found in 70% of on-treatment biopsies, with varying rates across subtypes (HR+/HER2−: 84%, TNBC: 62%, HER2+: 51%; p < 0.001). Patients with residual tumor on-treatment had an 8% pCR rate post-treatment (HR+/HER2−: 3%, TNBC: 19%, HER2+: 11%), while those without any invasive tumor had a 50% pCR rate (HR+/HER2−: 27%; TNBC: 48%, HER2+: 66%). Sensitivity for predicting residual disease was 0.81, with positive and negative predictive values of 0.92 and 0.50, respectively. Increasing TILs from baseline to on-treatment biopsy (if residual tumor was present) were linked to higher pCR likelihood in the overall cohort (OR 1.034, 95% CI 1.013–1.056 per % increase; p = 0.001) and with a longer DFS in TNBC (HR 0.980, 95% CI 0.963–0.997 per % increase; p = 0.026). Persisting or increased Ki-67 was associated with with lower pCR probability in the overall cohort (OR 0.957, 95% CI 0.928–0.986; p = 0.004) and shorter DFS in TNBC (HR 1.023, 95% CI 1.001–1.047; p = 0.04). Conclusion: On-treatment biopsies can predict patients unlikely to achieve pCR post-therapy. This could facilitate therapy adjustments for TNBC or HER2 + BC. They also might offer insights into therapy resistance mechanisms. Future research should explore whether standardized or expanded sampling enhances the accuracy of on-treatment biopsy procedures. Trial registration GeparQuattro (EudraCT 2005-001546-17), GeparQuinto (EudraCT 2006-005834-19) and GeparSixto (EudraCT 2011-000553-23).
CRIS-Team Scopus Importer:2024-10-04
Keywords: Breast cancer; Ki-67; Neoadjuvant therapy; Serial biopsies; TILs

Operative techniques and complications of extraction and transplantation of ovarian tissue: the Erlangen experience - Beckmann, Matthias; Dittrich, Ralf; Lotz, Laura; Oppelt, Patricia; Findeklee, Sebastian; Hildebrandt, Thomas; Heusinger, Katharina; Cupisti, Susanne; Mueller, Andreas (Archives of Gynecology and Obstetrics, 2017)
PURPOSE: Extracting ovarian tissue before oncologic therapy and transplanting it afterwards are increasingly being used to preserve fertility in women. This study describes standardized and safe operative procedures, with few complications, and reports the resulting ovarian function and pregnancy rates. METHODS: The standardized operative techniques for removing and transplanting ovarian tissue used at the Erlangen center are: for tissue removal, one-third to half of the tissue from one ovary is excised with scissors, without tissue coagulation; for subsequent transplantation, pieces of ovarian tissue are placed in a retroperitoneal pocket without closure of the pocket. RESULTS: Between January 2007 and December 2015, ovarian tissue was extracted in 399 women and transplanted following cancer therapy in 38. No surgical complications were observed within 28 days. To date, there have been ten pregnancies and nine live births after transplantation in seven different women; 26 of the 38 women developed hormonal activity, confirmed by a menstrual cycle or raised serum estradiol levels. CONCLUSIONS: The techniques for laparoscopic removal and transplantation of ovarian tissue described here provide a standardized method with a very low risk of complications. The pregnancy rate after ovarian tissue transplantation, currently 15-30%, can be expected to rise further in the near future.
EVALuna2:36149

Opinion of the German Society of Gynecology and Obstetrics on the Topic - More Knowledge "Risk Factors for Breast Cancer" - Seelbach-Goebel, Birgit; Beckmann, Matthias (Geburtshilfe und Frauenheilkunde, 2017)
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Optimization of Porcine Ovarian Follicle Isolation Methods for Better Developmental Potential - Fattahi, Amir; Liverani, Liliana; Dittrich, Ralf; Hoffmann, Inge; Boccaccini, Aldo R.; Beckmann, Matthias; Bleisinger, Nathalie (Tissue Engineering - Part A, 2020)
In the present study, we present a comparative analysis among the outputs of porcine follicle isolation using either mechanical technique alone or in combination with enzymes, proposing an optimized protocol useful for all further applications related to folliclein vitrogrowth and reproductive tissue engineering. The porcine follicles were isolated using mechanical technique alone (hand blender and scalpels) or in combination with collagenase or Liberase Dispase High (DH) at different doses applying different protocols. Finally, the number, morphology, and stage of isolated follicles were compared between the protocols. Moreover, the follicle viability (live/dead assay) and morphology (rhodamine phalloidin and 4 ',6-diamidino-2-phenylindole staining and scanning electron microscopy analysis) were evaluated after 10 days of culture. We found an optimum protocol for intact follicle isolation using the mechanical technique in combination with enzymes at a concentration of 0.5 mg/mL. However, the number of total isolated follicles and primordial follicles was significantly higher when collagenase was used compared to Liberase DH (p < 0.05), while Liberase DH could isolate a significantly higher percentage of preantral follicles. After 10 days of culture, the morphology and health status of follicles were statistically higher when Liberase DH was used in comparison with collagenase. Moreover, on the follicles extracted with Liberase DH, it was possible to observe theca cells covering part of the follicle surface. In conclusion, we demonstrated that the intact primary or secondary follicles could not be obtained using only mechanical methods, which led to the isolation of denuded oocytes and dramatically damaged follicles. We concluded that the collagenase-based follicle isolation could negatively affect the morphology and developmental potential of the follicles. Moreover, the incubation of ovarian cortex tissues with Liberase DH solution is an optimized protocol for porcine ovarian follicle isolation with developmental competence.
CRIS-Team WoS Importer:2020-07-24

Optimizing R with SparkR on a commodity cluster for biomedical research - Sedlmayr, Martin; Würfl, Tobias; Maier, Christian; Haeberle, Lothar; Fasching, Peter; Prokosch, Hans-Ulrich; Christoph, Jan (Computer Methods and Programs in Biomedicine, 2016)
Medical researchers are challenged today by the enormous amount of data collected in healthcare. Analysis methods such as genome-wide association studies (GWAS) are often computationally intensive and thus require enormous resources to be performed in a reasonable amount of time. While dedicated clusters and public clouds may deliver the desired performance, their use requires upfront financial efforts or anonymous data, which is often not possible for preliminary or occasional tasks. We explored the possibilities to build a private, flexible cluster for processing scripts in R based on commodity, non-dedicated hardware of our department.For this, a GWAS-calculation in R on a single desktop computer, a Message Passing Interface (MPI)-cluster, and a SparkR-cluster were compared with regards to the performance, scalability, quality, and simplicity.The original script had a projected runtime of three years on a single desktop computer. Optimizing the script in R already yielded a significant reduction in computing time (2 weeks). By using R-MPI and SparkR, we were able to parallelize the computation and reduce the time to less than three hours (2.6 h) on already available, standard office computers. While MPI is a proven approach in high-performance clusters, it requires rather static, dedicated nodes. SparkR and its Hadoop siblings allow for a dynamic, elastic environment with automated failure handling. SparkR also scales better with the number of nodes in the cluster than MPI due to optimized data communication.R is a popular environment for clinical data analysis. The new SparkR solution offers elastic resources and allows supporting big data analysis using R even on non-dedicated resources with minimal change to the original code. To unleash the full potential, additional efforts should be invested to customize and improve the algorithms, especially with regards to data distribution.
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Orofacial clefts alter early life oral microbiome maturation towards higher levels of potentially pathogenic species: A prospective observational study - Seidel, Corinna Lesley; Strobel, Karin; Weider, Matthias; Tschaftari, Marco; Unertl, Christoph; Willershausen, Ines; Weber, Manuel; Hörning, André; Morhart, Patrick; Schneider, Michael; Beckmann, Matthias; Bogdan, Christian; et al. (Journal of Oral Microbiology, 2023)
Orofacial clefts (OFC) present different phenotypes with a postnatal challenge for oral microbiota development. In order to investigate the impact of OFC on oral microbiota, smear samples from 15 neonates with OFC and 17 neonates without OFC were collected from two oral niches (tongue, cheek) at two time points, i.e. after birth (T0: Ø3d OFC group; Ø2d control group) and 4–5 weeks later (T1: Ø32d OFC group; Ø31d control group). Subsequently, the samples were analyzed using next-generation sequencing. We detected a significant increase of alpha diversity and anaerobic and Gram-negative species from T0 to T1 in both groups. Further, we found that at T1 OFC neonates presented a significantly lower alpha diversity (lowest values for high cleft severity) and significantly higher levels of Enterobacteriaceae (Citrobacter, Enterobacter, Escherichia-Shigella, Klebsiella), Enterococcus, Bifidobacterium, Corynebacterium, Lactocaseibacillus, Staphylococcus, Acinetobacter and Lawsonella compared to controls. Notably, neonates with unilateral and bilateral cleft lip and palate (UCLP/BCLP) presented similarities in beta diversity and a mixture with skin microbiota. However, significant differences were seen in neonates with cleft palate only compared to UCLP/BCLP with higher levels of anaerobic species. Our findings revealed an influence of OFC as well as cleft phenotype and severity on postnatal oral microbiota maturation.
CRIS-Team Scopus Importer:2023-01-20
Keywords: early life dysbiosis; microbiome maturation; neonates; oral microbiome; Orofacial clefts

Orofacial clefts lead to increased pro-inflammatory cytokine levels on neonatal oral mucosa - Seidel, Corinna Lesley; Percivalle, Elena; Tschaftari, Marco; Weider, Matthias; Strobel, Karin; Willershausen, Ines; Unertl, Christoph; Schmetzer, Helga M.; Weber, Manuel; Schneider, Michael; Frey, Benjamin; Gaipl, Udo; et al. (Frontiers in Immunology, 2022)
Orofacial clefts (OFC) are frequent congenital malformations characterized by insufficient separation of oral and nasal cavities and require presurgical infant orthopedics and surgical interventions within the first year of life. Wound healing disorders and higher prevalence of gingivitis and plaque levels are well-known challenges in treatment of children with OFC. However, oral inflammatory mediators were not investigated after birth using non-invasive sampling methods so far. In order to investigate the impact of OFC on oral cytokine levels, we collected tongue smear samples from 15 neonates with OFC and 17 control neonates at two time points (T), T0 at first consultation after birth, and T1, 4 to 5 weeks later. The samples were analyzed using multiplex immunoassay. Overall, we found significantly increased cytokine levels (TNF, IL-1β/-2/-6/-8/-10) in tongue smear samples from neonates with OFC compared to controls, especially at T0. The increase was even more pronounced in neonates with a higher cleft severity. Further, we detected a significant positive correlation between cleft severity score and distinct pro-inflammatory mediators (GM-CSF, IL-1β, IL-6, IL-8) at T0. Further, we found that breast-milk (bottle) feeding was associated with lower levels of pro-inflammatory cytokines (IL-6/-8) in neonates with OFC compared to formula-fed neonates. Our study demonstrated that neonates with OFC, especially with high cleft severity, are characterized by markedly increased inflammatory mediators in tongue smear samples within the first weeks of life potentially presenting a risk for oral inflammatory diseases. Therefore, an inflammatory monitoring of neonates with (severe) OFC and the encouragement of mother to breast-milk (bottle) feed might be advisable after birth and/or prior to cleft surgery.
CRIS-Team Scopus Importer:2022-12-16
Keywords: cleft lip and palate; cytokines; mucosal homeostasis; mucosal immunity; neonates; oral; oral inflammation; orofacial clefts

Outcome after neoadjuvant chemotherapy in elderly breast cancer patients - a pooled analysis of individual patient data from eight prospectively randomized controlled trials - von Waldenfels, Gabriel; Loibl, Sibylle; Furlanetto, Jenny; Machleidt, Anna; Lederer, Bianca; Denkert, Carsten; Hanusch, Claus; Kümmel, Sherko; von Minckwitz, Gunter; Schneeweiss, Andreas; Untch, Michael; Rhiem, Kerstin; et al. (Oncotarget, 2018)
Introduction: Recent studies showed the high and independent impact of age (<40 years) on pathologic complete response (pCR) and prognosis for patients undergoing neoadjuvant chemotherapy (NACT). Some physicians might not consider elderly patients (>65 years) for NACT due to poor prognosis or higher toxicity. The aim of this analysis is to help selecting appropriately elderly women who would benefit from NACT. Secondly, survival parameters are investigated in several histological subgroups. Methods: From 1998 to 2010, eight prospectively randomized German Breast Group (GBG) trials of anthracycline- and taxane-based NACT were performed and analyzed in this study. Results: Compared to the overall average, elderly women had significant larger tumors and more overall lymph node involvement. Histologically, they had more G2 tumors, more estrogen-receptor positive tumors. pCR (ypT0 ypN0) was strongly associated with age. The multivariable logistic regression analysis of clinical parameters showed that young age, clinical stage T4, invasive ductal cancer and poor differentiated breast cancer are predictive for high pCR. The multivariate analyses of molecular subgroups showed that age >65years is a predictor of significant lower pCR in HER2- breast cancers. Nonetheless, HER2+ patients showed pCR rates as high- and HR+/HER2+ even higher - pCR rates compared to younger patients. Discussion: This study underlines the unfavorable impact of higher age on pCR, but it shows a realistic chance for pCR if NACT is applied - especially for HER2+ patients. Furthermore, elderly patients with non-TNBC showed a good prognosis (comparable to younger patients) regarding overall survival, even if they do not have pCR.
EVALuna2:210017

Outcome after neoadjuvant chemotherapy in estrogen receptor-positive and progesterone receptor-negative breast cancer patients: a pooled analysis of individual patient data from ten prospectively randomized controlled neoadjuvant trials - Van Mackelenbergh, Marion T.; Denkert, Carsten; Nekljudova, Valentina; Karn, Thomas; Schem, Christian; Marme, Frederik; Stickeler, Elmar; Jackisch, Christian; Hanusch, Claus; Huober, Jens; Fasching, Peter; Blohmer, Jens-Uwe; et al. (Breast Cancer Research and Treatment, 2018)
The estrogen receptor (ER) is involved in control of progesterone receptor (PgR) expression and lack of PgR may be also a surrogate of altered growth factor signaling. The aim of this study was therefore to investigate PgR expression as predictive factor for response to neoadjuvant therapy and long-term outcome.Five thousand and six hundred and thirteen patients with primary breast cancer and positive ER expression from ten German neoadjuvant trials of anthracycline and taxane-based chemotherapy were included. Pathologic complete response (pCR), disease-free survival (DFS), distant disease-free survival (DDFS), overall survival (OS), and local recurrence-free survival (LRFS) were compared according to PgR expression.The lack of PgR expression (1172 patients) was associated with grade 3 (38.4 vs. 26.3%; p < 0.001), nodal involvement (>cN2) (6.8% vs. 4.7%; p = 0.004), and HER2 positivity (36.2 vs. 22.3%; p < 0.001). pCR rates of PgR-negative tumors were higher in the entire cohort (13.8 vs. 7.5%; p < 0.001) and in the HER2-negative subgroup (11.2 vs. 5.8%; p < 0.001). In multivariable logistic regression, PgR negativity was an independent predictive factor for pCR overall (OR 1.76; p < 0.001) and in the HER2-negative patients (OR 1.99; p < 0.001). Patients with PgR-negative disease had significantly worse outcome (p < 0.001, respectively). Multivariable Cox regression analysis revealed that PgR was an independent prognostic factor for DFS, OS, DDFS, and LRFS.ER-positive/PgR-negative breast carcinomas are associated with higher response but also worse long-term outcome after neoadjuvant therapy. PgR negativity is an independent predictive factor for pCR after neoadjuvant chemotherapy in ER-positive HER2-negative breast cancer.
EVALuna2:56119

Outcome and prognosis in uterine sarcoma and malignant mixed Mullerian tumor - Burghaus, Stefanie; Halmen, Sonja; Gaß, Paul; Mehlhorn, Grit; Schrauder, Michael G.; Lux, Michael P.; Renner, Stefan; Beckmann, Matthias; Hein, Alexander; Thiel, Falk (Archives of Gynecology and Obstetrics, 2016)
PURPOSE: There is low evidence regarding the optimal treatment in patients with uterine sarcomas and malignant mixed Mullerian tumors (MMMTs). This study provides an overview of experience at our center with patients diagnosed with uterine sarcoma and MMMT, in relation to the clinical management and outcome. METHODS: The medical records for 143 patients with low-grade endometrial stromal sarcoma (ESS), leiomyosarcoma (LMS), and high-grade (undifferentiated) endometrial sarcoma (UES) and MMMT were reviewed. All available clinical and pathological data were collected and analyzed. Putative prognostic factors were entered into a multivariate analysis using a Cox proportional hazards ratio model, and survival data were calculated. RESULTS: The 5-year overall survival rates were significantly different between patients with ESS, LMS, and UES and MMMT (86 vs. 40 vs. 57 vs. 45 %; P < 0.001). The multivariate analysis showed that the patients' age, higher FIGO stage (III-IV), a history of smoking, prior pelvic radiation, diabetes, and residual tumor after surgery were associated with a poorer overall survival. Histological subtypes of LMS (HR 4.68; 95 % CI 1.35-16.17), UES (HR 1.21; 95 % CI 0.26-5.77) and MMMT (HR 1.63; 95 % CI 0.42-6.43) were also associated with a poorer overall survival than ESS (P = 0.008). Adjuvant therapies showed no associations with overall survival. CONCLUSIONS: Adjuvant therapy has so far not shown any overall survival benefit, and the focus is therefore on primary surgery. In future studies, the entities should be investigated separately in relation to prognostic factors and effective therapeutic management.
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Ovarian function in young patients (pts) treated with postneoadjuvant palbociclib (PAL) and endocrine therapy (ET) for hormone receptor (HR)-positive, HER2-negative early breast cancer (BC): Explorative analysis in Penelope-B - Furlanetto, J.; Marme, F.; Thode, C.; Nekljudova, V.; Liu, Y.; Jimenez, M. Martin; Reimer, T.; Knudsen, E.; Denkert, C.; Bassy, M.; Martin, L-A.; Karn, T.; et al. (ANNALS OF ONCOLOGY, 2022)
CRIS-Team WoS Importer:2022-06-03

Ovarian tissue cryopreservation and retransplantation–what do patients think about it? - Lotz, Laura; Maktabi, Amina; Hoffmann, Inge; Findeklee, Sebastian; Beckmann, Matthias; Dittrich, Ralf (Reproductive Biomedicine Online, 2016)
Cryopreservation of ovarian tissue has been successfully applied clinically, with over 60 live births to date. The aim of the present study was to perform a survey of patients who have had ovarian tissue cryopreserved in the Department of Obstetrics and Gynecology, Erlangen University Hospital, in order to obtain information about: why patients opt for fertility preservation; their current fertility; pregnancy attempts and outcomes; and their intended plans for the cryopreserved ovarian tissue. In total, 147 women took part in the survey (average age 25.0 ± 7.0 years; response rate 48%; mean follow-up period 6 years). Sixty-six reported regular menstrual cycles; 48 were amenorrhoeic. Sixty-two women had tried to conceive; 33 reported pregnancies. Twenty-five had delivered healthy children after conceiving naturally; eight had conceived with assisted reproduction. Five patients had had their ovarian tissue retransplanted. Although many patients continued to have ovarian function, none of them regretted choosing cryopreservation of ovarian tissue. Cryopreservation of ovarian tissue is an effective option and is very important for women diagnosed with cancer. Analyses of the clinical outcomes in these patients are essential in order to identify those patients capable of benefiting most from the procedure and in order to improve the technique.
EVALuna2:32986

Ovarian Tissue Transplantation: Experience From Germany and Worldwide Efficacy - Lotz, Laura; Dittrich, Ralf; Hoffmann, Inge; Beckmann, Matthias (Clinical Medicine Insights: Reproductive Health, 2019)
Extraction of ovarian tissue prior to oncologic therapy and subsequent transplantation is being performed increasingly often to preserve fertility in women. The procedure can be performed at any time of the cycle and, therefore, generally does not lead to any delay in oncological therapy. Success rates with transplantation of cryopreserved ovarian tissue have reached promising levels. More than 130 live births have been reported worldwide with the aid of cryopreserved ovarian tissue and the estimated birth rate is currently approximately 30%. In Germany, Austria, and Switzerland, the FertiPROTEKT consortium has successfully achieved 21 pregnancies and 17 deliveries generated after 95 ovarian tissue transplantations by 2015, one of the largest case series worldwide confirming that ovarian tissue cryopreservation and transplantation are successful. Approximately, more than 400 ovarian tissue cryopreservation procedures are performed each year in the FertiPROTEKT consortium. and the request and operations for ovarian tissue transplantation have increased in recent years. Therefore. recommendations for managing transplantation of ovarian tissue to German-speaking reproductive medicine centers were developed. In this overview. these recommendations and our experience in ovarian tissue transplantation are presented and discussed with international procedures.
CRIS-Team WoS Importer:2019-10-22

Ovarian tissue transplantations in 196 women by FertiPROTEKT- live birth rate of 26.5% per woman is associated with female age and first versus repeated transplantation - Lotz, Laura; Bender-Liebenthron, J.; Dittrich, Ralf; Häberle, Lothar; Beckmann, Matthias; Germeyer, A.; Korell, M.; Saenger, N.; Von Wolff, M. (HUMAN REPRODUCTION, 2022)
CRIS-Team WoS Importer:2022-10-21

Overall survival (OS) results of the phase III MONALEESA-3 trial of postmenopausal patients (pts) with hormone receptor-positive (HR plus ), human epidermal growth factor 2-negative (HER2-) advanced breast cancer (ABC) treated with fulvestrant (FUL) (+) ribociclib (RIB) - Slamon, D. J.; Neven, P.; Chia, S.; Fasching, Peter; De Laurentiis, M.; Im, S-A.; Petrakova, K.; Bianchi, G. V.; Esteva, F. J.; Martin, M.; Nusch, A.; Sonke, G. S.; et al. (ANNALS OF ONCOLOGY, 2019)
CRIS-Team WoS Importer:2019-11-08

Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer - Slamon, Dennis J.; Neven, Patrick; Chia, Stephen; Fasching, Peter; De Laurentiis, Michelino; Im, Seock-Ah; Petrakova, Katarina; Bianchi, Giulia V.; Esteva, Francisco J.; Martin, Miguel; Nusch, Arnd; Sonke, Gabe S.; et al. (New England Journal of Medicine, 2020)
BACKGROUND In an earlier analysis of this phase 3 trial, ribociclib plus fulvestrant showed a greater benefit with regard to progression-free survival than fulvestrant alone in postmenopausal patients with hormone-receptor positive, human epidermal growth factor receptor 2 (HER2) negative advanced breast cancer. Here we report the results of a protocol-specified second interim analysis of overall survival. METHODS Patients were randomly assigned in a 2;1 ratio to receive either ribociclib or placebo in addition to fulvestrant as first-line or second-line treatment. Survival was evaluated by means of a stratified log-rank test and summarized with the use of Kaplan Meier methods. RES U ITS This analysis was based on 275 deaths: 167 among 484 patients (34.5%) receiving ribociclib and 108 among 242 (44.6 /o) receiving placebo. Ribociclib plus fulvestrant showed a significant overall survival benefit over placebo plus fulvestrant. The estimated overall survival at 42 months was 57.8% (95% confidence interval [CI], 52.0 to 63.2) in the ribociclib group and 45.9% (95% CI, 36.9 to 54.5) in the placebo group, for a 28 /0 difference in the relative risk of death (hazard ratio, 0.72; 95% Cl, 0.57 to 0.92; P=0.00455). The benefit was consistent across most subgroups. In a descriptive update, median progression-free survival among patients receiving first-line treatment was 33.6 months (95% CI, 27.1 to 41.3) in the ribociclib group and 19.2 months (95% Cl, 14.9 to 23.6) in the placebo group. No new safety signals were observed. CONCLUSIONS Ribociclib plus fulvestrant showed a significant overall survival benefit over placebo plus fulvestrant in patients with hormone-receptor positive, HER2-negative advanced breast cancer. (Funded by Novartis; MONALEESA-3 ClinicalTrials.gov number, NCT02422615.)
CRIS-Team WoS Importer:2020-02-21

Oxytocin receptor DNA methylation in postpartum depression - Kimmel, Mary; Clive, Makena; Gispen, Fiona; Guintivano, Jerry; Brown, Tori; Cox, Olivia; Beckmann, Matthias; Kornhuber, Johannes; Fasching, Peter; Osborne, Lauren M.; Binder, Elisabeth; Payne, Jennifer L.; et al. (Psychoneuroendocrinology, 2016)
The oxytocin receptor (OXTR) is a key regulator of stress and anxiety and may be regulated by both psychosocial risk factors and gonadal hormones, making it an attractive candidate for study in postpartum depression (PPD). The objective of this study was to investigate both serum hormone and PPD specific DNA methylation variation in the OXTR. Illumina HM450 microarray data generated in a prospective PPD cohort identified significant associations (P=0.014) with PPD in an intronic region in the OXTR located 4bp proximal to an estrogen receptor (ER) binding region. Pyrosequencing confirmed moderate evidence for an interaction of CpGs in the region with childhood abuse status to mediate PPD. These CpGs located on chr3 at positions 8810078 and 8810069 exhibited significant associations with postpartum depression scores from an independent cohort of 240 women with no prior psychiatric history. Hormone analysis suggested a PPD specific negative correlation of DNA methylation in the region with serum estradiol levels. Estradiol levels and OXTR DNA methylation exhibited a significant interaction to associate with the ratio of allopregnanolone to progesterone. Cumulatively, the data corroborate our previous hypotheses of a PPD specific increased sensitivity of epigenetic reprogramming at estrogen target genes and suggests that OXTR epigenetic variation may be an important mediator of mood relevant neuroactive steroid production.
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p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study - Köbel, Martin; Kang, Eun-Young; Weir, Ashley; Rambau, Peter F.; Lee, Cheng-Han; Nelson, Gregg S.; Ghatage, Prafull; Meagher, Nicola S.; Riggan, Marjorie J.; Alsop, Jennifer; Anglesio, Michael S.; Beckmann, Matthias; et al. (Journal of Pathology: Clinical Research, 2023)
Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.
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p53 and p16 expression profiles in vulvar cancer: a translational analysis by the Arbeitsgemeinschaft Gynäkologische Onkologie Chemo and Radiotherapy in Epithelial Vulvar Cancer study group - Woelber, Linn; Prieske, Katharina; Eulenburg, Christine; Oliveira-Ferrer, Leticia; de Gregorio, Nikolaus; Klapdor, Ruediger; Kalder, Matthias; Braicu, Iona; Fuerst, Sophie; Klar, Maximilian; Strauss, Hans Georg; Beckmann, Matthias; et al. (American Journal of Obstetrics and Gynecology, 2021)
Background: There are 2 known pathways for tumorigenesis of vulvar squamous cell carcinoma—a human papillomavirus–dependent pathway characterized by p16 overexpression and a human papillomavirus–independent pathway linked to lichen sclerosus, characterized by TP53 mutation. A correlation of human papillomavirus dependency with a favorable prognosis has been proposed. Objective: The objective of the study was to further understand the role of human papillomavirus and p53 status in vulvar squamous cell carcinoma and characterize its clinical relevance. Study Design: The Arbeitsgemeinschaft Gynaecological Oncology Chemo and Radiotherapy in Epithelial Vulvar Cancer-1 study is a retrospective cohort study of 1618 patients with primary vulvar squamous cell carcinoma Fédération Internationale de Gynécologie et d'Obstétrique stage ≥1B treated at 29 gynecologic cancer centers in Germany between 1998 and 2008. For this translational substudy, formalin-fixed paraffin-embedded tissue was collected. A tissue microarray was constructed (n=652 samples); p16 and p53 expression was determined by immunohistochemistry. Human papillomavirus status and subtype were analyzed by polymerase chain reaction. Results: p16 immunohistochemistry was positive in 166 of 550 tumors (30.2%); p53 staining in 187 of 597 tumors (31.3%). Only tumors with available information regarding p16 and p53 immunohistochemistry and without p53 silent expression pattern were further analyzed (n=411); 3 groups were defined: p53+ (n=163), p16+/p53− (n=132), and p16−/p53− (n=116). Human papillomavirus DNA was detected in 85.6% of p16+/p53− tumors; human papillomavirus-16 was the most common subtype (86.3%). Patients with p16+ tumors were younger (64 vs 72 years for p53+, respectively, 69 years for p16−/p53− tumors; P<.0001) and showed lower rates of lymph-node involvement (28.0% vs 42.3% for p53+, respectively, 30.2% for p16−/p53− tumors; P=.050). Notably, 2-year-disease-free and overall survival rates were significantly different among the groups: disease-free survival, 47.1% (p53+), 60.2% (p16−/p53−), and 63.9% (p16+/p53−) (P<.001); overall survival, 70.4% (p53+), 75.4% (p16−/p53−), and 82.5% (p16+/p53−) (P=.002). In multivariate analysis, the p16+/p53− phenotype showed a consistently improved prognosis compared with the other groups (hazard ratio, 0.66; 95% confidence interval, 0.44–0.99; P=.042). Conclusion: p16 overexpression is associated with an improved prognosis whereas p53 positivity is linked to an adverse outcome. Our data support the hypothesis of a clinically relevant third subgroup of vulvar squamous cell carcinoma with a p53−/p16− phenotype showing an intermediate prognosis that needs to be further characterized.
CRIS-Team Scopus Importer:2021-04-09
Keywords: HPV; p16; p53; prognosis; vulvar cancer

PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS - Southey, Melissa C.; Goldgar, David E.; Winqvist, Robert; Pylkas, Katri; Couch, Fergus; Tischkowitz, Marc; Foulkes, William D.; Dennis, Joe; Michailidou, Kyriaki; Van Rensburg, Elizabeth J.; Heikkinen, Tuomas; Nevanlinna, Heli; et al. (Journal of Medical Genetics, 2016)
The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study.We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant.For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10(-5)), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10(-8)) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p<=0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants.This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
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Palliative therapy concepts for pancreatic carcinoma - Brunner, Michaela; Grützmann, Robert; Weber, Georg (Chirurg, 2018)
The majority of patients with ductal pancreatic adenocarcinoma are already in a locally advanced or metastatic stage at the time of diagnosis and require palliative therapy. Interventional and operative measures are available for the restoration of biliary outflow in bile duct obstruction and the continuity of the upper intestinal lumen in duodenal or gastric outlet obstruction. In the presence of tumor-related pain, pain therapy according to the World Health Organization (WHO) scheme or a truncus coeliacus blockade, in cachexia a nutritional therapy and in thromboembolic events an anticoagulant therapy are used. An individualized palliative chemotherapy regimen should be selected for each patient, taking into account the patient's general condition and the side effects profile of the chemotherapeutic agents. Radiochemotherapy and local ablative therapies should currently only be used within the framework of studies. A palliative resection is not recommended according to current knowledge.
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Pap IVa (Papanicolaou-Karzinomdiagnostik) beim Zervixkarzinomscreening: Wie geht’s weiter? - Stübs, Frederik; Gaß, Paul; Beckmann, Matthias (gynäkologische praxis, 2021)
CRIS-Team Scopus Importer:2024-12-16

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche - Perry, John R. B.; Day, Felix; Elks, Cathy E.; Sulem, Patrick; Thompson, Deborah J.; Ferreira, Teresa; He, Chunyan; Chasman, Daniel I.; Esko, Toenu; Thorleifsson, Gudmar; Albrecht, Eva; Ang, Wei Q.; et al. (Nature, 2014)
Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and ?-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
EVALuna2:17437

Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis - Cortazar, Patricia; Zhang, Lijun; Untch, Michael; Mehta, Keyur; Costantino, Joseph P.; Wolmark, Norman; Bonnefoi, Herve; Cameron, David; Gianni, Luca; Valagussa, Pinuccia; Swain, Sandra M.; Prowell, Tatiana; et al. (Lancet, 2014)
Pathological complete response has been proposed as a surrogate endpoint for prediction of long-term clinical benefit, such as disease-free survival, event-free survival (EFS), and overall survival (OS). We had four key objectives: to establish the association between pathological complete response and EFS and OS, to establish the definition of pathological complete response that correlates best with long-term outcome, to identify the breast cancer subtypes in which pathological complete response is best correlated with long-term outcome, and to assess whether an increase in frequency of pathological complete response between treatment groups predicts improved EFS and OS.We searched PubMed, Embase, and Medline for clinical trials of neoadjuvant treatment of breast cancer. To be eligible, studies had to meet three inclusion criteria: include at least 200 patients with primary breast cancer treated with preoperative chemotherapy followed by surgery; have available data for pathological complete response, EFS, and OS; and have a median follow-up of at least 3 years. We compared the three most commonly used definitions of pathological complete response–ypT0 ypN0, ypT0/is ypN0, and ypT0/is–for their association with EFS and OS in a responder analysis. We assessed the association between pathological complete response and EFS and OS in various subgroups. Finally, we did a trial-level analysis to assess whether pathological complete response could be used as a surrogate endpoint for EFS or OS.We obtained data from 12 identified international trials and 11 955 patients were included in our responder analysis. Eradication of tumour from both breast and lymph nodes (ypT0 ypN0 or ypT0/is ypN0) was better associated with improved EFS (ypT0 ypN0: hazard ratio [HR] 0·44, 95% CI 0·39-0·51; ypT0/is ypN0: 0·48, 0·43-0·54) and OS (0·36, 0·30-0·44; 0·36, 0·31-0·42) than was tumour eradication from the breast alone (ypT0/is; EFS: HR 0·60, 95% CI 0·55-0·66; OS 0·51, 0·45-0·58). We used the ypT0/is ypN0 definition for all subsequent analyses. The association between pathological complete response and long-term outcomes was strongest in patients with triple-negative breast cancer (EFS: HR 0·24, 95% CI 0·18-0·33; OS: 0·16, 0·11-0·25) and in those with HER2-positive, hormone-receptor-negative tumours who received trastuzumab (EFS: 0·15, 0·09-0·27; OS: 0·08, 0·03, 0·22). In the trial-level analysis, we recorded little association between increases in frequency of pathological complete response and EFS (R(2)=0·03, 95% CI 0·00-0·25) and OS (R(2)=0·24, 0·00-0·70).Patients who attain pathological complete response defined as ypT0 ypN0 or ypT0/is ypN0 have improved survival. The prognostic value is greatest in aggressive tumour subtypes. Our pooled analysis could not validate pathological complete response as a surrogate endpoint for improved EFS and OS.US Food and Drug Administration.
EVALuna2:17518

Pathologically Tumor-free Resection Margin Distance as a Surrogate Parameter in Primary Vulvar Squamous Cell Cancer: Analysis of a Large Two-Center Patient Cohort - Balog, Eva; Stübs, Frederik; Berndt, Ronald; Dietl, Anna; Geppert, Carol-Immanuel; Hartmann, Arndt; Thunich, Oliver; Beckmann, Matthias; Koch, Martin C. (Geburtshilfe und Frauenheilkunde, 2025)
Background This study evaluated the role of tumor-free margin distances and other prognostic factors, including age, lymph-node metastases, lymphatic vessel invasion, and local recurrence, on the survival of patients with vulvar squamous cell carcinoma (VSCC) undergoing primary surgical treatment. Methods A retrospective analysis reviewed the records of 232 VSCC patients who had undergone primary radical local excision with R0 resection between 2009 and 2021 at ANregiomed Hospital Ansbach and Erlangen University Hospital (Germany). Patients, aged 18 and older with no distant metastases, were grouped by resection margin distances (1 to ≤Â 3Â mm, 3 to ≤Â 8Â mm, >Â 8Â mm) for survival analysis using the Kaplan-Meier and log-rank tests. A Cox proportional hazards regression model incorporating multiple covariates, selected using the best-subset selection method and guided by the Akaike information criterion (AIC), was used. In the next step, we conducted a separate analysis of the patients who experienced a local recurrence. Results The median age of the 232 patients analyzed was 69Â years, with a median follow-up period of 10.5Â years; 82 patients died. Survival varied significantly relative to resection margin distance (pÂ =Â 0.0022), with the highest rates in the 1 to ≤Â 3Â mm group and the lowest in the >Â 8Â mm group. Multivariate analysis revealed that age, lymphatic vessel invasion, and resection margin distance significantly influenced survival, with higher values associated with increased mortality. Out of 232 patients analyzed, 43 developed a local recurrence. In the group with resection margins of 1 to ≤Â 3Â mm, 37% of patients experienced a local recurrence. Among those with margins of 3 to ≤Â 8Â mm, 44% had a recurrence, while only 19% of patients with margins >Â 8Â mm showed a local recurrence. Conclusion The study underscored the significance of tumor-free margin distance as a surrogate marker for survival in VSCC patients. In addition to lymphatic vessel invasion as the most critical prognostic factor, tumor-free resection margin distance and age emerged as significant predictors of overall survival. The findings advocate for tailored, function-preserving surgical approaches to improve patient outcomes.
CRIS-Team Scopus Importer:2025-03-14
Keywords: resection margins; squamous cell cancer; vulvar cancer

Pathological Response in the Breast and Axillary Lymph Nodes after Neoadjuvant Systemic Treatment in Patients with Initially Node-Positive Breast Cancer Correlates with Disease Free Survival: An Exploratory Analysis of the GeparOcto Trial - Gerber, Bernd; Schneeweiss, Andreas; Möbus, Volker; Golatta, Michael; Tesch, Hans; Krug, David; Hanusch, Claus; Denkert, Carsten; Lübbe, Kristina; Heil, Jörg; Huober, Jens; Ataseven, Beyhan; et al. (Cancers, 2022)
Background: The conversion of initially histologically confirmed axillary lymph node-positive (pN+) to ypN0 after neoadjuvant systemic treatment (NAST) is an important prognostic factor in breast cancer (BC) patients and may influence surgical de-escalation strategies. We aimed to determine pCR rates in lymph nodes (pCR-LN), the breast (pCR-B), and both (tpCR) in women who present with pN+ BC, to assess predictors for response and the impact of pCR-LN, pCR-B, and tpCR on invasive disease-free survival (iDFS). Methods: Retrospective, exploratory analysis of 242 patients with pN+ at diagnosis from the multicentric, randomized GeparOcto trial. Results: Of 242 patients with initially pN+ disease, 134 (55.4%) had a pCR-LN, and 109 (45.0%) a pCR-B. Of the 109 pCR-B patients, 9 (8.3%) patients had involved LN, and 100 (41.3%) patients had tpCR. Those with involved LN still had a bad prognosis. As expected, pCR-B and intrinsic subtypes (TNBC and HER2+) were identified as independent predictors of pCR-LN. pCR-LN (ypN0; hazard ratio 0.42; 95%, CI 0.23–0.75; p = 0.0028 for iDFS) was the strongest independent prognostic factor. Conclusions: In initially pN+ patients undergoing NAST, the conversion to ypN0 is of high prognostic value. Surgical axillary staging after NAST is still essential in these patients to offer tailored treatment.
CRIS-Team Scopus Importer:2022-01-28
Keywords: Axillary surgery; Breast cancer; Lymph node; Neoadjuvant therapy; Pathological complete response; Prognosis

Pathology of Tumors Associated With Pathogenic Germline Variants in 9 Breast Cancer Susceptibility Genes - Mavaddat, Nasim; Dorling, Leila; Carvalho, Sara; Allen, Jamie; Gonzalez-Neira, Anna; Keeman, Renske; Bolla, Manjeet K.; Dennis, Joe; Wang, Qin; Ahearn, Thomas U.; Andrulis, Irene L.; Beckmann, Matthias; et al. (JAMA Oncology, 2022)
IMPORTANCE Rare germline genetic variants in several genes are associated with increased breast cancer (BC) risk, but their precise contributions to different disease subtypes are unclear. This information is relevant to guidelines for gene panel testing and risk prediction.
CRIS-Team WoS Importer:2022-02-11

Pathway-Based Analysis of Genome-Wide Association Data Identified SNPs in as Biomarker for Chemotherapy- Induced Neutropenia in Breast Cancer Patients - Bidadi, Behzad; Liu, Duan; Kalari, Krishna R.; Rübner, Matthias; Hein, Alexander; Beckmann, Matthias; Rack, Brigitte; Janni, Wolfgang; Fasching, Peter; Weinshilboum, Richard M.; Wang, Liewei (Frontiers in Pharmacology, 2018)
Neutropenia secondary to chemotherapy in breast cancer patients can be life-threatening and there are no biomarkers available to predict the risk of drug-induced neutropenia in those patients. We previously performed a genome-wide association study (GWAS) for neutropenia events in women with breast cancer who were treated with 5-fluorouracil, epirubicin and cyclophosphamide and recruited to the SUCCESS-A trial. A genome-wide significant single-nucleotide polymorphism (SNP) signal in the tumor necrosis factor superfamily member 13B () gene, encoding the cytokine B-cell activating factor (BAFF), was identified in that GWAS. Taking advantage of these existing GWAS data, in the present study we utilized a pathway-based analysis approach by leveraging knowledge of the pharmacokinetics and pharmacodynamics of drugs and breast cancer pathophysiology to identify additional SNPs/genes associated with the underlying etiology of chemotherapy-induced neutropenia. We identified three SNPs in the hyaluronan mediated motility receptor ( gene that were significantly associated with neutropenia ( < 1.0E-04). Those three SNPs were trans-expression quantitative trait loci for the expression of ( < 1.0E-04). The minor allele of these SNPs was associated with a decreased mRNA level. Additional functional studies performed with lymphoblastoid cell lines (LCLs) demonstrated that LCLs possessing the minor allele for the SNPs were more sensitive to drug treatment. Knock-down of in LCLs and HL-60 promyelocytic cells and treatment of those cells with BAFF modulated the cell sensitivity to chemotherapy treatment. These results demonstrate that SNP-dependent cytotoxicity of these chemotherapeutic agents might be related to expression level. In summary, utilizing a pathway-based approach for the analysis of GWAS data, we identified additional SNPs in the gene that were associated with neutropenia and also were correlated with expression.
EVALuna2:56169

Patient quality of life (QoL) from the GeparX trial on the addition of denosumab (Dmab) added to two different nab-paclitaxel (nP) regimens as neoadjuvant chemotherapy (NACT) in primary breast cancer (BC) - Reinisch, M.; Blohmer, J-U.; Link, T.; Just, M.; Untch, M.; Stoetzer, O.; Fasching, Peter; Schneeweiss, A.; Wimberger, P.; Seiler, S.; Huober, J.; Thill, M.; et al. (ANNALS OF ONCOLOGY, 2022)
CRIS-Team WoS Importer:2022-06-03

Patient-reported outcomes and hospitalization data in patients with HER2-positive metastatic breast cancer receiving trastuzumab deruxtecan or trastuzumab emtansine in the phase III DESTINY-Breast03 study - Curigliano, G.; Dunton, K.; Rosenlund, M.; Janek, M.; Cathcart, J.; Liu, Y.; Fasching, Peter; Iwata, H. (Annals of Oncology, 2023)
Background: In the DESTINY-Breast03 clinical trial, trastuzumab deruxtecan (T-DXd) showed superior progression-free survival and overall survival versus trastuzumab emtansine (T-DM1) and manageable safety in patients with human epidermal growth factor receptor 2 (HER2)-positive (HER2+) metastatic breast cancer. Here, patient-reported outcomes (PROs) are reported along with hospitalization data. Patients and methods: Patients in DESTINY-Breast03 were assessed for prespecified PRO measures, including European Organization for Research and Treatment of Cancer quality of life (EORTC-QoL) questionnaires [the oncology-specific EORTC Quality of Life Questionnaire Core 30 (QLQ-C30) and breast cancer-specific EORTC QLQ-BR45] and the generic EuroQol 5-dimension 5-level questionnaire (EQ-5D-5L) visual analogue scale. Analyses included change from baseline, time to definitive deterioration (TDD), and hospitalization-related endpoints. Results: EORTC QLQ-C30 baseline global health status (GHS) scores for T-DXd (n = 253) and T-DM1 (n = 260) were similar, with no clinically meaningful change (<10-point change from baseline) while on either treatment (median treatment duration: T-DXd, 14.3 months; T-DM1, 6.9 months). TDD analyses of QLQ-C30 GHS (primary PRO variable) and all other prespecified PROs (QLQ-C30 subscales, the QLQ-BR45 arm symptoms scale, and the EQ-5D-5L visual analogue scale) suggested T-DXd was numerically favored over T-DM1 based on TDD hazard ratios. Of all randomized patients, 18 (6.9%) receiving T-DXd versus 19 (7.2%) receiving T-DM1 were hospitalized, and the median time to first hospitalization was 219.5 versus 60.0 days, respectively. Conclusions: In DESTINY-Breast03, EORTC GHS/QoL was maintained on both therapies throughout treatment, indicating that despite the longer treatment duration with T-DXd versus T-DM1, health-related QoL did not worsen on T-DXd. Furthermore, TDD hazard ratios numerically favored T-DXd over T-DM1 in all prespecified variables of interest including pain, suggesting T-DXd may delay time until health-related QoL deterioration compared with T-DM1. Median time to first hospitalization was three times longer with T-DXd versus T-DM1. Together with reported improved efficacy and manageable toxicity, these results support the overall benefit of T-DXd for patients with HER2+ metastatic breast cancer.
CRIS-Team Scopus Importer:2023-06-30
Keywords: breast cancer; hospitalization; quality of life; trastuzumab deruxtecan; trastuzumab emtansine

Patient-reported outcomes (PRO) focused on adverse events (PRO-AEs) in adjuvant and metastatic breast cancer: clinical and translational implications - Stefanovic, Stefan; Wallwiener, Markus; Karic, Uros; Domschke, Christoph; Katic, Luka; Taran, Florin-Andrei; Pesic, Aleksandra; Hartkopf, Andreas; Hadji, Peyman; Teufel, Martin; Schuetz, Florian; Sohn, Christof; et al. (Supportive Care in Cancer, 2017)
PURPOSE: The capture of adequate treatment outcomes and quality of life (QOL) of advanced breast cancer patients in clinical routine represents a great challenge. Patient-reported outcomes (PROs) are data elements directly reported by patients about experiences with care, including symptoms, functional status, or quality of life. There is growing interest in the medical community for the evaluation and implementation of PROs of adverse events (PRO-AEs). Recent interest in PROs in health care has evolved in the context of patient centeredness. Our primary objective was to identify trials that had implemented PRO-AEs in the breast cancer treatment setting, thereby demonstrating its feasibility. We aimed to identify published studies that used patient reports to assess AEs during and after breast cancer treatment, to identify clinician underreported and modifiable AEs that are important to patients, and to analyze the feasibility and usefulness of PRO instrument implementation in everyday oncological practice with special attention given to electronic-based PRO instruments. METHODS: We conducted a systematic search of PubMed for studies that used PRO instruments to assess AEs of breast cancer treatment in the metastatic and adjuvant settings. Two authors independently reviewed the search results and decided which studies fully met the predefined inclusion criteria. RESULTS: The search yielded 606 publications. The two reviewers found that 9 studies met the inclusion criteria. Three AEs were identified as important to patients but inadequately reported by health care providers, namely hot flushes, vaginal dryness, and weight gain. CONCLUSIONS: PROs and PRO-AEs are the consequence of contemporary concepts of patient-centered medicine and the growing feasibility, utility, and implications of collecting data using modern technology. Furthermore, the willingness of patients to utilize innovative applications for their own health has been increasing in parallel to the enhanced impact of the World Wide Web. Especially, the coverage of the metastatic situation promises numerous findings on the structure and quality of health care, enabling implementation of individually tailored interventions. Remote electronic self-reporting (i.e., home reporting) is feasible and is associated with high compliance levels.
EVALuna2:36208

Patient-reported outcomes (PROs) from DESTINY-Breast03, a randomized phase III study of trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (pts) with HER2-positive (HER2+) metastatic breast cancer (MBC) - Curigliano, G.; Dunton, K.; Rosenlund, M.; Janek, M.; Cathcart, J.; Liu, Y.; Fasching, Peter; Iwata, H. (ANNALS OF ONCOLOGY, 2022)
CRIS-Team WoS Importer:2022-06-03

Patient-reported outcomes (PROs) in advanced breast cancer (ABC) treated with ribociclib plus fulvestrant: Results from MONALEESA-3 - Fasching, Peter; Esteva, F. J.; Pivot, X.; Nusch, A.; Beck, J. T.; Chan, A.; Pieris-Gunatilaka, A.; Wang, Y.; Lanoue, B.; Chandiwana, D.; Neven, P. (ANNALS OF ONCOLOGY, 2018)
CRIS-Team WoS Importer:2019-03-08

Patient-reported outcomes (PROs) in advanced breast cancer (ABC) treated with ribociclib (RIB) plus fulvestrant (FUL) as first-line (1L) and second-line (2L) therapy in MONALEESA-3 (ML-3) - Fasching, Peter; Neven, P.; Jerusalem, G.; Beck, J. T.; Chan, A.; De Laurentiis, M.; Bianchi, G. V.; Martin Jimenez, M.; Chia, S.; Gaur, A.; Sondhi, M.; Rodriguez-Lorenc, K.; et al. (ANNALS OF ONCOLOGY, 2020)
CRIS-Team WoS Importer:2020-06-26

Patient survival and tumor characteristics associated with CHEK2:p.I157T - findings from the Breast Cancer Association Consortium - Muranen, Taru A.; Blomqvist, Carl; Doerk, Thilo; Jakubowska, Anna; Heikkila, Paivi; Fagerholm, Rainer; Greco, Dario; Aittomaki, Kristiina; Bojesen, Stig E.; Shah, Mitul; Dunning, Alison M.; Rhenius, Valerie; et al. (Breast Cancer Research, 2016)
BACKGROUND: P.I157T is a CHEK2 missense mutation associated with a modest increase in breast cancer risk. Previously, another CHEK2 mutation, the protein truncating c.1100delC has been associated with poor prognosis of breast cancer patients. Here, we have investigated patient survival and characteristics of breast tumors of germ line p.I157T carriers. METHODS: We included in the analyses 26,801 European female breast cancer patients from 15 studies participating in the Breast Cancer Association Consortium. We analyzed the association between p.I157T and the clinico-pathological breast cancer characteristics by comparing the p.I157T carrier tumors to non-carrier and c.1100delC carrier tumors. Similarly, we investigated the p.I157T associated risk of early death, breast cancer-associated death, distant metastasis, locoregional relapse and second breast cancer using Cox proportional hazards models. Additionally, we explored the p.I157T-associated genomic gene expression profile using data from breast tumors of 183 Finnish female breast cancer patients (ten p.I157T carriers) (GEO: GSE24450). Differential gene expression analysis was performed using a moderated t test. Functional enrichment was investigated using the DAVID functional annotation tool and gene set enrichment analysis (GSEA). The tumors were classified into molecular subtypes according to the St Gallen 2013 criteria and the PAM50 gene expression signature. RESULTS: P.I157T was not associated with increased risk of early death, breast cancer-associated death or distant metastasis relapse, and there was a significant difference in prognosis associated with the two CHEK2 mutations, p.I157T and c.1100delC. Furthermore, p.I157T was associated with lobular histological type and clinico-pathological markers of good prognosis, such as ER and PR expression, low TP53 expression and low grade. Gene expression analysis suggested luminal A to be the most common subtype for p.I157T carriers and CDH1 (cadherin 1) target genes to be significantly enriched among genes, whose expression differed between p.I157T and non-carrier tumors. CONCLUSIONS: Our analyses suggest that there are fundamental differences in breast tumors of CHEK2:p.I157T and c.1100delC carriers. The poor prognosis associated with c.1100delC cannot be generalized to other CHEK2 mutations.
EVALuna2:32945

Pattern of invasion in stage I mucinous ovarian cancer is prognostic within 2-years of diagnosis - Meagher, Nicola; Koebel, Martin; Anderson, Lyndal; Tan, Adeline; Bolithon, Adelyn; Anglesio, Michael; Cohen, Paul; Crowe, Philip; Doherty, Jennifer; Fasching, Peter; Harris, Holly; Hogdall, Estrid; et al. (ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY, 2021)
CRIS-Team WoS Importer:2021-09-24

Pattern of SMARCB1 (INI1) and SMARCA4 (BRG1) in poorly differentiated endometrioid adenocarcinoma of the uterus: analysis of a series with emphasis on a novel SMARCA4-deficient dedifferentiated rhabdoid variant - Strehl, Johanna D.; Wachter, David; Fiedler, Jutta; Heimerl, Engelbert; Beckmann, Matthias; Hartmann, Arndt; Agaimy, Abbas (Annals of Diagnostic Pathology, 2015)
The role of the switch/sucrose nonfermenting chromatin remodeling complex in the initiation and progression of cancer is emerging. In the female genital tract, only ovarian small cell carcinoma, hypercalcemic type harbors recurrent inactivating SMARCA4 mutations. Otherwise, only rare case reports documented SMARCB1 involvement in endometrial cancer. We analyzed 24 grade 3 uterine endometrioid adenocarcinomas and 2 undifferentiated carcinomas for immunohistochemical expression of SMARCB1 and SMARCA4. All tumors showed high-grade nuclear features with a predominance of solid growth pattern. All cases showed intact nuclear SMARCB1 expression in all tumor cells. However, 1 case of a 78-year-old woman showed complete loss of SMARCA4 in 90% of the tumor with retained expression in 10% of the tumor. The SMARCA4-intact component was a moderate-to-poorly differentiated endometrioid adenocarcinoma. The SMARCA4-deficient dominating component showed solid growth of highly anaplastic undifferentiated large cells with prominent rhabdoid features. None of the 25 SMARCA4-intact cases showed rhabdoid cell morphology. To our knowledge, this is the first systematic study of SMARCB1 and SMARCA4 expression in endometrioid adenocarcinoma of uterus and the first description of a novel SMARCA4-deficient variant of dedifferentiated/undifferentiated endometrial carcinoma. The presence of a differentiated SMARCA4-intact endometrioid component points to a novel pathway of dedifferentiation in endometrioid adenocarcinoma as a consequence of a "second hit." This case further underlines the close link between the "rhabdoid phenotype" and the SWI/SNF pathway.
EVALuna2:6700

Patterns and Trends of Herbal Medicine Use among Patients with Gynecologic Cancer - Theuser, Anna Katharin; Hack, Carolin; Fasching, Peter; Antoniadis, Sophia; Grasruck, Katharina; Wasner, Sonja; Knoll, Stefanie; Sievers, Hartwig; Beckmann, Matthias; Thiel, Falk C. (Geburtshilfe und Frauenheilkunde, 2021)
Background More and more information about complementary and integrative medicine is becoming available, especially among cancer patients. However, little is known about the use of herbal medicine by patients with gynecologic cancers. This study aimed to assess the use of herbal products by gynecologic cancer patients compared with healthy controls. Methods This cross-sectional study was conducted at the Department for Gynecology and Obstetrics of Erlangen University Hospital and included 201 patients with gynecologic cancer and 212 healthy controls. Use of herbal medicines was evaluated using a standardized questionnaire. Medical information on cancer patients was collected from hospital records. Group comparisons were done using a logistic regression model. Risk ratios were assessed using a Poisson regression model. Results Gynecologic cancer patients used herbal medicine significantly less often than healthy persons. 69% of gynecologic cancer patients and 81% of healthy participants reported using herbal products. 40% of cancer patients and 56% of healthy persons reported using plants for medicinal purposes. Motives of cancer patients for using herbal medicine included treatment of cancer-related symptoms. The major source of information for both groups was family and friends. Conclusions Although herbal medicine was used less by patients with gynecologic cancer, herbal products were used by both cancer patients and healthy individuals. To provide cancer patients with optimal therapy, oncologists should be informed about the herbal products used by their patients as this will allow them to take their patients' self-medication with herbal medicine into account. Counseling by oncologists on the use of herbal medicine should be encouraged.
CRIS-Team Scopus Importer:2021-07-02
Keywords: cancer; complementary and alternative medicine; gynecologic oncology; herbal medicine; integrative medicine

Patterns of Associations with Epidemiologic Factors by High-Grade Serous Ovarian Cancer Gene Expression Subtypes - Collin, Lindsay J.; Cushing-Haugen, Kara L.; Terry, Kathryn L.; Goode, Ellen L.; Wu, Anna H.; Harris, Holly R.; Sasamoto, Naoko; Cramer, Daniel W.; Modugno, Francesmary; Elishaev, Esther; Fu, Zhuxuan; Moysich, Kirsten B.; et al. (Cancer Epidemiology Biomarkers & Prevention, 2025)
Background: Ovarian high-grade serous carcinomas (HGSC) comprise four distinct molecular subtypes based on mRNA expression patterns, with differential survival. Understanding risk factor associations is important to elucidate the etiology of HGSC. We investigated associations between different epidemiologic risk factors and HGSC molecular subtypes. Methods: We pooled data from 11 case-control studies with epidemiologic and tumor gene expression data from custom NanoString CodeSets developed through a collaboration within the Ovarian Tumor Tissue Analysis consortium. The PrOTYPEvalidated NanoString-based 55-gene classifier was used to assign HGSC gene expression subtypes. We examined associations between epidemiologic factors and HGSC subtypes in 2,070 cases and 16,633 controls using multivariable-adjusted polytomous regression models. Results: Among the 2,070 HGSC cases, 556 (27%) were classified as C1.MES, 340 (16%) as C5.PRO, 538 (26%) as C2.IMM, and 636 (31%) as C4.DIF. The key factors, including oral contraceptive use, parity, breastfeeding, and family history of ovarian cancer, were similarly associated with all subtypes. Heterogeneity was observed for several factors. Former smoking [OR = 1.25; 95% confidence interval (CI) = 1.03, 1.51] and genital powder use (OR = 1.42; 95% CI = 1.08, 1.86) were uniquely associated with C2.IMM. History of endometriosis was associated with C5.PRO (OR = 1.46; 95% CI = 0.98, 2.16) and C4.DIF (OR = 1.27; 95% CI = 0.94, 1.71) only. Family history of breast cancer (OR = 1.44; 95% CI = 1.16, 1.78) and current smoking (OR = 1.40; 95% CI = 1.11, 1.76) were associated with C4.DIF only. Conclusions: This study observed heterogeneous associations of epidemiologic and modifiable factors with HGSC molecular subtypes. Impact: The different patterns of associations may provide key information about the etiology of the four subtypes.
CRIS-Team Scopus Importer:2025-05-16

PD-L1 Expression and Silva Invasion Pattern in Villoglandular Adenocarcinoma of the Uterine Cervix - Dietl, Anna; Beckmann, Matthias; Stübs, Frederik; Gaß, Paul; Emons, Julius; Hartmann, Arndt; Erber, Ramona (International Journal of Gynecological Pathology, 2024)
Villoglandular adenocarcinoma (VGA) of the uterine cervix is a rare subtype of endocervical adenocarcinoma in young women. Between 2007 and 2020, all women with endocervical adenocarcinoma were retrospectively reviewed to find patients with VGA. Eight patients in whom pure VGA had been diagnosed were included. The mean age at initial diagnosis was 36.3 years (range 24–46). After surgical treatment, patients were followed up for 59 months (range 16–150). To date, all patients are alive with no evidence of disease. Neither lymph node involvement nor lymphovascular invasion was found. Furthermore, we examined the samples with a focus on morphological invasion pattern (Silva), stromal tumor-infiltrating lymphocytes (sTILs), and immunohistochemical programmed death ligand-1 (PD-L1) expression. PD-L1 expression was observed in 7/8 using the combined positive score (cutoff ≥ 1%), 1/8 of VGAs using the tumor proportion score (cutoff ≥ 1%), and 7/8 using the immune cell (cutoff ≥ 1%). Using combined positive score and immune cell, PD-L1 expression was seen in 7/8 of pattern B and C tumors, with significantly higher expression in tumors with destructive-type patterns (Po0.05, A vs. B+C). Using tumor proportion score, no significant difference in PD-L1 expression was seen between VGAs with different invasion patterns. VGAs demonstrated twice higher sTILs in tumors with destructive-type invasion patterns. Our observations suggest that PD-L1 expression, tumor invasion patterns, and sTILs do not correlate with the excellent prognosis of pure VGA.
CRIS-Team Scopus Importer:2024-06-28
Keywords: Cervix; CPS; PD-L1; Silva pattern; TIL; Villoglandular adenocarcinoma

PD-L1-Expression in in primary and recurrent vulvar squamous cell cancer - Stübs, Frederik; Knöll, Antje; Hartmann, Arndt; Leikauf, Leah-Sophie; Matek, Christian; John, Nelson; Häberle, Lothar; Beckmann, Matthias; Geppert, Carol-Immanuel (Gynecologic Oncology, 2025)
Background: Squamous cell vulvar carcinoma is a rare malignant disease of women. In higher tumor stages survival rates are poor. Therapy options are limited. Immunoncology plays an increasing role in the treatment of gynecology cancers. Data on the expression of PD-L1 in vulvar cancer are rare and contradictory. We sought to describe the expression of PD-L1 in VSCC in respect to the clinicopathologic characteristics of the tumor. Study design: We conducted a retrospective analysis including women with primary and recurrent vulvar cancer between 2000 and 2021. A next generation tissue micro array (ngTMA) was constructed for the analysis of PD-L1 expression. Results: In total 238 women with primary VSCC and 66 cases of local or distant recurrent vulvar cancer were included. 80 women with primary VSCC (33.6 %) had tumors with common positive score (CPS) <1 and 63 women (26.5 %) had tumors with CPS 1- < 10 and 95 women with CPS ≥10 (39.9 %). In the PD-L1 positive group the rates of p53+, groin metastasis, lymphatic invasion and tumor infiltration lymphocytes were higher as compared to PD-L1 negative (CPS <1). There was no significant influence of CPS in overall survival in addition to other prognostic factors (P = 0.13, likelihood ratio test). Conclusion: PD-L1 expression in primary vulvar cancer is associated with poorer prognosis. Hence, PD-L1 is a possible target for immune checkpoint inhibitors and women might benefit from special treatment options.
CRIS-Team Scopus Importer:2025-01-31
Keywords: Checkpoint inhibitor; Immune oncology; PD-L1-expression; Tissue micro array; Tumor infiltrating lymphocytes; Vulvar cancer

Pelvic Lymphadenectomy in Vulvar Cancer – Does it make sense? - Woelber, Linn; Bommert, Mareike; Prieske, Katharina; Fischer, Inger; Zu Eulenburg, Christine; Vettorazzi, Eik; Harter, Philipp; Jueckstock, Julia; Hilpert, Felix; De Gregorio, Niko; Iborra, Severine; Sehouli, Jalid; et al. (Geburtshilfe und Frauenheilkunde, 2020)
Since the publication of the updated German guideline in 2015, the recommendations for performing pelvic lymphadenectomy (LAE) in patients with vulvar cancer (VSCC) have changed considerably. The guideline recommends surgical lymph node staging in all patients with a higher risk of pelvic lymph node involvement. However, the current data do not allow the population at risk to be clearly defined, therefore, the indication for pelvic lymphadenectomy is still not clear. There are currently two published German patient populations who had pelvic LAE which can be used to investigate both the prognostic effect of histologically verified pelvic lymph node metastasis and the relation between inguinal and pelvic lymph node involvement. A total of 1618 patients with primary FIGO stage ≥ IB VSCC were included in the multicenter AGO CaRE-1 study (1998-2008), 70 of whom underwent pelvic LAE. During a retrospective single-center evaluation carried out at the University Medical Center Hamburg-Eppendorf (UKE), a total of 514 patients with primary VSCC treated between 1996-2018 were evaluated, 21 of whom underwent pelvic LAE. In both cohorts, around 80% of the patients who underwent pelvic LAE were inguinally node-positive, with a median number of three affected groin lymph nodes. There were no cases of pelvic lymph node metastasis without inguinal lymph node metastasis in either of the two cohorts. Between 33-35% of the inguinal node-positive patients also had pelvic lymph node metastasis; the median number of affected groin lymph nodes in these patients was high (> 4), and the maximum median diameter of the largest inguinal metastasis was > 40 mm in both cohorts. Pelvic lymph node staging and pelvic radiotherapy is therefore probably not necessary for the majority of node-positive patients with VSCC, as the relevant risk of pelvic lymph node involvement was primarily found in node-positive patients with high-grade disease. More, ideally prospective data collections are necessary to validate the relation between inguinal and pelvic lymph node involvement.
CRIS-Team Scopus Importer:2020-12-25
Keywords: lymph node metastasis; pelvic lymphadenectomy; prognosis; recurrence; vulvar cancer

Pembrolizumab for early triple-negative breast cancer - Schmid, P.; Cortes, J.; Pusztai, L.; McArthur, H.; Kümmel, S.; Bergh, J.; Denkert, C.; Park, Y. H.; Hui, R.; Harbeck, N.; Takahashi, M.; Foukakis, T.; et al. (New England Journal of Medicine, 2020)
Background: Previous trials showed promising antitumor activity and an acceptable safety profile associated with pembrolizumab in patients with early triple-negative breast cancer. Whether the addition of pembrolizumab to neoadjuvant chemotherapy would significantly increase the percentage of patients with early triple-negative breast cancer who have a pathological complete response (defined as no invasive cancer in the breast and negative nodes) at definitive surgery is unclear. Methods: In this phase 3 trial, we randomly assigned (in a 2:1 ratio) patients with previously untreated stage II or stage III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) every 3 weeks plus paclitaxel and carboplatin (784 patients; the pembrolizumab-chemotherapy group) or placebo every 3 weeks plus paclitaxel and carboplatin (390 patients; the placebo-chemotherapy group); the two groups then received an additional four cycles of pembrolizumab or placebo, and both groups received doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After definitive surgery, the patients received adjuvant pembrolizumab or placebo every 3 weeks for up to nine cycles. The primary end points were a pathological complete response at the time of definitive surgery and event-free survival in the intention-to-treat population. Results: At the first interim analysis, among the first 602 patients who underwent randomization, the percentage of patients with a pathological complete response was 64.8% (95% confidence interval [CI], 59.9 to 69.5) in the pembrolizumab-chemotherapy group and 51.2% (95% CI, 44.1 to 58.3) in the placebo-chemotherapy group (estimated treatment difference, 13.6 percentage points; 95% CI, 5.4 to 21.8; P<0.001). After a median follow-up of 15.5 months (range, 2.7 to 25.0), 58 of 784 patients (7.4%) in the pembrolizumab-chemotherapy group and 46 of 390 patients (11.8%) in the placebo-chemotherapy group had disease progression that precluded definitive surgery, had local or distant recurrence or a second primary tumor, or died from any cause (hazard ratio, 0.63; 95% CI, 0.43 to 0.93). Across all treatment phases, the incidence of treatment-related adverse events of grade 3 or higher was 78.0% in the pembrolizumab-chemotherapy group and 73.0% in the placebo-chemotherapy group, including death in 0.4% (3 patients) and 0.3% (1 patient), respectively. Conclusions: Among patients with early triple-negative breast cancer, the percentage with a pathological complete response was significantly higher among those who received pembrolizumab plus neoadjuvant chemotherapy than among those who received placebo plus neoadjuvant chemotherapy.
CRIS-Team Scopus Importer:2020-03-17

Pembrolizumab in combination with nab-paclitaxel for the treatment of patients with early-stage triple-negative breast cancer – A single-arm phase II trial (NeoImmunoboost, AGO-B-041) - Fasching, Peter; Hein, Alexander; Kolberg, Hans Christian; Häberle, Lothar; Uhrig, Sabrina; Rübner, Matthias; Belleville, Erik; Hack, Carolin; Fehm, Tanja N.; Janni, Wolfang; Hartmann, Arndt; Erber, Ramona; et al. (European Journal of Cancer, 2023)
Background: Pembrolizumab is approved for the neoadjuvant/adjuvant treatment of early triple-negative breast cancer (TNBC) patients in combination with chemotherapy. The Keynote-522 trial used platinum chemotherapy. As neoadjuvant nab-paclitaxel (nP) is also highly effective in triple-negative breast cancer patients, this study investigates the response to nP-containing neoadjuvant chemotherapy in combination with pembrolizumab. Patients and methods: NeoImmunoboost (AGO-B-041/NCT03289819) is a multicenter, prospective single-arm phase II trial. Patients were treated with 12 weekly cycles of nP followed by four three-weekly cycles of epirubicin/cyclophosphamide. Pembrolizumab was given three-weekly in combination with these chemotherapies. The study was planned for 50 patients. After 25 patients, the study was amended to include a pre-chemotherapy single application of pembrolizumab. The primary aim was pathological complete response (pCR), and the secondary aims were safety and quality of life. Results: Of 50 included patients, 33 (66.0%; 95%confidence interval: 51.2%–78.8%) had a (ypT0/is ypN0) pCR. The pCR rate in the per-protocol population (n = 39) was 71.8% (95%confidence interval: 55.1%–85.0%). The most common adverse events of any grade were fatigue (58.5%), peripheral sensory neuropathy (54.7%) and neutropenia (52.8%). The pCR rate in the cohort of 27 patients with a pre-chemotherapy pembrolizumab dose was 59.3%, and 73.9% in the 23 patients without pre-chemotherapy dose. Conclusions: pCR rates after NACT with nP and anthracycline combined with pembrolizumab are encouraging. With acceptable side-effect profiles, this treatment might be a reasonable alternative to platinum-containing chemotherapy in cases of contraindications. However, without data from randomised trials and long-term follow up, platinum/anthracycline/taxane-based chemotherapy remains the standard combination chemotherapy for pembrolizumab.
CRIS-Team Scopus Importer:2023-03-24
Keywords: Neoadjuvant chemotherapy; PD-L1; Pembrolizumab; Triple-negative

Percent mammographic density and dense area as risk factors for breast cancer - Rauh, C.; Hack, Caroline; Häberle, Lothar; Hein, Alexander; Engel, Anne; Schrauder, Michael G.; Fasching, Peter; Jud, Sebastian; Ekici, Arif Bülent; Loehberg, C. R.; Meier-Meitinger, Martina; Ozan-Mergner, Sevil Julia; et al. (Geburtshilfe und Frauenheilkunde, 2012)
Purpose: Mammographic characteristics are known to be correlated to breast cancer risk. Percent mammographic density (PMD), as assessed by computer-assisted methods, is an established risk factor for breast cancer. Along with this assessment the absolute dense area (DA) of the breast is reported as well. Aim of this study was to assess the predictive value of DA concerning breast cancer risk in addition to other risk factors and in addition to PMD. Methods: We conducted a case control study with hospital-based patients with a diagnosis of invasive breast cancer and healthy women as controls. A total of 561 patients and 376 controls with available mammographic density were included into this study. We describe the differences concerning the common risk factors BMI, parital status, use of hormone replacement therapy (HRT) and menopause between cases and controls and estimate the odds ratios for PMD and DA, adjusted for the mentioned risk factors. Furthermore we compare the prediction models with each other to find out whether the addition of DA improves the model. Results: Mammographic density and DA were highly correlated with each other. Both variables were as well correlated to the commonly known risk factors with an expected direction and strength, however PMD (ρ = 0.56) was stronger correlated to BMI than DA (ρ = 0.11). The group of women within the highest quartil of PMD had an OR of 2.12 (95 % CI: 1.25-3.62). This could not be seen for the fourth quartile concerning DA. However the assessment of breast cancer risk could be improved by including DA in a prediction model in addition to common risk factors and PMD. Conclusions: The inclusion of the parameter DA into a prediction model for breast cancer in addition to established risk factors and PMD could improve the breast cancer risk assessment. As DA is measured together with PMD in the process of computer-assisted assessment of PMD it might be considered to include it as one additional breast cancer risk factor that is obtained from breast imaging. © Georg Thieme Verlag KG Stuttgart · New York.
CRIS-Team Scopus Importer:2021-07-19
Keywords: breast cancer; mammographic density; risk

Performance of Photon-Counting Breast Computed Tomography, Digital Mammography, and Digital Breast Tomosynthesis in Evaluating Breast Specimens - Rößler, Ann-Christin; Kalender, Willi Alfred; Kolditz, Daniel; Steiding, Christian; Ruth, Veikko; Preuss, Caroline; Peter, Sandra Christina; Brehm, Barbara; Hammon, Matthias; Schulz-Wendtland, Rüdiger; Wenkel, Evelyn (Academic Radiology, 2017)
This study compared a novel photon-counting breast computed tomography (pcBCT) system with digital mammography (DM) and digital breast tomosynthesis (DBT) systems. For this reason, surgical specimens were examined with all three techniques and rated by three observers.A total of 30 surgical specimens were investigated with DM, DBT, and pcBCT; the associated images were shown to three experienced radiologists. Findings (22 microcalcifications and 23 mass lesions) were recorded and compared to the results of the pathological examination. Sensitivity and specificity for detection of microcalcifications and lesions were calculated and displayed using receiver operating characteristic curves.Sensitivity for microcalcifications was 82% for DM, 70% for DBT, and 85% for pcBCT. Specificity for microcalcifications was 71% for DM, 75% for DBT, and 83% for pcBCT. Sensitivity for lesions was 45% for DM, 62% for DBT, and 65% for pcBCT. Specificity for lesions was 76% for DM, 62% for DBT, and 76% for pcBCT.pcBCT showed a comparable or superior performance compared to the clinically approved DM and DBT systems. Mass lesion detectability can be increased further by the use of contrast media.
EVALuna2:14619

Perinatal Outcome in Pregnant Women With Isolated Oligohydramnios Diagnosed With the Single Deepest Pocket Method - Dammer, Ulf; Pretscher, Jutta; Weiss, Christel; Schneider, Michael; Faschingbauer, Florian; Beckmann, Matthias; Kehl, Sven (In Vivo, 2024)
AIM: The aim of this study was to investigate perinatal outcome in singleton pregnancies at term with isolated oligohydramnios, diagnosed by using the single deepest pocket method. PATIENTS AND METHODS: In this historic cohort study, the perinatal outcomes of 196 women with isolated oligohydramnios at term, diagnosed by using the single deepest pocket method, were compared to 8,676 women with normal amniotic fluid volume. The primary outcome measure was the Cesarean section rate. Further outcome parameters included the rate of induction of labor, abnormal cardiotocography, umbilical cord pH and base excess, Apgar, meconium-stained liquor and admission to neonatal intensive care unit. RESULTS: In the group with isolated oligohydramnios, there were significantly more Cesarean sections (p=0.0081) and more abnormal cardiotocographies (p=0.0005). Univariate and multivariate analyses showed that this difference was seen particularly in nulliparous women (p=0.0025 for Cesarean section and 0.0368 for abnormal cardiotocography). Peripartal and perinatal outcome parameters were not different between the two groups. CONCLUSION: In women with isolated oligohydramnios at term, there is no impact on fetal outcome. The influence of isolated oligohydramnios on the rate of cesarean section and abnormal cardiotocography is considered to be less than that of parity.
CRIS-Team Scopus Importer:2024-03-15
Keywords: abnormal cardiotocography; amniotic fluid; Cesarean section; Oligohydramnios; perinatal outcome; SDP; single deepest pocket

Permacol collagen paste for cryptoglandular and Crohn's anal fistula - Brunner, Michaela; Schneider, Ignaz Hans Friedrich; Guenther, K.; Grützmann, Robert; Matzel, Klaus (Techniques in Coloproctology, 2019)
BackgroundPermacol collagen paste, an acellular crosslinked porcine dermal collagen matrix suspension, is a new treatment option for anal fistula. Data remain limited, however, and as yet only the results of one case of Crohn's fistula treated with Permacol paste has been reported. The aim of this study was to assess the use of Permacol collagen paste in patients with cryptoglandular and Crohn's perianal fistulae.MethodsA prospective study was conducted on patients with anal fistula, treated with Permacol paste. Patients were followed at 1week, 6 and 12months, and on demand thereafter. The main focus was on fistula healing and postoperative continence. The former was defined as the absence of signs of recurrence on clinical examination, proctoscopy and rigid rectoscopy. Fecal incontinence was assessed before surgery and at each follow-up.ResultsThirty patients (19 women, 11 men; mean age 46years), 12 (40%) of whom had Crohn's disease were included. The average number of previous fistula operations was 6. All patients had 6months of follow-up, and 24 patients (80%) had 12months of follow-up. The healing rate in all patients was 57% (17 of 30 patients) at 6months and 63% (15 of 24 patients) at 12months. One patient reported a worsening of fecal incontinence at 12 months; 2 patients had adverse events (perianal pain: n=1, fluid accumulation n=1) requiring fistula drainage. Patient characteristics, healing, incontinence, and adverse events did not differ significantly between patients with and without Crohn's disease.ConclusionsOur data indicate that Permacol paste is a safe and moderately effective treatment for cryptoglandular and Crohn's fistulae.
CRIS-Team WoS Importer:2019-04-12

Personal Profiling im Bereich der Senologie - Behrens, Annika; Beckmann, Matthias; Fasching, Peter; Hübner, Hanna; Emons, Julius (Die Radiologie, 2025)
Background: The concept of personalized medicine is becoming increasingly important. The possibilities of diagnostics include not only genetic and molecular tumor profiles, but also the use of precise and individual imaging techniques. Objectives: The development and implementation of suitable diagnostic procedures with high sensitivity and specificity, which are at the same time tailored to the individual risk factors and biological characteristics of the patient, remain a challenge. Materials and methods: To enable personalized profiling, comprehensive diagnostics must be established that take into account all parameters such as imaging, molecular and genetic markers as well as real-world data and the use of artificial intelligence. This article sheds light on different approaches to personalized diagnostics in breast cancer and highlights the current clinical standard, innovative areas of research and the resulting challenges. Conclusion: The highest hurdles for newer imaging techniques are the standardization of image analysis and the validation of these techniques in large clinical trials. The use of artificial intelligence requires not only appropriate technical and medical expertise, but also a sensitive approach to issues such as data protection and patient privacy. Real-world registries offer insights into real world treatment situations and are therefore of great importance.
CRIS-Team Scopus Importer:2025-02-17
Keywords: Artificial intelligence; Big data—mammography; Breast cancer; Breast diagnostics; Early detection

Perspectives of patients and clinicians on big data and AI in health: a comparative empirical investigation - Hummel, Patrik; Braun, Matthias; Bischoff, Serena; Samhammer, David; Seitz, Katharina; Fasching, Peter; Dabrock, Peter (AI and Society, 2024)
Background: Big data and AI applications now play a major role in many health contexts. Much research has already been conducted on ethical and social challenges associated with these technologies. Likewise, there are already some studies that investigate empirically which values and attitudes play a role in connection with their design and implementation. What is still in its infancy, however, is the comparative investigation of the perspectives of different stakeholders. Methods: To explore this issue in a multi-faceted manner, we conducted semi-structured interviews as well as focus group discussions with patients and clinicians. These empirical methods were used to gather interviewee’s views on the opportunities and challenges of medical AI and other data-intensive applications. Results: Different clinician and patient groups are exposed to medical AI to differing degrees. Interviewees expect and demand that the purposes of data processing accord with patient preferences, and that data are put to effective use to generate social value. One central result is the shared tendency of clinicians and patients to maintain individualistic ascriptions of responsibility for clinical outcomes. Conclusions: Medical AI and the proliferation of data with import for health-related inferences shape and partially reconfigure stakeholder expectations of how these technologies relate to the decision-making of human agents. Intuitions about individual responsibility for clinical outcomes could eventually be disrupted by the increasing sophistication of data-intensive and AI-driven clinical tools. Besides individual responsibility, systemic governance will be key to promote alignment with stakeholder expectations in AI-driven and data-intensive health settings.
CRIS-Team Scopus Importer:2024-01-12
Keywords: Big data; Ethics; Health; Interviews; Privacy; Self-determination; Stakeholder

Phase III post-neoadjuvant study evaluating sacituzumab govitecan (SG), an antibody drug conjugate in primary HER2-negative breast cancer patients with high relapse risk after standard neoadjuvant treatment: SASCIA - Marme, F.; Hanusch, C.; Furlanetto, J.; Denkert, C.; Link, T.; Untch, M.; Blohmer, J-U.; Jackisch, C.; Reinisch, M.; Rhiem, K. E.; Schneeweiss, A.; Solbach, C.; et al. (ANNALS OF ONCOLOGY, 2021)
CRIS-Team WoS Importer:2021-10-15

Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3 - Slamon, Dennis J.; Neven, Patrick; Chia, Stephen; Fasching, Peter; De Laurentiis, Michelino; Im, Seock-Ah; Petrakova, Katarina; Bianchi, Giulia Val; Esteva, Francisco J.; Martin, Miguel; Nusch, Arnd; Sonke, Gabe S.; et al. (Journal of Clinical Oncology, 2018)
Purpose This phase III study evaluated ribociclib plus fulvestrant in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer who were treatment naïve or had received up to one line of prior endocrine therapy in the advanced setting. Patients and Methods Patients were randomly assigned at a two-to-one ratio to ribociclib plus fulvestrant or placebo plus fulvestrant. The primary end point was locally assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. Results A total of 484 postmenopausal women were randomly assigned to ribociclib plus fulvestrant, and 242 were assigned to placebo plus fulvestrant. Median progression-free survival was significantly improved with ribociclib plus fulvestrant versus placebo plus fulvestrant: 20.5 months (95% CI, 18.5 to 23.5 months) versus 12.8 months (95% CI, 10.9 to 16.3 months), respectively (hazard ratio, 0.593; 95% CI, 0.480 to 0.732; P < .001). Consistent treatment effects were observed in patients who were treatment naïve in the advanced setting (hazard ratio, 0.577; 95% CI, 0.415 to 0.802), as well as in patients who had received up to one line of prior endocrine therapy for advanced disease (hazard ratio, 0.565; 95% CI, 0.428 to 0.744). Among patients with measurable disease, the overall response rate was 40.9% for the ribociclib plus fulvestrant arm and 28.7% for placebo plus fulvestrant. Grade 3 adverse events reported in ≥ 10% of patients in either arm (ribociclib plus fulvestrant v placebo plus fulvestrant) were neutropenia (46.6% v 0%) and leukopenia (13.5% v 0%); the only grade 4 event reported in ≥ 5% of patients was neutropenia (6.8% v 0%). Conclusion Ribociclib plus fulvestrant might represent a new first- or second-line treatment option in hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer.
EVALuna2:210018

Phase II neoadjuvant study of GDC-9545+palbociclib (palbo) vs anastrozole (A) plus palbo in postmenopausal women with estrogen receptor-positive, HER2-negative, untreated early breast cancer (ER+/HER2-eBC) - Hurvitz, Sara A.; Fasching, Peter; Park, Yeon Hee; Quiroga, Vanesa; Crnjevic, Tanja Badovinac; Fresco, Rodrigo; Lopez-Valverde, Vanesa; Steinseifer, Jutta; Ye, Chenglin; Bardia, Aditya (CANCER RESEARCH, 2021)
CRIS-Team WoS Importer:2021-03-26

pH dependence of the decomposition behavior of urogynecological fixation materials - Keckstein, P.; Lotz, Laura; Palmisano, Ralf; Hübner, Sabine; Apeleo Zubiri, Benjamin; Spiecker, Erdmann; Burghaus, Stefanie; Beckmann, Matthias; Hoeffmann,; Dittrich, Ralf; Hein, Alexander; Lermann, Johannes (GEBURTSHILFE UND FRAUENHEILKUNDE, 2022)
CRIS-Team WoS Importer:2022-11-04

PHIP - a novel candidate breast cancer susceptibility locus on 6q14.1 - Jiao, Xiang; Aravidis, Christos; Marikkannu, Rajeshwari; Rantala, Johanna; Picelli, Simone; Adamovic, Tatjana; Liu, Tao; Maguire, Paula; Kremeyer, Barbara; Luo, Liping; Von Holst, Susanna; Kontham, Vinaykumar; et al. (Oncotarget, 2017)
Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD >2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene.
EVALuna2:36117

Physical activity levels are positively related to progression-free survival and reduced adverse events in advanced ER+ breast cancer - Zimmer, Philipp; Esser, Tobias; Lueftner, Diana; Schuetz, Florian; Baumann, Freerk T.; Rody, Achim; Schneeweiss, Andreas; Hartkopf, Andreas D.; Decker, Thomas; Uleer, Christoph; Stoetzer, Oliver J.; Foerster, Frank; et al. (BMC Medicine, 2024)
Background : Increased levels of physical activity are associated with a reduction of breast cancer mortality, especially in postmenopausal women with positive hormone receptor status. So far, previous observational case–control and cohort studies have focused on associations between overall leisure time physical activity and survival of women with breast cancer in general. Methods: In this multicenter prospective cohort study, conducted in Germany between 30th August 2012 to 29th December 2017, we investigated general physical activity in a homogenous sample of n = 1440 postmenopausal women with advanced (inoperable locally advanced or metastatic), hormone receptor-positive breast cancer receiving the same therapy (everolimus and exemestane). Self-reported physical activity was assessed using the Godin Leisure Time Exercise Questionnaire (GLTEQ) before and every 3 months during treatment. Participants were then classified into “active” and “insufficiently active” to screen their activity behavior the week prior to medical treatment. In addition, changes in physical activity patterns were assessed. Adjusted Cox regression analyses were performed for the activity categories to determine hazard ratios (HR). Besides progression-free survival (PFS), adverse events (AEs), QoL, and fatigue were assessed every 3 months until study termination. Results: Compared to “insufficiently active” patients, “active” individuals indicated a significantly longer PFS (HR: 0.84 [0.74; 0.984], p =.0295). No significant differences were observed for changes of physical activity behavior. Patients who reported to be “active” at baseline revealed significantly fewer AEs compared to “insufficiently” active patients. In detail, both severe and non-severe AEs occurred less frequently in the “active” patients group. In line with that, QoL and fatigue were better in physical “active” patients compared to their insufficient active counterparts at the last post-baseline assessment. Participants who remained or become active indicated less AEs, a higher QoL, and reduced fatigue levels. Conclusions: Physical activity behavior prior to medical treatment might have prognostic value in patients with advanced breast cancer in terms of extending the PFS. Moreover, physical activity before and during treatment may reduce treatment-related side effects and improve patients’ QoL and fatigue. Trial registration: EUPAS9462. Registered 30th October 2012 “retrospectively registered.”
CRIS-Team Scopus Importer:2024-10-18
Keywords: Adverse events; Breast cancer; Exercise; Fatigue; Physical activity; Quality of life; Survival

PIK3CA mutations are associated with lower rates of pathologic complete response to anti-human epidermal growth factor receptor 2 (her2) therapy in primary HER2-overexpressing breast cancer - Loibl, Sibylle; Von Minckwitz, Gunter; Schneeweiss, Andreas; Paepke, Stefan; Lehmann, Annika; Rezai, Mahdi; Zahm, Dirk M.; Sinn, Peter; Khandan, Fariba; Eidtmann, Holger; Dohnal, Karel; Heinrichs, Clemens; et al. (Journal of Clinical Oncology, 2014)
Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in breast cancer, with mutations in PIK3CA being the most common. This study investigated the association between PIK3CA genotype and pathologic complete response (pCR) rates in human epidermal growth factor receptor 2 (HER2)-positive breast cancer treated with either dual or single anti-HER2 treatment in addition to neoadjuvant chemotherapy.PIK3CA mutations in 504 tumor samples from participants in the neoadjuvant GeparQuattro, GeparQuinto, and GeparSixto studies were evaluated. All HER2-positive patients received either trastuzumab or lapatinib or the combination plus anthracycline-taxane chemotherapy. PIK3CA mutations were evaluated in formalin-fixed, paraffin-embedded tissues from core biopsies with a tumor cell content of >= 20% by using classical Sanger sequencing of exon 9 and exon 20.Overall, 21.4% of the patients harbored a PIK3CA mutation. Detection of a PIK3CA mutation was significantly associated with a lower pCR rate (19.4% with PIK3CA mutation v 32.8% with PIK3CA wild-type; odds ratio [OR], 0.49; 95% CI, 0.29 to 0.83; P = .008). In the 291 hormone receptor (HR) -positive tumors, pCR rate was 11.3% with a PIK3CA mutation compared with 27.5% with PIK3CA wild-type (OR, 0.34; 95% CI, 0.15 to 0.78; P = .011). In 213 patients with HR-negative tumors, pCR rate was 30.4% with PIK3CA mutation and 40.1% without (OR, 0.65; 95% CI, 0.32 to 1.32; P = .233; interaction test P = .292). In multivariable analysis, HR status and PIK3CA status provided independent predictive information. In patients with PIK3CA mutation, the pCR rates were 16%, 24.3%, and 17.4% with lapatinib, trastuzumab, and the combination, respectively (P = .654) and in the wild-type group, they were 18.2%, 33.%, and 37.1%, respectively (P = .017). Disease-free survival and overall survival were not statistically significantly different between patients with mutant and wild-type PIK3CA.HER2-positive breast carcinomas with a PIK3CA mutation are less likely to achieve a pCR after neoadjuvant anthracycline-taxane-based chemotherapy plus anti-HER2 treatment, even if a dual anti-HER2 treatment is given.
EVALuna2:17509

Piwi-like 1 and piwi-like 2 expression in breast cancer - Erber, Ramona; Meyer, Julia; Taubert, Helge; Fasching, Peter; Wach, Sven; Häberle, Lothar; Gaß, Paul; Schulz-Wendtland, Rüdiger; Landgraf, Laura; Olbricht, Sabrina; Jung, Rudolf; Beckmann, Matthias; et al. (Cancers, 2020)
PIWI-like 1 and PIWI-like 2 play a role in stem cell self-renewal, and enhanced expression has been reported for several tumor entities. However, few studies have investigated PIWI-like 1 and PIWI-like 2 expressions in breast cancer subtypes regarding prognosis. Therefore, we examined protein expression in a large consecutive cohort of breast cancer patients and correlated it to breast cancer subtypes and survival outcome. PIWI-like 1 and PIWI-like 2 expressions were evaluated using immunohistochemistry in a cohort of 894 breast cancer patients, of whom 363 were eligible for further analysis. Percentage and intensity of stained tumor cells were analyzed and an immunoreactive score (IRS) was calculated. The interaction of PIWI-like 1 and PIWI-like 2 showed a prognostic effect on survival. For the combination of high PIWI-like 1 and low PIWI-like 2 expressions, adjusted hazard ratios (HRs) were significantly higher with regard to overall survival (OS) (HR 2.92; 95% confidence interval (CI) 1.24, 6.90), disease-free survival (DFS) (HR 3.27; 95% CI 1.48, 7.20), and distant disease-free survival (DDFS) (HR 7.64; 95% CI 2.35, 24.82). Both proteins were significantly associated with molecular-like and PAM50 subgroups. Combining high PIWI-like 1 and low PIWI-like 2 expressions predicted poorer prognosis and both markers were associated with aggressive molecular subtypes.
CRIS-Team Scopus Importer:2020-11-20
Keywords: Breast cancer; HER2; Luminal A; Luminal B; Molecular breast cancer subtypes; PIWI-like 1; PIWI-like 2; PIWIL1; PIWIL2; TNBC

Plasticity of patient-matched normal mammary epithelial cells is dependent on autologous adipose-derived stem cells - Kengelbach-Weigand, Annika; Tasbihi, Kereshmeh; Strissel, Pamela; Schmid, Rafael; Marques, Jasmin Monteiro; Beier, Justus; Beckmann, Matthias; Strick, Reiner; Horch, Raymund E.; Boos, Anja (Scientific Reports, 2019)
Due to the increasing clinical application of adipose-derived stem cells (ADSC), e.g. lipotransfer for breast reconstruction, this study aimed to gain novel insights regarding ADSC influence on breast tissue remodeling and determine patient-dependent factors affecting lipotransfer as well as begin to address its oncological risks. The ADSC secretome was analyzed from five normal breast reduction patients and contained elevated levels of growth factors, cytokines and proteins mediating invasion. ADSC/ADSC secretomes were tested for their influence on the function of primary mammary epithelial cells, and tumor epithelial cells using cell culture assays. ADSC/ADSC secretomes significantly stimulated proliferation, transmigration and 3D-invasion of primary normal and tumor epithelial cells. IL-6 significantly induced an EMT and invasion. The ADSC secretome significantly upregulated normal epithelial cell gene expression including MMPs and ECM receptors. Our study supports that ADSC and its secretome promote favorable conditions for normal breast tissue remodeling by changing the microenvironment. and may also be important regarding residual breast cancer cells following surgery.
CRIS-Team Scopus Importer:2019-08-06

PML-nuclear bodies decrease with age and their stress response is impaired in aged individuals - Wenger, Barbara; Schwegler, Manuela; Brunner, Michaela; Daniel, Christoph; Schmidt, Manfred; Fietkau, Rainer; Distel, Luitpold (BMC Geriatrics, 2014)
Promyelocytic leukemia nuclear bodies (PML-NBs) have been depicted as structures which are involved in processing cell damages and DNA double-strand break repairs. The study was designed to evaluate differences in patients' PML-NBs response to stress factors like a cancerous disease and ionizing radiation exposure dependent on age.In order to clarify the role of PML-NBs in the aging process, we examined peripheral blood monocytes of 134 cancer patients and 41 healthy individuals between 22 and 92 years of age, both before and after in vitro irradiation. Additionally, we analyzed the samples of the cancer patients after in vivo irradiation. Cells were immunostained and about 1600 cells per individual were analyzed for the presence of PML- and ?H2AX foci.The number of existing PML-NBs per nucleus declined with age, while the number of ?H2AX foci increased with age. There was a non-significant trend that in vivo irradiation increased the number of PML-NBs in cells of young study participants, while in older individuals PML-NBs tended to decrease. It can be assumed that PML-NBs decrease in number during the process of aging.The findings suggest that there is a dysfunctional PML-NBs stress response in aged cells.
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Polygenic risk modeling for prediction of epithelial ovarian cancer risk - Dareng, Eileen O.; Tyrer, Jonathan P.; Barnes, Daniel R.; Jones, Michelle R.; Yang, Xin; Aben, Katja K. H.; Adank, Muriel A.; Agata, Simona; Andrulis, Irene L.; Anton-Culver, Hoda; Antonenkova, Natalia N.; Aravantinos, Gerasimos; et al. (European Journal of Human Genetics, 2022)
Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
CRIS-Team WoS Importer:2022-01-28

Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes - Mavaddat, Nasim; Michailidou, Kyriaki; Dennis, Joe; Lush, Michael; Fachal, Laura; Lee, Andrew; Tyrer, Jonathan P.; Chen, Ting-Huei; Wang, Qin; Bolla, Manjeet K.; Yang, Xin; Adank, Muriel A.; et al. (American Journal of Human Genetics, 2019)
Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.
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Polygenic score distribution differences across European ancestry populations: implications for breast cancer risk prediction - Yiangou, Kristia; Mavaddat, Nasim; Dennis, Joe; Zanti, Maria; Wang, Qin; Bolla, Manjeet K.; Abubakar, Mustapha; Ahearn, Thomas U.; Andrulis, Irene L.; Anton-Culver, Hoda; Antonenkova, Natalia N.; Arndt, Volker; et al. (Breast Cancer Research, 2024)
Background: The 313-variant polygenic risk score (PRS313) provides a promising tool for clinical breast cancer risk prediction. However, evaluation of the PRS313 across different European populations which could influence risk estimation has not been performed. Methods: We explored the distribution of PRS313 across European populations using genotype data from 94,072 females without breast cancer diagnosis, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 223,316 females without breast cancer diagnosis from the UK Biobank. The mean PRS was calculated by country in the BCAC dataset and by country of birth in the UK Biobank. We explored different approaches to reduce the observed heterogeneity in the mean PRS across the countries, and investigated the implications of the distribution variability in risk prediction. Results: The mean PRS313 differed markedly across European countries, being highest in individuals from Greece and Italy and lowest in individuals from Ireland. Using the overall European PRS313 distribution to define risk categories, leads to overestimation and underestimation of risk in some individuals from these countries. Adjustment for principal components explained most of the observed heterogeneity in the mean PRS. The mean estimates derived when using an empirical Bayes approach were similar to the predicted means after principal component adjustment. Conclusions: Our results demonstrate that PRS distribution differs even within European ancestry populations leading to underestimation or overestimation of risk in specific European countries, which could potentially influence clinical management of some individuals if is not appropriately accounted for. Population-specific PRS distributions may be used in breast cancer risk estimation to ensure predicted risks are correctly calibrated across risk categories.
CRIS-Team Scopus Importer:2025-02-04
Keywords: Breast cancer; Polygenic risk scores; Risk calibration; Risk prediction

Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression - Darabi, Hatef; Mccue, Karen; Beesley, Jonathan; Michailidou, Kyriaki; Nord, Silje; Kar, Siddhartha; Humphreys, Keith; Thompson, Deborah; Ghoussaini, Maya; Bolla, Manjeet K.; Dennis, Joe; Wang, Qin; et al. (American Journal of Human Genetics, 2015)
Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5' of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.
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Polymorphisms in inflammation pathway genes and endometrial cancer risk - Delahanty, Ryan J.; Xiang, Yong-Bing; Spurdle, Amanda; Beeghly-Fadiel, Alicia; Long, Jirong; Thompson, Deborah; Tomlinson, Ian; Yu, Herbert; Lambrechts, Diether; Doerk, Thilo; Goodman, Marc T.; Zheng, Ying; et al. (Cancer Epidemiology Biomarkers & Prevention, 2013)
Background: Experimental and epidemiologic evidence have suggested that chronic inflammation may play a critical role in endometrial carcinogenesis. Methods: To investigate this hypothesis, a two-stage study was carried out to evaluate single-nucleotide polymorphisms (SNP) in inflammatory pathway genes in association with endometrial cancer risk. In stage I, 64 candidate pathway genes were identified and 4,542 directly genotyped or imputed SNPs were analyzed among 832 endometrial cancer cases and 2,049 controls, using data from the Shanghai Endometrial Cancer Genetics Study. Linkage disequilibrium of stage I SNPs significantly associated with endometrial cancer (P < 0.05) indicated that the majority of associations could be linked to one of 24 distinct loci. One SNP from each of the 24 loci was then selected for follow-up genotyping. Of these, 21 SNPs were successfully designed and genotyped in stage II, which consisted of 10 additional studies including 6,604 endometrial cancer cases and 8,511 controls. Results: Five of the 21 SNPs had significant allelic odds ratios (ORs) and 95% confidence intervals (CI) as follows: FABP1, 0.92 (0.85-0.99); CXCL3, 1.16 (1.05-1.29); IL6, 1.08 (1.00-1.17); MSR1, 0.90 (0.82-0.98); and MMP9, 0.91 (0.87-0.97). Two of these polymorphisms were independently significant in the replication sample (rs352038 in CXCL3 and rs3918249 in MMP9). The association for the MMP9 polymorphism remained significant after Bonferroni correction and showed a significant association with endometrial cancer in both Asian- and European-ancestry samples. Conclusions: These findings lend support to the hypothesis that genetic polymorphisms in genes involved in the inflammatory pathway may contribute to genetic susceptibility to endometrial cancer. Impact statement: This study adds to the growing evidence that inflammation plays an important role in endometrial carcinogenesis. © 2012 American Association for Cancer Research.
CRIS-Team Scopus Importer:2021-07-19

Polymorphisms in the RANK/RANKL genes and their effect on bone specific prognosis in breast cancer patients - Hein, Alexander; Bayer, Christian M.; Schrauder, Michael G.; Haeberle, Lothar; Heusinger, Katharina; Strick, Reiner; Ruebner, Matthias; Lux, Michael P.; Renner, Stefan; Schulz-Wendtland, Rüdiger; Ekici, Arif Bülent; Hartmann, Arndt; et al. (BioMed Research International, 2014)
The receptor activator of NF-?B (RANK) pathway is involved in bone health as well as breast cancer (BC) pathogenesis and progression. Whereas the therapeutic implication of this pathway is established for the treatment of osteoporosis and bone metastases, the application in adjuvant BC is currently investigated. As genetic variants in this pathway have been described to influence bone health, aim of this study was the prognostic relevance of genetic variants in RANK and RANKL. Single nucleotide polymorphisms in RANK(L) (rs1054016/rs1805034/rs35211496) were genotyped and analyzed with regard to bone metastasis-free survival (BMFS), disease-free survival, and overall survival for a retrospective cohort of 1251 patients. Cox proportional hazard models were built to examine the prognostic influence in addition to commonly established prognostic factors. The SNP rs1054016 seems to influence BMFS. Patients with two minor alleles had a more favorable prognosis than patients with at least one common allele (HR 0.37 (95% CI: 0.17, 0.84)), whereas other outcome parameters remained unaffected. rs1805034 and rs35211496 had no prognostic relevance. The effect of rs1054016(RANKL) adds to the evidence that the RANK pathway plays a role in BC pathogenesis and progression with respect to BMFS, emphasizing the connection between BC and bone health.
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Pooled analysis of patient (pt)-reported outcomes (PROs) in the MONALEESA (ML)-2,-3, and-7 trials: Additional results and key subgroup findings - Fasching, Peter; Bardia, A.; Nusch, A.; Jerusalem, G.; Chan, A.; El Saghir, N. S.; Conejo, E. Alba; Im, S-A.; Janni, W.; Chandiwana, D.; Lanoue, B. R.; Thuerigen, A.; et al. (ANNALS OF ONCOLOGY, 2021)
CRIS-Team WoS Importer:2021-05-28

Pooled analysis of patient (pt)-reported quality of life (QOL) in the MONALEESA (ML)-2,-3, and-7 trials of ribociclib (RIB) plus endocrine therapy (ET) to treat hormone receptore-positive, HER2-negative (HR+/HER2L) advanced breast cancer (ABC) - Fasching, Peter; Bardia, A.; Nusch, A.; Jerusalem, G.; Chan, A.; El Saghir, N.; Alba, E.; Im, S-A.; Janni, W.; Chandiwana, D.; Lanoue, B.; Thuerigen, A.; et al. (ANNALS OF ONCOLOGY, 2020)
CRIS-Team WoS Importer:2020-10-30

Pooled Analysis of the Prognostic Relevance of Circulating Tumor Cells in Primary Breast Cancer - Janni, Wolfgang J.; Rack, Brigitte; Terstappen, Leon W. M. M.; Pierga, Jean-Yves; Taran, Florin-Andrei; Fehm, Tanja; Hall, Carolyn; De Groot, Marco R.; Bidard, Francois-Clement; Friedl, Thomas W. P.; Fasching, Peter; Brucker, Sara Y.; et al. (Clinical Cancer Research, 2016)
PURPOSE: Although unequivocal evidence has shown the prognostic relevance of circulating tumor cells (CTC) in the peripheral blood of patients with metastatic breast cancer, less evidence is available for the prognostic relevance of CTCs at the time of primary diagnosis. EXPERIMENTAL DESIGN: We conducted a pooled analysis of individual data from 3,173 patients with nonmetastatic (stage I-III) breast cancer from five breast cancer institutions. The prevalence and numbers of CTCs were assessed at the time of primary diagnosis with the FDA-cleared CellSearch System (Janssen Diagnostics, LLC). Patient outcomes were analyzed using meta-analytic procedures, univariate log-rank tests, and multivariate Cox proportional hazard regression analyses. The median follow-up duration was 62.8 months. RESULTS: One or more CTCs were detected in 20.2% of the patients. CTC-positive patients had larger tumors, increased lymph node involvement, and a higher histologic tumor grade than did CTC-negative patients (all P < 0.002). Multivariate Cox regressions, which included tumor size, nodal status, histologic tumor grade, and hormone receptor and HER2 status, confirmed that the presence of CTCs was an independent prognostic factor for disease-free survival [HR, 1.82; 95% confidence interval (CI), 1.47-2.26], distant disease-free survival (HR, 1.89; 95% CI, 1.49-2.40), breast cancer-specific survival (HR, 2.04; 95% CI, 1.52-2.75), and overall survival (HR, 1.97; 95% CI, 1.51-2.59). CONCLUSIONS: In patients with primary breast cancer, the presence of CTCs was an independent predictor of poor disease-free, overall, breast cancer-specific, and distant disease-free survival. Clin Cancer Res; 22(10); 2583-93. ©2016 AACR.
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Pooled analysis of the prognostic relevance of progesterone receptor status in five German cohort studies - Salmen, Jessica; Neugebauer, Julia; Fasching, Peter; Häberle, Lothar; Huober, Jens; Woeckel, Achim; Rauh, Claudia; Schuetz, Florian; Weissenbacher, Tobias; Kost, Bernd; Stickeler, Elmar; Klar, Maximilian; et al. (Breast Cancer Research and Treatment, 2014)
The progesterone receptor (PR) has been increasingly well described as an important mediator of the pathogenesis and progression of breast cancer. The aim of this study was to assess the role of PR status as a prognostic factor in addition to other well-established prognostic factors. Data from five independent German breast cancer centers were pooled. A total of 7,965 breast cancer patients were included for whom information about their PR status was known, as well as other patient and tumor characteristics commonly used as prognostic factors. Cox proportional hazards models were built to compare the predictive value of PR status in addition to age at diagnosis, tumor size, nodal status, grading, and estrogen receptor (ER) status. PR status significantly increased the accuracy of prognostic predictions with regard to overall survival, distant disease-free survival, and local recurrence-free survival. There were differences with regard to its prognostic value relative to subgroups such as nodal status, ER status, and grading. The prognostic value of PR status was greatest in patients with a positive nodal status, negative ER status, and low grading. The PR-status adds prognostic value in addition to ER status and should not be omitted from clinical routine testing. The significantly greater prognostic value in node-positive and high-grade tumors suggests a greater role in the progression of advanced and aggressive tumors.
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Population distribution of lifetime risk of ovarian cancer in the United States - Pearce, Celeste Leigh; Stram, Daniel O.; Ness, Roberta B.; Stram, Douglas A.; Roman, Lynda D.; Templeman, Claire; Lee, Alice W.; Menon, Usha; Fasching, Peter; Mcalpine, Jessica N.; Doherty, Jennifer A.; Modugno, Francesmary; et al. (Cancer Epidemiology Biomarkers & Prevention, 2015)
In U.S. women, lifetime risk of ovarian cancer is 1.37%, but some women are at a substantially lower or higher risk than this average.We have characterized the distribution of lifetime risk in the general population. Published data on the relative risks and their variances for five well-accepted risk and protective factors for ovarian cancer, oral contraceptive use, parity, tubal ligation, endometriosis, and first-degree family history of ovarian cancer in conjunction with a genetic risk score using genome-wide significant common, low penetrance variants were used. The joint distribution of these factors (i.e., risk/protective factor profiles) was derived using control data from four U.S. population-based studies, providing a broad representation of women in the United States.A total of 214 combinations of risk/protective factors were observed, and the lifetime risk estimates ranged from 0.35% [95% confidence interval (CI), 0.29-0.42] to 8.78% (95% CI, 7.10-10.9). Among women with lifetime risk ranging from 4% to 9%, 73% had no family history of ovarian cancer; most of these women had a self-reported history of endometriosis.Profiles including the known modifiable protective factors of oral contraceptive use and tubal ligation were associated with a lower lifetime risk of ovarian cancer. Oral contraceptive use and tubal ligation were essentially absent among the women at 4% to 9% lifetime risk.This work demonstrates that there are women in the general population who have a much higher than average lifetime risk of ovarian cancer. Preventive strategies are available. Should effective screening become available, higher than average risk women can be identified.
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Possible Rates of Detection of Neonatal Sepsis Pathogens in the Context of Microbiological Diagnostics in Mothers – Real World Data - Kuld, Raffael; Krauth, Alexander; Kühr, Joachim; Krämer, Janine; Dittrich, Ralf; Häberle, Lothar; Müller, Andreas (Geburtshilfe und Frauenheilkunde, 2023)
Objective The aim of this study was to identify the rate of detection of neonatal sepsis pathogens in maternal microbiological smears. Study Design This is a retrospective study conducted at a Level 1 perinatal center in the context of routine care from 2014 to 2019. For all premature infants and neonates with neonatal sepsis, the neonatal and maternal microbiological findings were examined to see if there was a match. Results During the study period, a total of 948 premature or newborn infants were identified as having a neonatal infection. Among all of the premature or newborn infants, 209 (22%) met the diagnostic criteria for neonatal sepsis; of these, 157 were premature births and 52 were full-term births. We evaluated the microbiological findings for these 209 mother and child pairs. No pathogens were detected in 27 out of 157 mothers of premature infants (17.1%) and in 31 out of 52 mothers of full-term infants (59.6%). In the premature infant group there were pairs with matching pathogens in 30 out of 130 cases (23.1%, 95% CI: 16.1-31.3), and in the full-term infant group there was a match in 4 out of 21 cases (19%, 95% CI: 5.4-41.9). The number needed to test to have a 90% probability of success for pathogen detection varies between 9 and 11 in the most favorable case and 26 and 32 in the least favorable case, depending on the evaluation method. Conclusion In cases of neonatal sepsis, the sepsis-causing pathogen was successfully detected through prior analysis of a maternal smear in 7% of full-term infants and in 19% of premature infants. The number needed to test was relatively high in all groups. The value of maternal smears for identifying neonatal sepsis-causing pathogens needs to be critically questioned.
CRIS-Team Scopus Importer:2023-12-08
Keywords: bacterial infection; infections; normal birth; pregnancy; premature birth

Potential of spiral breast computed tomography to increase patient comfort compared to DM - Wetzl, Matthias; Wenkel, Evelyn; Dietzel, Matthias; Siegler, Lisa; Emons, Julius; Dethlefsen, Ebba; Heindl, Felix; Kuhl, Christiane; Uder, Michael; Ohlmeyer, Sabine (European Journal of Radiology, 2021)
Purpose: To intra-individually compare patient comfort of spiral breast computed tomography (SBCT) versus digital mammography (DM).
CRIS-Team WoS Importer:2022-02-04

Power-MF: Robust fetal QRS detection from non-invasive fetal electrocardiogram recordings - Jäger, Katharina; Nissen, Michael; Rahm, Simone; Titzmann, Adriana; Fasching, Peter; Beilner, Janina; Eskofier, Björn; Leutheuser, Heike (Physiological Measurement, 2024)
Objective. Perinatal asphyxia poses a significant risk to neonatal health, necessitating accurate fetal heart rate monitoring for effective detection and management. The current gold standard, cardiotocography, has inherent limitations, highlighting the need for alternative approaches. The emerging technology of non-invasive fetal electrocardiography shows promise as a new sensing technology for fetal cardiac activity, offering potential advancements in the detection and management of perinatal asphyxia. Although algorithms for fetal QRS detection have been developed in the past, only a few of them demonstrate accurate performance in the presence of noise and artifacts. Approach. In this work, we propose Power-MF, a new algorithm for fetal QRS detection combining power spectral density and matched filter techniques. We benchmark Power-MF against three open-source algorithms on two recently published datasets (Abdominal and Direct Fetal ECG Database: ADFECG, subsets B1 Pregnancy and B2 Labour; Non-invasive Multimodal Foetal ECG-Doppler Dataset for Antenatal Cardiology Research: NInFEA). Main results. Our results show that Power-MF outperforms state-of-the-art algorithms on ADFECG (B1 Pregnancy: 99.5 % ± 0.5 % F1-score, B2 Labour: 98.0 % ± 3.0 % F1-score) and on NInFEA in three of six electrode configurations by being more robust against noise. Significance. Through this work, we contribute to improving the accuracy and reliability of fetal cardiac monitoring, an essential step toward early detection of perinatal asphyxia with the long-term goal of reducing costs and making prenatal care more accessible.<br

Practice-Changing Perspectives regarding Systemic Therapy in Early Breast Cancer: Opinions of German Experts regarding the 17th St. Gallen International Consensus Conference - Kolberg-Liedtke, Cornelia; Lueftner, Diana; Brucker, Sara Y.; Budach, Wilfried; Denkert, Carsten; Fasching, Peter; Haidinger, Renate; Harbeck, Nadia; Huober, Jens; Jackisch, Christian; Janni, Wolfgang; Krug, David; et al. (Breast Care, 2022)
The general topic of this year's 17th St. Gallen (SG) International Consensus Conference on the treatment of patients with early breast cancer (SG-BCC) was "Customizing local and systemic therapies for women with early breast cancer. " This topic considers that each treatment decision must also consider the cancer-specific situation of the individual patient. This year, the votes of the SG-BCC were again discussed taking into account the multidisciplinary German S3 Guidelines and the recommendations of the Breast Cancer Working Group of the AGO (Arbeitsgemeinschaft Gynakologische Onkologie; AGO Mamma). As the international panel of the SG-BCC consists of experts from different countries, the votes do represent an international cross-section of opinions. Therefore, it is useful to discuss the voting results with respect to the German evidence-based treatment guidelines. This publication focuses mainly on systemic treatment.
CRIS-Team WoS Importer:2022-06-17

Precancerous Lesions of the Cervix, Vulva and Vagina According to the 2014 WHO Classification of Tumors of the Female Genital Tract - Reich, O.; Regauer, S.; Marth, C.; Schmidt, D.; Horn, L. -C.; Dannecker, C.; Menton, M.; Beckmann, Matthias (Geburtshilfe und Frauenheilkunde, 2015)
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Preconceptual Counseling, Prenatal Care and peripartum Management of Female Patients with Ullrich-Turner Syndrome and a High-risk cardiovascular Profile - Pontones, Constanza; Lubrich, Hannah; Schwenke, E.; Cupisti, Susanne; Dittrich, Ralf; Kehl, Sven; Beckmann, Matthias; Fahlbusch, C.; Oppelt, Patricia (GEBURTSHILFE UND FRAUENHEILKUNDE, 2020)
CRIS-Team WoS Importer:2020-10-30

PRECYCLE Impact of CANKADO-based eHealth-support on quality of life in metastatic breast cancer patients treated with palbociclib and endocrine therapy - Degenhardt, T.; Fasching, Peter; Lueftner, D.; Mueller, V.; Thomssen, C.; Schem, C.; Witzel, I.; Decker, T.; Tesch, H.; Kuemmel, S.; Uleer, C.; Wuerstlein, R.; et al. (ANNALS OF ONCOLOGY, 2019)
CRIS-Team WoS Importer:2019-11-08

PRECYCLE: multicenter, randomized phase IV intergroup trial to evaluate the impact of eHealth-based patient-reported outcome (PRO) assessment on quality of life in patients with hormone receptor positive, HER2 negative locally advanced or metastatic breast cancer treated with palbociclib and an aromatase inhibitor or palbociclib and fulvestrant - Degenhardt, Tom; Fasching, Peter; Lüftner, Diana; Müller, Volkmar; Thomssen, Christoph; Schem, Christian; Witzel, Isabell; Decker, Thomas; Tesch, Hans; Kümmel, Sherko; Uleer, Christoph; Wuerstlein, Rachel; et al. (Trials, 2023)
Background: Efficacy and quality of life (QoL) are key criteria for therapy selection in metastatic breast cancer (MBC). In hormone receptor positive (HR +) human epidermal growth factor receptor 2 negative (HER2 −) MBC, addition of targeted oral agents such as everolimus or a cycline-dependent kinase 4/6 (CDK 4/6) inhibitor (e.g., palbociclib, ribociclib, abemaciclib) to endocrine therapy substantially prolongs progression-free survival and in the case of a CDK 4/6i also overall survival. However, the prerequisite is adherence to therapy over the entire course of treatment. However, particularly with new oral drugs, adherence presents a challenge to disease management. In this context, factors influencing adherence include maintaining patients’ satisfaction and early detection/management of side effects. New strategies for continuous support of oncological patients are needed. An eHealth-based platform can help to support therapy management and physician–patient interaction. Methods: PreCycle is a multicenter, randomized, phase IV trial in HR + HER2 − MBC. All patients (n = 960) receive the CDK 4/6 inhibitor palbociclib either in first (62.5%) or later line (37.5%) together with endocrine therapy (AI, fulvestrant) according to national guidelines. PreCycle evaluates and compares the time to deterioration (TTD) of QoL in patients supported by eHealth systems with substantially different functionality: CANKADO active vs. inform. CANKADO active is the fully functional CANKADO-based eHealth treatment support system. CANKADO inform is a CANKADO-based eHealth service with a personal login, documentation of daily drug intake, but no further functions. To evaluate QoL, the FACT-B questionnaire is completed at every visit. As little is known about relationships between behavior (e.g., adherence), genetic background, and drug efficacy, the trial includes both patient-reported outcome and biomarker screening for discovery of forecast models for adherence, symptoms, QoL, progression free survival (PFS), and overall survival (OS). Discussion: The primary objective of PreCycle is to test the hypothesis of superiority for time to deterioration (TTD) in terms of DQoL = “Deterioration of quality of life” (FACT-G scale) in patients supported by an eHealth therapy management system (CANKADO active) versus in patients merely receiving eHealth-based information (CANKADO inform). EudraCT Number: 2016–004191-22
CRIS-Team Scopus Importer:2023-06-02
Keywords: CDK 4/6 inhibitor; eHealth; Endocrine therapy; Metastatic breast cancer; Patient-reported outcome; Quality of life

PredictCBC-2.0: a contralateral breast cancer risk prediction model developed and validated in 200,000 patients - Giardiello, Daniele; Hooning, Maartje J.; Hauptmann, Michael; Keeman, Renske; Heemskerk-Gerritsen, B. A. M.; Becher, Heiko; Blomqvist, Carl; Bojesen, Stig E.; Bolla, Manjeet K.; Camp, Nicola J.; Czene, Kamila; Devilee, Peter; et al. (Breast Cancer Research, 2022)
Background: Prediction of contralateral breast cancer (CBC) risk is challenging due to moderate performances of the known risk factors. We aimed to improve our previous risk prediction model (PredictCBC) by updated follow-up and including additional risk factors. Methods: We included data from 207,510 invasive breast cancer patients participating in 23 studies. In total, 8225 CBC events occurred over a median follow-up of 10.2 years. In addition to the previously included risk factors, PredictCBC-2.0 included CHEK2 c.1100delC, a 313 variant polygenic risk score (PRS-313), body mass index (BMI), and parity. Fine and Gray regression was used to fit the model. Calibration and a time-dependent area under the curve (AUC) at 5 and 10 years were assessed to determine the performance of the models. Decision curve analysis was performed to evaluate the net benefit of PredictCBC-2.0 and previous PredictCBC models. Results: The discrimination of PredictCBC-2.0 at 10 years was higher than PredictCBC with an AUC of 0.65 (95% prediction intervals (PI) 0.56–0.74) versus 0.63 (95%PI 0.54–0.71). PredictCBC-2.0 was well calibrated with an observed/expected ratio at 10 years of 0.92 (95%PI 0.34–2.54). Decision curve analysis for contralateral preventive mastectomy (CPM) showed the potential clinical utility of PredictCBC-2.0 between thresholds of 4 and 12% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. Conclusions: Additional genetic information beyond BRCA1/2 germline mutations improved CBC risk prediction and might help tailor clinical decision-making toward CPM or alternative preventive strategies. Identifying patients who benefit from CPM, especially in the general breast cancer population, remains challenging.
CRIS-Team Scopus Importer:2022-11-04
Keywords: BCAC; BRCA1/2 germline mutation; Breast Cancer Association Consortium; Breast cancer genetic predisposition; Clinical decision-making; Contralateral breast cancer; Contralateral preventive mastectomy; Polygenic risk score; Prediction performance; Risk prediction

Predicting attention deficit hyperactivity disorder using pregnancy and birth characteristics - Schwenke, Eva; Fasching, Peter; Faschingbauer, Florian; Pretscher, Jutta; Kehl, Sven; Peretz, Roberta; Keller, Andrea; Häberle, Lothar; Eichler, Anna; Irlbauer-Müller, Viktoria; Dammer, Ulf; Beckmann, Matthias; et al. (Archives of Gynecology and Obstetrics, 2018)
PURPOSE: The aim of this study was to evaluate maternal, prenatal, perinatal, and postpartum parameters as risk factors for the later development of an attention deficit hyperactivity disorder (ADHD) in the child. METHODS: Women who had given birth at Erlangen University Hospital between 1996 and 1999 were sent a questionnaire in 2009. The results of the questionnaire were correlated with the prospectively collected data for the births in 1996-1999. RESULTS: A total of 573 mother and child pairs were analyzed. Forty-four of the mothers reported that their child had ADHD (7.7%). No significant associations were found for the following parameters: mother's age; mother's educational level; number of the pregnancy; maternal weight before and at the end of pregnancy; mother's height; alcohol consumption during pregnancy; mode of delivery; gestational week; birthweight; umbilical artery blood values; Apgar score at 5 and 10 min; or breastfeeding. The parameters of smoking in pregnancy and an Apgar score lower than 7 after 1 min were significantly associated with a risk for later development of ADHD. CONCLUSIONS: This analysis of maternal, prenatal, perinatal, and postnatal parameters found that smoking in pregnancy and a low Apgar score 1 min after birth are associated with a significantly greater risk for the development of ADHD. Beyond the question of the causal mechanism involved, this is a relevant finding, since smoking during pregnancy is a preventable risk factor.
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Predicting mammographic density with linear ultrasound transducers - Behrens, Annika; Fasching, Peter; Schwenke, Eva; Gaß, Paul; Häberle, Lothar; Heindl, Felix; Heusinger, Katharina; Lotz, Laura; Lubrich, Hannah; Preuß, Caroline; Schneider, Michael; Schulz-Wendtland, Rüdiger; et al. (European Journal of Medical Research, 2023)
Background: High mammographic density (MD) is a risk factor for the development of breast cancer (BC). Changes in MD are influenced by multiple factors such as age, BMI, number of full-term pregnancies and lactating periods. To learn more about MD, it is important to establish non-radiation-based, alternative examination methods to mammography such as ultrasound assessments. Methods: We analyzed data from 168 patients who underwent standard-of-care mammography and performed additional ultrasound assessment of the breast using a high-frequency (12 MHz) linear probe of the VOLUSON® 730 Expert system (GE Medical Systems Kretztechnik GmbH & Co OHG, Austria). Gray level bins were calculated from ultrasound images to characterize mammographic density. Percentage mammographic density (PMD) was predicted by gray level bins using various regression models. Results: Gray level bins and PMD correlated to a certain extent. Spearman’s ρ ranged from − 0.18 to 0.32. The random forest model turned out to be the most accurate prediction model (cross-validated R 2, 0.255). Overall, ultrasound images from the VOLUSON® 730 Expert device in this study showed limited predictive power for PMD when correlated with the corresponding mammograms. Conclusions: In our present work, no reliable prediction of PMD using ultrasound imaging could be observed. As previous studies showed a reasonable correlation, predictive power seems to be highly dependent on the device used. Identifying feasible non-radiation imaging methods of the breast and their predictive power remains an important topic and warrants further evaluation. Trial registration 325-19 B (Ethics Committee of the medical faculty at Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Germany).
CRIS-Team Scopus Importer:2023-10-13
Keywords: Breast cancer risk; Percent mammographic density; Ultrasound

Predicting prognosis of breast cancer patients with brain metastases in the BMBC registry: Comparison of three different - Riecke, K.; Mueller, V.; Neunhoeffer, T.; Weide, R.; Schmidt, M.; Park-Simon, T. -W.; Mundhenke, Christoph; Polasik, A.; Hesse, T.; Luebbe, K.; Laakmann, E.; Thill, M.; et al. (ANNALS OF ONCOLOGY, 2020)
CRIS-Team WoS Importer:2020-06-26

Predicting prognosis of breast cancer patients with brain metastases in the BMBC registry—comparison of three different GPA prognostic scores - Riecke, Kerstin; Müller, Volkmar; Weide, Rudolf; Schmidt, Marcus; Park‐simon, Tjoung Won; Möbus, Volker; Mundhenke, Christoph; Polasik, Arkadius; Lübbe, Kristina; Hesse, Tobias; Laakmann, Elena; Thill, Marc; et al. (Cancers, 2021)
Several scores have been developed in order to estimate the prognosis of patients with brain metastases (BM) by objective criteria. The aim of this analysis was to validate all three published graded‐prognostic‐assessment (GPA)‐scores in a subcohort of 882 breast cancer (BC) patients with BM in the Brain Metastases in the German Breast Cancer (BMBC) registry. The median age at diagnosis of BM was 57 years. All in all, 22.3% of patients (n = 197) had triple‐negative, 33.4% (n = 295) luminal A like, 25.1% (n = 221) luminal B/HER2‐enriched like and 19.2% (n = 169) HER2 positive like BC. Age ≥60 years, evidence of extracranial metastases (ECM), higher number of BM, triple‐negative subtype and low Karnofsky‐Performance‐Status (KPS) were all associated with worse overall survival (OS) in univariate analysis (p < 0.001 each). All three GPA‐scores were associated with OS. The breast‐GPA showed the highest probability of classifying patients with survival above 12 months in the best prognostic group (specificity 68.7% compared with 48.1% for the updated breast‐GPA and 21.8% for the original GPA). Sensitivities for predicting 3 months survival were very low for all scores. In this analysis, all GPA‐scores showed only moderate diagnostic accuracy in predicting the OS of BC patients with BM.
CRIS-Team Scopus Importer:2021-03-05
Keywords: Brain metastases; Breast cancer; Prognostic scores

Predicting prognosis of breast cancer patients with brain metastases in the BMBC registry - comparison of three different prognostic scores - Riecke, K.; Mueller,; Neunhoeffer, T.; Weide, R.; Schmidt, M.; Park-Simon, T. W.; Mundhenke, Christoph; Polasik, A.; Hesse, T.; Luebbe, K.; Laakmann, E.; Thill, M.; et al. (GEBURTSHILFE UND FRAUENHEILKUNDE, 2020)
CRIS-Team WoS Importer:2020-10-30

Predicting Triple-Negative Breast Cancer Subtype Using Multiple Single Nucleotide Polymorphisms for Breast Cancer Risk and Several Variable Selection Methods - Häberle, Lothar; Hein, Alexander; Rübner, Matthias; Schneider, Michael; Ekici, Arif Bülent; Gaß, Paul; Hartmann, Arndt; Schulz-Wendtland, Rüdiger; Beckmann, Matthias; Lo, Wing-Yee; Schroth, Werner; Brauch, Hiltrud; et al. (Geburtshilfe und Frauenheilkunde, 2017)
Studies of triple-negative breast cancer have recently been extending the inclusion criteria and incorporating additional molecular markers into the selection criteria, opening up scope for targeted therapies. The screening phases required for studies of this type are often prolonged, since the process of determining the molecular subtype and carrying out additional biomarker assessment is time-consuming. Parameters such as germline genotypes capable of predicting the molecular subtype before it becomes available from pathology might be helpful for treatment planning and optimizing the timing and cost of screening phases. This appears to be feasible, as rapid and low-cost genotyping methods are becoming increasingly available. The aim of this study was to identify single nucleotide polymorphisms (SNPs) for breast cancer risk capable of predicting triple negativity, in addition to clinical predictors, in breast cancer patients.This cross-sectional observational study included 1271 women with invasive breast cancer who were treated at a university hospital. A total of 76 validated breast cancer risk SNPs were successfully genotyped. Univariate associations between each SNP and triple negativity were explored using logistic regression analyses. Several variable selection and regression techniques were applied to identify a set of SNPs that together improve the prediction of triple negativity in addition to the clinical predictors of age at diagnosis and body mass index (BMI). The most accurate prediction method was determined by cross-validation.The SNP rs10069690 (TERT, CLPTM1L) was the only significant SNP (corrected p = 0.02) after correction of p values for multiple testing in the univariate analyses. This SNP and three additional SNPs from the genes RAD51B, CCND1, and FGFR2 were selected for prediction of triple negativity. The addition of these SNPs to clinical predictors increased the cross-validated area under the curve (AUC) from 0.618 to 0.625. Age at diagnosis was the strongest predictor, stronger than any genetic characteristics.Prediction of triple-negative breast cancer can be improved if SNPs associated with breast cancer risk are added to a prediction rule based on age at diagnosis and BMI. This finding could be used for prescreening purposes in complex molecular therapy studies for triple-negative breast cancer.
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Prediction and clinical utility of a contralateral breast cancer risk model - Giardiello, Daniele; Steyerberg, Ewout W.; Hauptmann, Michael; Adank, Muriel A.; Akdeniz, Delal; Blomqvist, Carl; Bojesen, Stig E.; Bolla, Manjeet K.; Brinkhuis, Mariël; Chang-Claude, Jenny; Czene, Kamila; Devilee, Peter; et al. (Breast Cancer Research, 2019)
BACKGROUND: Breast cancer survivors are at risk for contralateral breast cancer (CBC), with the consequent burden of further treatment and potentially less favorable prognosis. We aimed to develop and validate a CBC risk prediction model and evaluate its applicability for clinical decision-making. METHODS: We included data of 132,756 invasive non-metastatic breast cancer patients from 20 studies with 4682 CBC events and a median follow-up of 8.8 years. We developed a multivariable Fine and Gray prediction model (PredictCBC-1A) including patient, primary tumor, and treatment characteristics and BRCA1/2 germline mutation status, accounting for the competing risks of death and distant metastasis. We also developed a model without BRCA1/2 mutation status (PredictCBC-1B) since this information was available for only 6% of patients and is routinely unavailable in the general breast cancer population. Prediction performance was evaluated using calibration and discrimination, calculated by a time-dependent area under the curve (AUC) at 5 and 10 years after diagnosis of primary breast cancer, and an internal-external cross-validation procedure. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility. RESULTS: In the multivariable model, BRCA1/2 germline mutation status, family history, and systemic adjuvant treatment showed the strongest associations with CBC risk. The AUC of PredictCBC-1A was 0.63 (95% prediction interval (PI) at 5 years, 0.52-0.74; at 10 years, 0.53-0.72). Calibration-in-the-large was -0.13 (95% PI: -1.62-1.37), and the calibration slope was 0.90 (95% PI: 0.73-1.08). The AUC of Predict-1B at 10 years was 0.59 (95% PI: 0.52-0.66); calibration was slightly lower. Decision curve analysis for preventive contralateral mastectomy showed potential clinical utility of PredictCBC-1A between thresholds of 4-10% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. CONCLUSIONS: We developed a reasonably calibrated model to predict the risk of CBC in women of European-descent; however, prediction accuracy was moderate. Our model shows potential for improved risk counseling, but decision-making regarding contralateral preventive mastectomy, especially in the general breast cancer population where limited information of the mutation status in BRCA1/2 is available, remains challenging.
CRIS-Team Scopus Importer:2019-12-31
Keywords: BRCA mutation carriers; Clinical decision-making; Contralateral breast cancer; Risk prediction model

Prediction of breast cancer risk based on profiling with common genetic variants - Mavaddat, Nasim; Pharoah, Paul D. P.; Michailidou, Kyriaki; Tyrer, Jonathan; Brook, Mark N.; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Dunning, Alison M.; Shah, Mitul; Luben, Robert; Brown, Judith; et al. (Journal of the National Cancer Institute, 2015)
Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking.We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates.There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer.The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this repor
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Prediction of contralateral breast cancer: external validation of risk calculators in 20 international cohorts - Giardiello, Daniele; Hauptmann, Michael; Steyerberg, Ewout W.; Adank, Muriel A.; Akdeniz, Delal; Blom, Jannet C.; Blomqvist, Carl; Bojesen, Stig E.; Bolla, Manjeet K.; Brinkhuis, Mariel; Chang-Claude, Jenny; Czene, Kamila; et al. (Breast Cancer Research and Treatment, 2020)
Background Three tools are currently available to predict the risk of contralateral breast cancer (CBC). We aimed to compare the performance of the Manchester formula, CBCrisk, and PredictCBC in patients with invasive breast cancer (BC). Methods We analyzed data of 132,756 patients (4682 CBC) from 20 international studies with a median follow-up of 8.8 years. Prediction performance included discrimination, quantified as a time-dependent Area-Under-the-Curve (AUC) at 5 and 10 years after diagnosis of primary BC, and calibration, quantified as the expected-observed (E/O) ratio at 5 and 10 years and the calibration slope. Results The AUC at 10 years was: 0.58 (95% confidence intervals [CI] 0.57-0.59) for CBCrisk; 0.60 (95% CI 0.59-0.61) for the Manchester formula; 0.63 (95% CI 0.59-0.66) and 0.59 (95% CI 0.56-0.62) for PredictCBC-1A (for settings where BRCA1/2 mutation status is available) and PredictCBC-1B (for the general population), respectively. The E/O at 10 years: 0.82 (95% CI 0.51-1.32) for CBCrisk; 1.53 (95% CI 0.63-3.73) for the Manchester formula; 1.28 (95% CI 0.63-2.58) for PredictCBC-1A and 1.35 (95% CI 0.65-2.77) for PredictCBC-1B. The calibration slope was 1.26 (95% CI 1.01-1.50) for CBCrisk; 0.90 (95% CI 0.79-1.02) for PredictCBC-1A; 0.81 (95% CI 0.63-0.99) for PredictCBC-1B, and 0.39 (95% CI 0.34-0.43) for the Manchester formula. Conclusions Current CBC risk prediction tools provide only moderate discrimination and the Manchester formula was poorly calibrated. Better predictors and re-calibration are needed to improve CBC prediction and to identify low- and high-CBC risk patients for clinical decision-making.
CRIS-Team WoS Importer:2020-04-24

Prediction of pathological complete response after neoadjuvant chemotherapy for HER2-negative breast cancer patients with routine immunohistochemical markers. - Häberle, Lothar; Erber, Ramona; Gaß, Paul; Hein, Alexander; Niklos, Melitta; Volz, Bernhard; Hack, Carolin; Schulz-Wendtland, Rüdiger; Hübner, Hanna; Goossens, Chloe; Christgen, Matthias; Dörk, Thilo; et al. (Breast Cancer Research, 2025)
BACKGROUND: Pathological complete response (pCR) is an established surrogate marker for prognosis in patients with breast cancer (BC) after neoadjuvant chemotherapy. Individualized pCR prediction based on clinical information available at biopsy, particularly immunohistochemical (IHC) markers, may help identify patients who could benefit from preoperative chemotherapy. METHODS: Data from patients with HER2-negative BC who underwent neoadjuvant chemotherapy from 2002 to 2020 (n = 1166) were used to develop multivariable prediction models to estimate the probability of pCR (pCR-prob). The most precise model identified using cross-validation was implemented in an online calculator and a nomogram. Associations among pCR-prob, prognostic IHC3 distant recurrence and disease-free survival were studied using Cox regression and Kaplan-Meier analyses. The model's utility was further evaluated in independent external validation cohorts. RESULTS: 273 patients (23.4%) achieved a pCR. The most precise model had across-validated area under the curve (AUC) of 0.84, sensitivity of 0.82, and specificity of 0.71. External validation yielded AUCs between 0.75 (95% CI, 0.70-0.81) and 0.83 (95% CI, 0.78-0.87). The higher the pCR-prob, the greater the prognostic impact of pCR status (presence/absence): hazard ratios decreased from 0.55 (95% central range, 0.07-1.77) at 0% to 0.20 (0.11-0.31) at 50% pCR-prob. Combining pCR-prob and IHC3 score further improved the precision of disease-free survival prognosis. CONCLUSIONS: A pCR prediction model for neoadjuvant therapy decision-making was established. Combining pCR and recurrence prediction allows identification of not only patients who benefit most from neoadjuvant chemotherapy, but also patients with a very unfavorable prognosis for whom alternative treatment strategies should be considered.
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Prediction of pathological complete response and prognosis in patients with neoadjuvant treatment for triple-negative breast cancer - Gaß, Paul; Lux, Michael P.; Rauh, Claudia; Hein, Alexander; Bani, Mayada; Fießler, Cornelia; Hartmann, Arndt; Häberle, Lothar; Pretscher, Jutta; Erber, Ramona; Wachter, David; Schulz-Wendtland, Rüdiger; et al. (BMC Cancer, 2018)
BACKGROUND: It has been reported that pathological complete response is an important surrogate marker for disease-free survival and overall survival in patients with triple-negative breast cancer. This study investigates predictors of the response to neoadjuvant platinum-based or anthracycline-based treatment, and of the prognosis, in patients with triple-negative breast cancer. METHODS: A total of 121 patients with triple-negative breast cancer received neoadjuvant treatment with either platinum or anthracycline between 2008 and 2013. Pathological complete response was assessed relative to different treatments using logistic regression models with age, clinical tumor stage, grading, and Ki-67 as predictors and interaction terms, to obtain adjusted and subgroup-specific results. The impact of the pathological complete response rate on disease-free survival and overall survival was also analyzed. RESULTS: The pathological complete response rate was higher after platinum/taxane treatment compared with anthracycline/taxane (50.0% vs. 41.8%), but this was not significant in the adjusted analysis (OR 1.44; 95% CI, 0.68 to 3.09). A high histological grade (G3) was a predictor for higher pathological complete response in platinum-based therapy (OR 2.27; 95% CI, 1.00 to 5.30). The effect of neoadjuvant chemotherapy on pathological complete response was significantly different for G1-2 vs. G3 (Pinteraction = 0.013), and additional subgroup-specific differences were noted. Pathological complete response was a predictor for improved disease-free survival and overall survival in both treatment groups, with and without platinum chemotherapy. CONCLUSIONS: This retrospective study of patients with triple-negative breast cancer adds to the evidence that the treatment effect of platinum may be greatest particularly in G3 tumors. In addition, the effect of pathological complete response on the prognosis does not depend on the treatment used.
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Preexisting musculoskeletal burden and its development under letrozole treatment in early breast cancer patients - Nabieva, Naiba; Häberle, Lothar; Brucker, Sara Y.; Janni, Wolfgang; Volz, Bernhard; Löhberg, Christian; Hartkopf, Andreas D.; Walter, Christina Barbara; Baake, Gerold; Fridman, Alexander; Malter, Wolfram; Wuerstlein, Rachel; et al. (International Journal of Cancer, 2019)
One of the most common adverse events (AEs) occurring during treatment with aromatase inhibitors (AIs) is musculoskeletal pain. The aim of our study was to analyze the influence of preexisting muscle/limb pain and joint pain on the development of AI-induced musculoskeletal AEs. Women eligible for upfront adjuvant endocrine therapy with letrozole were included in the PreFace study, a multicenter phase IV trial. During the first treatment year, they were asked to record musculoskeletal AEs monthly by answering questions regarding pain symptoms and rating the pain intensity on a numeric rating scale from 0 (no pain) to 10 (very strong pain). Pain values were compared using nonparametric statistical tests. Overall, 1,416 patients were evaluable. The average pain value over all time points in women with preexisting muscle/limb pain was 4.3 (median 4.3); in those without preexisting pain, it was 2.0 (median 1.7). In patients without preexisting muscle/limb pain, pain levels increased relatively strongly within the first 6 months (mean increase +0.9, p < 0.00001) in comparison with those with preexisting pain (mean increase +0.3, p < 0.001), resulting in a statistically significant difference (p < 0.00001) between the two groups. The development of joint pain was similar in the two groups. Women without preexisting muscle/limb pain or joint pain have the greatest increase in pain after the start of adjuvant AI therapy. Women with preexisting pain have significantly higher pain values. The main increase in pain values takes place during the first 6 months of treatment.
Keywords: aromatase inhibitor; arthralgia/joint pain; breast cancer; endocrine treatment/therapy; letrozole; myalgia/muscle and limb pain

Pregnancies and live births after 20 transplantations of cryopreserved ovarian tissue in a single center - Dittrich, Ralf; Hackl, Janina; Lotz, Laura; Hoffmann, Inge; Beckmann, Matthias (Fertility and Sterility, 2015)
To report the results of 20 orthotopic retransplantations of cryopreserved ovarian tissue after cancer treatment.Retrospective analysis.Tertiary gynecology department.Twenty patients with malignant disease: 11 with hematological malignancies (55%), four with breast cancer (20%), three with anal cancer (15%), and two with ovarian cancer (10%); the mean age before oncological treatment was 30.5 years.Ovarian tissue was removed from patients in various centers in Germany in 2005-2009. All patients received chemotherapy and/or radiotherapy. Afterward, 17 patients had complete premature ovarian insufficiency, while three still showed some ovarian activity. Overnight transportation of tissue before freezing was necessary in eight cases. Cryopreservation followed slow freezing protocols in all cases. Retransplantation was performed at Erlangen University Hospital 3.75 years after extraction, on average. Thawed tissue was transplanted into a peritoneal pouch in the broad ligament region, below the tube, in 16 cases. Fragments were sutured both onto the remaining ovary and into a peritoneal pouch in four cases.Restoration of ovarian activity, pregnancy, birth.Ovarian activity resumed in all patients except one. Seven patients conceived, with one miscarriage and four ongoing pregnancies. Four patients delivered healthy babies. One pregnancy and live birth after oocyte donation need to be considered separately.These data clearly demonstrate that preserving fertility by cryopreserving ovarian tissue is a successful and safe clinical option that can be considered for selected cancer patients.
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Pregnancy and Obstetrical Outcomes in Women Over 40 Years of Age - Dietl, A.; Cupisti, S.; Beckmann, Matthias; Schwab, M.; Zollner, U. (Geburtshilfe und Frauenheilkunde, 2015)
Introduction: Delayed childbearing is increasing, and advanced maternal age has been associated with an increased risk of obstetrical complications. The purpose of this study was to evaluate pregnancy outcomes in women with advanced maternal age (>= 40 years). Methods: Maternal and obstetrical data were collected from the Department of Obstetrics and Gynecology of the University of Wuerzburg for the period from 2006 to 2011. In this retrospective analysis we compared the outcomes for women aged >= 40 years (n = 405) with those of three younger subgroups (I: < 30 y; II: 30-34 y; III: 35-39 y). Results: Pregnant women older than 40 years had more chronic diseases such as hypertension, needed medical treatment more frequently and had a higher thrombosis risk. Pregnancy-induced diseases such as gestational diabetes, preeclampsia and pregnancy-associated hypertension occurred more often in women >= 40 years of age. Compared to mothers who were younger than 30 years, primiparous women >= 40 years had a more than four times higher overall cesarean section rate and four times higher elective cesarean section rate. Furthermore, they required longer hospital stays, both after cesarean section and after vaginal delivery. The preterm birth rate (<= 32 weeks of gestation) was similar across the different age groups. Conclusions: The outcomes of pregnancy and childbirth and for newborns born to women >= 40 years did not vary significantly from those of younger women if the following conditions were met: a) pre-existing chronic diseases were treated medically and dietetically; b) pregnancy-induced morbidity was monitored regularly and controlled medically; c) women attended regular prenatal check-ups; d) a healthy lifestyle was adhered to during pregnancy, and e) delivery occurred in a perinatal center.
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Preliminary observations on whole-ovary xenotransplantation as an experimental model for fertility preservation - Nichols-Burns, Stephanie M.; Lotz, Laura; Schneider, Heike; Adamek, Edyta; Daniel, Christoph; Stief, Andrea; Grigo, Christina; Klump, Dorothee; Hoffmann, Inge; Beckmann, Matthias; Dittrich, Ralf (Reproductive Biomedicine Online, 2014)
Ovarian tissue preservation and retransplantation is a promising strategy to restore fertility in cancer survivors. Ischaemia accompanying ovarian tissue grafting, however, can lead to significant follicle loss. Transplantation of the whole ovary by vascular anastomosis has been considered as an alternative to prevent widespread ischaemic damage. In this study, the feasibility and function of transplanting whole ovary with intact vasculature were evaluated, with the goal of developing a xenograft model for studies using donated human ovaries. Whole-swine ovaries with vascular pedicles were perfused and transplanted as intact ovaries by anastomosis into irradiated ovariectomized nude rats (n = 10). The observation period was between 1 and 4 weeks. Fresh swine ovaries served as controls (n = 10). Ovarian stroma and follicle populations were assessed through histological examination in both transplanted and control ovaries. Most of the transplanted whole ovaries (n = 6) maintained stromal quality and all preantral follicle classes were represented, although follicle numbers decreased compared with fresh control. Four transplanted ovaries were fibrotic after 1-4 weeks within the nude rat. Our results demonstrate transplantation of whole-pig ovary into nude rats is possible and support development of this xenograft model system for human studies.
EVALuna2:15573

Prenatal alcohol exposure and the facial phenotype in adolescents: A study based on meconium ethyl glucuronide - Maschke, Janina; Roetner, Jakob; Goecke, Tamme; Fasching, Peter; Beckmann, Matthias; Kratz, Oliver; Moll, Gunther; Lenz, Bernd; Kornhuber, Johannes; Eichler, Anna (Brain Sciences, 2021)
Here, we explore the effects of prenatal alcohol exposure (PAE) in adolescence. We investigated associations between meconium ethyl glucoronide (EtG) and facial malformation. For 29 children (66/63 male/female; M = 13.3, SD = 0.32, 12–14 years), PAE was implemented by newborn meconium EtG and maternal self-reports during the third trimester. Cognitive development was operationalized by standardized scores (WISC V). The EtG cut-off values were set at ≥10 ng/g (n = 32, 24.8% EtG10+) and ≥112 ng/g (n = 20, 15.5% EtG112+). The craniofacial shape was measured using FAS Facial Photographic Analysis Software. EtG10+− and EtG112+-affected children exhibited a shorter palpebral fissure length (p = 0.031/p = 0.055). Lip circularity was smaller in EtG112+-affected children (p = 0.026). Maternal self-reports were not associated (p > 0.164). Lip circularity correlated with fluid reasoning (EtG10+ p = 0.031; EtG112+ p = 0.298) and working memory (EtG10+ p = 0.084; EtG112+ p = 0.144). The present study demonstrates visible effects of the facial phenotype in exposed adolescents. Facial malformation was associated with a child’s cognitive performance in the alcohol-exposed group. The EtG biomarker was a better predictor than maternal self-reports.
CRIS-Team Scopus Importer:2021-03-19
Keywords: Alcohol; Biomarker; Craniofacial shape; Ethyl glucuronide (EtG); Facial malformations; Inner canthal distance; Intrauterine alcohol exposure; Lip circularity; Meconium; Palpebral fissure length

Prenatal Alcohol Exposure Is Associated With Adverse Cognitive Effects and Distinct Whole-Genome DNA Methylation Patterns in Primary School Children - Frey, Silke; Eichler, Anna; Stonawski, Valeska; Kriebel, Jennifer; Wahl, Simone; Gallati, Sabina; Goecke, Tamme W.; Fasching, Peter A.; Beckmann, Matthias W.; Kratz, Oliver; Moll, Gunther; Heinrich, Hartmut; et al. (Frontiers in Behavioral Neuroscience, 2018)
Prenatal alcohol exposure (PAE) is known to elicit a broad range of systemic effects, including neurophysiological alterations that result in adverse behavioral and cognitive outcomes. However, molecular pathways underlying these long-term intrauterine effects remain to be investigated. Here, we tested a hypothesis that PAE may lead to epigenetic alterations to the DNA resulting in attentional and cognitive alterations of the children. We report the results of the study that included 156 primary school children of the Franconian Cognition and Emotion Studies (FRANCES) cohort which were tested for an objective marker of PAE, ethyl glucuronide (EtG) in meconium at birth. Thirty-two newborns were found to be exposed to alcohol with EtG values above 30 ng/g (EtG+). Previously we described PAE being associated with lower IQ and smaller amplitude of the event-related potential component P3 in go trials (Go-P3), which indicates a reduced capacity of attentional resources. Whole-genome methylation analysis of the buccal cell DNA revealed 193 differentially methylated genes in children with positive meconium EtG, that were clustered into groups involved in epigenetic modifications, neurodegeneration, neurodevelopment, axon guidance and neuronal excitability. Furthermore, we detected mediation effects of the methylation changes in DPP10 and SLC16A9 genes on the EtG related cognitive and attention-related deficits. Our results suggest that system-wide epigenetic changes are involved in long-term effects of PAE. In particular, we show an epigenetic mediation of PAE effects on cognition and attention-related processes.
EVALuna2:36368

Prenatal and adult androgen activities in alcohol dependence - Lenz, Bernd; Mühle, Christiane; Braun, B.; Weinland, C.; Bouna-Pyrrou, Polyxeni; Behrens, Juliane; Kubis, S.; Mikolaiczik, Katrin; Muschler, M. -R.; Saigali, Sarah; Sibach, M.; Tanovska, P.; et al. (Acta Psychiatrica Scandinavica, 2017)
OBJECTIVE: Alcohol dependence is more prevalent in men than in women. The evidence for how prenatal and adult androgens influence alcohol dependence is limited. We investigated the effects of prenatal and adult androgen activity on alcohol dependence. Moreover, we studied how the behaviours of pregnant women affect their children's prenatal androgen load. METHOD: We quantified prenatal androgen markers (e.g., second-to-fourth finger length ratio [2D : 4D]) and blood androgens in 200 early-abstinent alcohol-dependent in-patients and 240 controls (2013-2015, including a 12-month follow-up). We also surveyed 134 women during pregnancy (2005-2007) and measured the 2D : 4D of their children (2013-2016). RESULTS: The prenatal androgen loads were higher in the male alcohol-dependent patients compared to the controls (lower 2D : 4D, P = 0.004) and correlated positively with the patients' liver transaminase activities (P < 0.001) and alcohol withdrawal severity (P = 0.019). Higher prenatal androgen loads and increasing androgen levels during withdrawal predicted earlier and more frequent 12-month hospital readmission in alcohol-dependent patients (P < 0.005). Moreover, stress levels (P = 0.002), alcohol (P = 0.010) and tobacco consumption (P = 0.017), and lifetime stressors (P = 0.019) of women during pregnancy related positively to their children's prenatal androgen loads (lower 2D : 4D). CONCLUSION: Androgen activities in alcohol-dependent patients and behaviours of pregnant women represent novel preventive and therapeutic targets of alcohol dependence.
EVALuna2:33408

Prenatal Androgen Influence on Addictive Behaviour in Adolescence Vorgeburtlicher Androgen- einfluss auf süchtiges Verhalten in der Adoleszenz - Lenz, Bernd; Eichler, Anna; Buchholz, Verena Nadine; Fasching, Peter; Kornhuber, Johannes (Sucht, 2021)
Background: Men consume alcohol, tobacco, and illicit drugs more often than women, and they are more prone to pathological gambling and addictive internet gaming. These sex differences are already found during adolescence. The consumption patterns are related to externalizing behavior. In addition to social influences, biological factors play a central role in the development of these differences between men and women. Prenatal exposure to androgens and estrogens shape the brain development with functional and structural effects that persist into adulthood. Intrauterine sex hormone exposure is related to maternal risk factors such as stress and substance use. Aim: In this narrative review, we discuss the potential impact of prenatal androgen exposure in the womb on the development of addictive behaviors and self-regulation in later life. In recent years, this issue has been addressed by animal experiments with direct modulation of prenatal androgenization and clinical association studies based on biomarkers such as the second-to-fourth finger lengths ratio (2D:4D). Results: The available body of literature suggests that reinforced brain androgenization during the intrauterine development increases the risk for addictive behaviors and deficits in self-regulation capacity in later life. Finally, we also discuss prevention strategies during pregnancy targeting this model and refer to the Maternal Health and Infant Development in the Follow-up after Pregnancy and a Mindfulness Intervention study. This investigation is a subproject of the IMAC-Mind research collaborative project to improve mental health and reduce addiction risk in childhood and adolescence through mindfulness.
CRIS-Team Scopus Importer:2021-12-24
Keywords: addiction; adolescence; dependence; prenatal development; testosterone

Prenatal Correction of X-Linked Hypohidrotic Ectodermal Dysplasia - Schneider, Holm; Faschingbauer, Florian; Schuepbach-Mallepell, Sonia; Koerber, Iris; Wohlfart, Sigrun; Dick, Angela; Wahlbuhl, Mandy; Kowalczyk-Quintas, Christine; Vigolo, Michele; Kirby, Neil; Tannert, Corinna; Rompel, Oliver; et al. (New England Journal of Medicine, 2018)
Genetic deficiency of ectodysplasin A (EDA) causes X-linked hypohidrotic ectodermal dysplasia (XLHED), in which the development of sweat glands is irreversibly impaired, an condition that can lead to life-threatening hyperthermia. We observed normal development of mouse fetuses with Eda mutations after they had been exposed in utero to a recombinant protein that includes the receptor-binding domain of EDA. We administered this protein intraamniotically to two affected human twins at gestational weeks 26 and 31 and to a single affected human fetus at gestational week 26; the infants, born in week 33 (twins) and week 39 (singleton), were able to sweat normally, and XLHED-related illness had not developed by 14 to 22 months of age. (Funded by Edimer Pharmaceuticals and others.).
EVALuna2:35486

Presence of circulating tumor cells in high-risk early breast cancer during follow-up and prognosis - Trapp, Elisabeth; Janni, Wolfgang; Schindlbeck, Christian; Jückstock, Julia; Andergassen, Ulrich; De Gregorio, Amelie; Alunni-Fabbroni, Marianna; Tzschaschel, Marie; Polasik, Arkadius; Koch, Julian G.; Friedl, Thomas W.P.; Fasching, Peter; et al. (Journal of the National Cancer Institute, 2019)
Background: The prognostic relevance of circulating tumor cells (CTCs) at the time of primary diagnosis has been well established. However, little information is available regarding their prognostic relevance to follow-up care. Methods: The multicenter, open-label, phase III SUCCESS A trial compared two adjuvant chemotherapy regimens followed by 2 vs 5 years of zoledronate for early-stage, high-risk breast cancer patients. The presence of CTCs was assessed before and 2 years after chemotherapy using the FDA-approved CellSearch System. Overall survival (OS) and disease-free survival (DFS) were analyzed using univariate log-rank tests and multivariable Cox regressions. OS and DFS were measured starting from an assessment of CTCs 2 years after the completion of chemotherapy. All statistical tests were two-sided. Results: The sample included 1087 patients who participated in the translational research program of the SUCCESS A trial and for whom sufficient translational data were available regarding CTC status at baseline and at the 2-year follow-up visit. Two years after chemotherapy, 198 (18.2%) patients were CTC-positive. The median follow-up after this timepoint was 37 months. Cox regressions that included CTC status at baseline revealed that CTC status 2 years after chemotherapy had statistically significant and independent prognostic relevance for OS (hazard ratio [HR] ¼ 3.91, 95% confidence interval [CI] ¼ 2.04 to 7.52, P < .001) and DFS (HR ¼ 2.31, 95% CI ¼ 1.50 to 3.55, P < .001). Conclusion: The presence of CTCs 2 years after chemotherapy was associated with decreased OS and DFS. Based on these results, active individualized surveillance strategies for breast cancer survivors based on biomarkers should be reconsidered.
CRIS-Team Scopus Importer:2019-09-24

Prevalence and course of pregnancy symptoms using self-reported pregnancy app symptom tracker data - Nissen, Michael; Barrios Campo, Nuria; Flaucher, Madeleine; Jäger, Katharina; Titzmann, Adriana; Blunck, Dominik; Fasching, Peter; Engelhardt, Victoria; Eskofier, Björn; Leutheuser, Heike (npj Digital Medicine, 2023)
During pregnancy, almost all women experience pregnancy-related symptoms. The relationship between symptoms and their association with pregnancy outcomes is not well understood. Many pregnancy apps allow pregnant women to track their symptoms. To date, the resulting data are primarily used from a commercial rather than a scientific perspective. In this work, we aim to examine symptom occurrence, course, and their correlation throughout pregnancy. Self-reported app data of a pregnancy symptom tracker is used. In this context, we present methods to handle noisy real-world app data from commercial applications to understand the trajectory of user and patient-reported data. We report real-world evidence from patient-reported outcomes that exceeds previous works: 1,549,186 tracked symptoms from 183,732 users of a smartphone pregnancy app symptom tracker are analyzed. The majority of users track symptoms on a single day. These data are generalizable to those users who use the tracker for at least 5 months. Week-by-week symptom report data are presented for each symptom. There are few or conflicting reports in the literature on the course of diarrhea, fatigue, headache, heartburn, and sleep problems. A peak in fatigue in the first trimester, a peak in headache reports around gestation week 15, and a steady increase in the reports of sleeping difficulty throughout pregnancy are found. Our work highlights the potential of secondary use of industry data. It reveals and clarifies several previously unknown or disputed symptom trajectories and relationships. Collaboration between academia and industry can help generate new scientific knowledge.
CRIS-Team Scopus Importer:2023-10-20

Prevalence of Circulating Tumor Cells After Adjuvant Chemotherapy With or Without Anthracyclines in Patients With HER2-negative, Hormone Receptor-positive Early Breast Cancer - Schramm, Amelie; Schochter, Fabienne; Friedl, Thomas W. P.; De Greqorio, Nikolaus; Andergassen, Ulrich; Alunni-Fabbroni, Marianna; Trapp, Elisabeth; Jaeger, Bernadette; Heinrich, Georg; Camara, Oumar; Decker, Thomas; Ober, Angelika; et al. (Clinical Breast Cancer, 2017)
BACKGROUND: Use of anthracycline-based chemotherapy in patients with early breast cancer (EBC) has been well-established but is often associated with cardiotoxicity. Based on data suggesting a limited benefit of anthracyclines in human epidermal growth factor receptor 2 (HER2)-negative patients, the Simultaneous Study of Docetaxel Based Anthracycline Free Adjuvant Treatment Evaluation, as well as Life Style Intervention Strategies (SUCCESS) C study randomized patients to either anthracycline-containing or anthracycline-free chemotherapy. Given the proven prognostic value of circulating tumor cells (CTCs) in EBC, we compared the prevalence of CTCs after chemotherapy between both treatment arms for a preliminary efficacy assessment. METHODS: The SUCCESS C trial (NCT00847444) is an open-label, phase III study randomizing 3547 patients with HER2-negative EBC to either 3 cycles of epirubicin, 5-fluorouracil, and cyclophosphamide followed by 3 cycles of docetaxel (FEC-DOC) or 6 cycles of docetaxel and cyclophosphamide (DOC-C). CTC status was prospectively evaluated in hormone receptor-positive patients at the time of last chemotherapy cycle using the US Food and Drug Administration-approved CellSearch System (Janssen Diagnostics). RESULTS: Data on CTC status were available for 1766 patients. Overall, CTCs were found in 221 (12.5%) patients. Univariate analyses revealed that presence of CTCs at time of last chemotherapy cycle was not significantly associated with tumor or patient characteristics (all P > .1). There was no significant difference with respect to presence of CTCs between patients randomized to FEC-DOC or DOC-C (11.5% vs. 13.6%; P = .18). CONCLUSIONS: The comparable prevalence of CTCs at the time of last chemotherapy cycle may indicate that anthracycline-free chemotherapy is equally effective to anthracycline-containing chemotherapy in HER2-negative, hormone receptor-positive EBC. However, efficacy data from the final survival analysis of SUCCESS C have to be awaited to confirm these preliminary findings.
EVALuna2:36189

Prevalence of circulating tumor cells in early breast cancer patients 2 and 5 years after adjuvant treatment - Bauer, Emanuel C. A.; Schochter, Fabienne; Widschwendter, Peter; Degregorio, Amelie; Andergassen, Ulrich; Friedl, Thomas W. P.; Fasching, Peter; Fehm, Tanja; Schneeweiss, Andreas; Beckmann, Matthias; Pantel, Klaus; Janni, Wolfgang; et al. (Breast Cancer Research and Treatment, 2018)
Several studies have provided evidence on the prognostic relevance of circulating tumor cells (CTCs) detected before and after chemotherapy regarding overall survival (OS) and progression-free survival (PFS) in early breast cancer (EBC). We provide data on the prevalence of CTCs 2 and 5 years after primary diagnosis in a cohort of patients with EBC.The SUCCESS study is a multicenter, prospective, randomized trial comparing PFS in primary breast cancer patients undergoing one of two adjuvant chemotherapy regimens followed by 2 versus 5 years of treatment with zoledronate. CTCs from patients without signs of breast cancer recurrence were analyzed in peripheral blood using the FDA cleared CellSearch® System (Veridex, USA) 2 and 5 years after primary diagnosis.CTCs were detected at 2 and 5 years after primary diagnosis in 96 (16.7%) and 47 (8.2%) of the 574 patients, respectively. There were no associations between CTC status and patient and tumor characteristics or treatment regimens. In 442 (77.0%) patients, no CTCs were detected at either of the two time points, and in 11 patients (1.9%), CTCs were found at both 2 and 5 years after primary diagnosis. In 85 (14.8%) patients, CTCs were present 2 years after primary diagnosis but not after 5 years, while 36 (6.3%) patients had CTCs in their blood only at the 5-year follow-up.In patients with EBC, CTCs can be detected even 5 years after primary diagnosis without clinical signs of disease recurrence.
EVALuna2:56145

Prevalence of SARS-CoV-2 in Pregnant Women Assessed by RT-PCR in Franconia, Germany: First Results of the SCENARIO Study (SARS-CoV-2 prEvalence in pregNAncy and at biRth In FrancOnia) - Hein, Alexander; Kehl, Sven; Häberle, Lothar; Tiemann, Carsten; Peuker, Rebecca; Mereutanu, Denise; Stumpfe, Florian; Faschingbauer, Florian; Meyer-Schlinkmann, Kirstin; Koch, Martin C.; Kainer, Franz; Dammer, Ulf; et al. (Geburtshilfe und Frauenheilkunde, 2022)
Purpose Detection of SARS-CoV-2-infected pregnant women admitted to maternity units during a pandemic is crucial. In addition to the fact that pregnancy is a risk factor for severe COVID-19 and that medical surveillance has to be adjusted in infected women and their offspring, knowledge about infection status can provide the opportunity to protect other patients and healthcare workers against virus transmission. The aim of this prospective observational study was to determine the prevalence of SARS-CoV-2 infection among pregnant women in the hospital setting. Material and Methods All eligible pregnant women admitted to the nine participating hospitals in Franconia, Germany, from 2 June 2020 to 24 January 2021 were included. COVID-19-related symptoms, secondary diseases and pregnancy abnormalities were documented. SARS-CoV-2 RNA was detected by RT-PCR from nasopharyngeal swabs. The prevalence of acute SARS-CoV-2 infection was estimated by correcting the positive rate using the Rogan-Gladen method. The risk of infection for healthcare workers during delivery was estimated using a risk calculator. Results Of 2414 recruited pregnant women, six were newly diagnosed RT-PCR positive for SARS-CoV-2, which yielded a prevalence of SARS-CoV-2 infection of 0.26% (95% CI, 0.10-0.57%). Combining active room ventilation and wearing FFP2 masks showed an estimated reduction of risk of infection for healthcare workers in the delivery room to < 1%. Conclusions The prevalence of newly diagnosed SARS-CoV-2 infection during pregnancy in this study is low. Nevertheless, a systematic screening in maternity units during pandemic situations is important to adjust hygienic and medical management. An adequate hygienic setting can minimise the calculated infection risk for medical healthcare workers during patients' labour.
CRIS-Team Scopus Importer:2022-02-25
Keywords: COVID-19; infection; pregnancy; prevalence; SARS-CoV-2

Prevention of Cervical Cancer - Hillemanns, Peter; Friese, Klaus; Dannecker, Christian; Klug, Stefanie; Seifert, Ulrike; Iftner, Thomas; Haedicke, Juliane; Loening, Thomas; Horn, Lars; Schmidt, Dietmar; Ikenberg, Hans; Steiner, Manfred; et al. (Geburtshilfe und Frauenheilkunde, 2019)
Aims Annual opportunistic screening for cervical carcinoma has been done in Germany since 1971. The creation of this S3 guideline meets an important need, outlined in the National Cancer Plan, with regard to screening for cervical cancer, as this guideline aims to provide important information and support for planned organized screening for cervical cancer in Germany. Methods With the financial support of German Cancer Aid, 21 professional societies developed evidence-based statements and recommendations (classified using the GRADE system) for the screening, management and treatment of precancerous conditions of the cervix. Two independent scientific institutes compiled systematic reviews for this guideline. Recommendations The second part of this short summary deals with the triage, treatment and follow-up care of cervical dysplasia. With regard to those women who do not participate in screening, the guideline authors recommend sending out repeat invitation letters or an HPV self-collection kit. Colposcopy should be carried out for further investigation if cytology findings are Pap II-p and HPV test results are positive or if the results of an HPV 16 or HPV 18 screening test are positive. A single abnormal Pap smear should be triaged and investigated using HPV testing or p16/Ki67 dual staining.
CRIS-Team Scopus Importer:2019-05-02
Keywords: cervical cancer; cervical intraepithelial neoplasia (CIN); cervical precancerous condition; HPV

Prevention of Cervical Cancer: Guideline of the DGGG and the DKG (S3 Level, AWMF Register Number 015/027OL, December 2017) - Part 1 with Introduction, Screening and the Pathology of Cervical Dysplasia - Hillemanns, Peter; Friese, Klaus; Dannecker, Christian; Klug, Stefanie; Seifert, Ulrike; Iftner, Thomas; Haedicke, Juliane; Loening, Thomas; Horn, Lars; Schmidt, Dietmar; Ikenberg, Hans; Steiner, Manfred; et al. (Geburtshilfe und Frauenheilkunde, 2019)
Annual opportunistic screening for cervical carcinoma has been carried out in Germany since 1971. The creation of this S3 guideline meets an important need, outlined in the National Cancer Plan, with regard to screening for cervical cancer, as the guideline aims to provide important information and support for planned organized screening for cervical cancer in Germany. With the financial support of German Cancer Aid, 21 professional societies developed evidence-based statements and recommendations (classified using the GRADE system) for the screening, management and treatment of precancerous conditions of the cervix. Two independent scientific institutes compiled systematic reviews for this guideline. The first part of this short summary presents the pathological basis and considers various questions related to screening for cervical cancer. As also reported in earlier reviews, the meta-analysis by Kleijnen Systematic Reviews showed that HPV-based screening offers better protection against invasive cervical cancer compared to cytology-based screening. The authors of this guideline therefore recommend - in accordance with the guideline of the Joint National Committee of Germany (Gemeinsamer Bundesauschuss, G-BA) - that women aged 35 and above should be examined at regular intervals (at least every 3 years) and undergo HPV-based screening. Co-testing can also be carried out. Women between the ages of 20 and 35 should have cytological screening every 2 years.
EVALuna2:157339

Primäre Prävention - Mamma- und Genitalkarzinome - Preu, Caroline; Heindl, Felix; Hein, Alexander; Koch, Martin; Ga, Paul; Beckmann, Matthias; Lux, Michael P.; Emons, Julius (TumorDiagnostik & Therapie, 2019)
Zusammenfassung In den letzten Jahren haben sich Diagnostik und Therapie im Bereich der gynäkologischen Onkologie und Senologie stetig weiterentwickelt. Dennoch ist das Versterben an einer Krebserkrankung in den hoch entwickelten Ländern eine der häufigsten Todesursachen der Frau 1. Manahmen zur Primärprävention sind daher von hoher Bedeutung, um die Morbidität und Mortalität von Krebserkrankungen zu senken.
CRIS-Team Scopus Importer:2019-08-13
Keywords: Endometriumkarzinom; Mammakarzinom; Ovarialkarzinom; primäre Prävention; Zervixkarzinom

Primary results of the AGO-Zervix-1 Study: A prospective, randomized phase III study to compare the effects of paclitaxel and topotecan with those of cisplatin and topotecan in the treatment of patients with recurrent and persistent cervical cancer - Gaß, Paul; Thiel, Falk C.; Häberle, Lothar; Ackermann, Sven; Theuser, Anna Katharin; Hummel, Nadine; Boehm, Sibylle; Kimmig, Rainer; Reinthaller, Alexander; Becker, Sven; Hilpert, Felix; Janni, Wolfgang; et al. (Gynecologic Oncology, 2024)
Background: Before the era of immunotherapies and antibody–drug conjugates, there were limited chemotherapeutic options for patients with recurrent and metastatic cervical cancer. Combination therapies with cisplatin have shown some superiority over monotherapy. This study examined platinum-free treatment regimens, comparing a combination of topotecan and paclitaxel (TP) with topotecan and cisplatin (TC) in patients with recurrent or metastatic cervical cancer, with or without prior platinum-based treatment. Methods: The AGO-Zervix-1 Study (NCT01405235) is a prospective, randomized phase III study in which patients were randomly assigned at a 1:1 ratio to treatment within the control arm with topotecan (0.75 mg/m2) on days 1–3 and cisplatin (50 mg/m2) on day 1 every 3 weeks and in the study arm topotecan (1.75 mg/m2) and paclitaxel (70 mg/m2) on days 1, 8, and 15 every 4 weeks or treatment. The primary study aim was overall survival; progression-free survival, toxicity, and quality of life were secondary aims. The interim and final analysis is here reported after recruitment of 173 of 312 planned patients. Results: Median overall survival in the TP arm was 9.6 months, compared with 12.0 months in the TC arm (log-rank test, P = 0.33). Median progression-free survival rates were 4.4 months with TP and 4.2 months with TC (log-rank test, P = 0.47). Leukopenia and nausea/vomiting were more frequent in the cisplatin-containing arm. Otherwise, toxicity profiles were comparable. There were no differences in FACT-G–assessed quality of life. Conclusion: Platinum-based combination chemotherapy remains the standard of care chemotherapy regimen for patients with recurrent or metastatic cervical cancer.
CRIS-Team Scopus Importer:2024-03-29
Keywords: Cervical cancer; Cisplatin; Metastatic; Paclitaxel; Recurrent; Topotecan

Primary Therapy of Early Breast Cancer: Evidence, Controversies, Consensus - Untch, Michael; Thomssen, Christoph; Bauerfeind, Ingo; Braun, Michael; Brucker, Sara Y.; Felberbaum, Ricardo; Hagemann, Friederike; Haidinger, Renate; Hönig, Arnd; Huober, Jens; Jackisch, Christian; Kolberg, Hans Christian; et al. (Geburtshilfe und Frauenheilkunde, 2019)
The results of the international St. Gallen Consensus Conference for the treatment of patients with primary breast cancer were discussed this year by a working group of leading breast cancer experts in view of the therapy recommendations for everyday clinical practice in Germany. Three of the breast cancer experts are also members of this year's St. Gallen panel. The comparison of the St. Gallen recommendations with the annually updated treatment recommendations of the AGO 2019 as well as the S3 guideline is useful, since the recommendations of the St. Gallen panel represent the opinions of experts from various countries and disciplines. The recommendations of the S3 guideline and AGO are based on evidence-based research of the literature. This year's 16th St. Gallen conference featured the motto Magnitude of clinical benefit. In addition to the evidence-based data, each therapeutic decision must also undergo a benefit/risk assessment of the patient's individual situation and be discussed with the patient.
CRIS-Team Scopus Importer:2019-06-28
Keywords: axilla; early breast cancer; locoregional therapy; neoadjuvant treatment; St. Gallen consensus 2019; systemic therapy

Primary Therapy of Patients with Early Breast Cancer: Evidence, Controversies, Consensus: Opinions of German Specialists to the 14th St. Gallen International Breast Cancer Conference 2015 (Vienna 2015) - Untch, M.; Harbeck, N.; Huober, J.; Von Minckwitz, G.; Gerber, B.; Kreipe, H. -H.; Liedtke, C.; Marschner, N.; Moebus, V.; Scheithauer, H.; Schneeweiss, A.; Thomssen, C.; et al. (Geburtshilfe und Frauenheilkunde, 2015)
For the first time, this year's St. Gallen International Consensus Conference on the treatment of patients with primary breast cancer, which takes place every two years, was held not in St. Gallen (Switzerland) but - for logistical reasons - in Vienna (Austria) under its usual name. The 2015 St. Gallen International Consensus Conference was the 14th of its kind. As the international panel of the St. Gallen conference consists of experts from different countries, the consensus mirrors an international cross-section of opinions. From a German perspective, it was considered useful to translate the results of the votes of the St. Gallen conference into practical suggestions, particularly in light of the recently updated treatment guideline of the Gynecologic Oncology Group (AGO-Mamma 2015) in Germany. A German group consisting of 14 breast cancer experts, three of whom are members of the international St. Gallen panel, has therefore provided comments on the results of this year's votes at the 2015 St. Gallen Consensus Conference and their impact on clinical care in Germany. The 14th St. Gallen conference once again focused on surgery of the breast and the axilla, radio-oncologic and systemic treatment options for primary breast cancer depending on tumor biology, and the clinical use of multigene assays. The conference also considered targeted therapies for older and for younger patients, including the diagnosis/treatment of breast cancer during and after pregnancy and the preservation of fertility.
EVALuna2:17567

Prioritization and Resource Allocation in the Context of the COVID-19 Pandemic: Recommendations for Colorectal and Pancreatic Cancer in Germany - Lugnier, Celine; Sommerlatte, Sabine; Attenberger, Ulrike; Beer, Ambros J.; Bentz, Martin; Benz, Stefan R.; Birkner, Thomas; Büntzel, Jens; Ebert, Matthias P.A.; Fasching, Peter; Fischbach, Wolfgang; Fokas, Emmanouil; et al. (Oncology Research and Treatment, 2024)
In the context of the COVID-19 pandemic, there has been a scarcity of resources with various effects on the care of cancer patients. This paper provides an English summary of a German guideline on prioritization and resource allocation for colorectal and pancreatic cancer in the context of the pandemic. Based on a selective literature review as well as empirical and ethical analyses, the research team of the CancerCOVID Consortium drafted recommendations for prioritizing diagnostic and treatment measures for both entities. The final version of the guideline received consent from the executive boards of nine societies of the Association of Scientific Medical Societies in Germany (AWMF), 20 further professional organizations and 22 other experts from various disciplines as well as patient representatives. The guiding principle for the prioritization of decisions is the minimization of harm. Prioritization decisions to fulfill this overall goal should be guided by (1) the urgency relevant to avoid or reduce harm, (2) the likelihood of success of the diagnostic or therapeutic measure advised, and (3) the availability of alternative treatment options. In the event of a relevant risk of harm as a result of prioritization, these decisions should be made by means of a team approach. Gender, age, disability, ethnicity, origin, and other social characteristics, such as social or insurance status, as well as the vehemence of a patient's treatment request and SARS-CoV-2 vaccination status should not be used as prioritization criteria. The guideline provides concrete recommendations for (1) diagnostic procedures, (2) surgical procedures for cancer, and (3) systemic treatment and radiotherapy in patients with colorectal or pancreatic cancer within the context of the German healthcare system.
CRIS-Team Scopus Importer:2024-06-14
Keywords: Colorectal cancer; Guideline; Pancreatic cancer; Pandemic; Resource allocation

Prognosis of Patients with Early Breast Cancer Receiving 5 Years vs 2 Years of Adjuvant Bisphosphonate Treatment: A Phase 3 Randomized Clinical Trial - Friedl, Thomas W. P.; Fehm, Tanja; Mueller, Volkmar; Lichtenegger, Werner; Blohmer, Jens; Lorenz, Ralf; Forstbauer, Helmut; Fink, Visnja; Bekes, Inga; Huober, Jens; Jueckstock, Julia; Schneeweiss, Andreas; et al. (JAMA Oncology, 2021)
Importance: Bisphosphonate treatment in patients with early breast cancer has become part of care, but the optimal treatment duration is still unclear. Objective: To compare 2 vs 5 years of zoledronate treatment following adjuvant chemotherapy in patients with early breast cancer. Design, Setting, and Participants: The SUCCESS A phase 3 multicenter randomized open-label clinical trial with a 2 × 2 factorial design enrolled 3754 patients from September 21, 2005, to March 12, 2007 (last patient out, May 7, 2014). Final data analysis was conducted from September 2019 to October 2020. In 250 German study centers, patients were eligible for participation in the SUCCESS A trial if they had either node-positive or high-risk node-negative (defined as at least 1 of the following: tumor size ≥ pT2, histologic grade 3, negative hormone receptor status, or age ≤35 years) primary invasive breast cancer. Interventions: Patients were first randomized to adjuvant chemotherapy with 3 cycles of fluorouracil, epirubicin, and cyclophosphamide followed by 3 cycles of docetaxel with or without gemcitabine (not presented in this report). After chemotherapy, patients underwent a second randomization of 5 years of zoledronate treatment (4 mg intravenously every 3 months for 2 years, followed by 4 mg intravenously every 6 months for 3 years) vs 2 years of zoledronate treatment (4 mg intravenously every 3 months for 2 years). Main Outcomes and Measures: The primary end point of the study was disease-free survival; secondary end points were overall survival, distant disease-free survival, and the incidence of skeletal-related adverse events. Survival times were measured from 2 years after the start of zoledronate treatment (landmark analysis). Results: Overall, data on 2987 patients were available for analysis; median age was 53 (range, 21-86) years. Disease-free survival, overall survival, and distant disease-free survival did not differ significantly between the 2 treatment arms (5 vs 2 years) as shown by adjusted multivariable Cox proportional hazards regression models (disease-free survival: hazard ratio [HR], 0.97; 95% CI, 0.75-1.25; P =.81; overall survival: HR, 0.98; 95% CI, 0.67-1.42; P =.90; distant disease-free survival: HR, 0.87; 95% CI, 0.65-1.18; P =.38). Adverse events were observed more often in the 5-year (46.2%) vs 2-year (27.2%) zoledronate treatment arm, which was particularly true for the skeletal-related events bone pain (5 years, 8.3% vs 2 years, 3.7%) and arthralgia (5 years, 5.1% vs 2 years, 3.1%). Conclusions and Relevance: The results of this phase 3 randomized clinical trial indicate that extending the zoledronate treatment beyond 2 years does not improve the prognosis of high-risk patients with early breast cancer receiving chemotherapy, suggesting that the currently recommended bisphosphonate treatment duration of 3 to 5 years could be reduced. Trial Registration: ClinicalTrials.gov Identifier: NCT02181101.
CRIS-Team Scopus Importer:2021-07-09

Prognosis prediction with the IHC3 score in patients with node-negative, hormone receptor-positive, HER2-negative early breast cancer - Seitz, Katharina; Goossens, Chloe; Hübner, Hannah; Gaß, Paul; Uhrig, Sabrina; Heindl, Felix; Emons, Julius; Rübner, Matthias; Anetsberger, Daniel; Hartmann, Arndt; Beckmann, Matthias; Erber, Ramona; et al. (ESMO Open, 2024)
Background: Prognostication has been used to identify patient populations that could potentially benefit from treatment de-escalation. In patients with hormone receptor-positive (HRpos), human epidermal growth factor receptor 2-negative (HER2neg) early breast cancer (eBC), treatment de-escalation classically involved omitting chemotherapy. With recently developed specialized therapies that require hands-on side-effect management, the therapeutic landscape is changing and therapy decisions are no longer based only on prognosis, but also consider potential side-effects. Therefore, identification of patient groups based on prognostication has gained importance. Materials and methods: In this retrospective analysis, a population of 2359 node-negative HRpos/HER2neg eBC patients was selected from all patients treated at the University Breast Center of Franconia, Germany between 2002 and 2021. The prognostic value of the IHC3 score (incorporating immunohistochemical measurements of the estrogen and progesterone receptor status and Ki-67) with clinical parameters (lymph node status, tumor stage, grading) regarding invasive disease-free survival (iDFS) and overall survival (OS) was assessed. Results: IHC3 positively correlated with Ki-67 expression and inversely correlated with hormone receptor expression. IHC3 categorized into quartiles identified patients with a more unfavorable prognosis: 5-year and 10-year iDFS rates for patients in the highest versus the lowest quartile were 84% versus 95% and 70% versus 88%, respectively. A sensitivity analysis of distant disease-free survival showed similar results to those of iDFS. Five-year and 10-year OS rates for patients in the highest versus the lowest quartile were, respectively, 92% versus 97% and 81% versus 92%. Conclusions: IHC3 is able to define prognostic groups in patients with node-negative, HRpos/HER2neg eBC. Node-negative patients with a high IHC3 score had the worst prognosis, which was comparable to that of node-positive patients described in recent trials. This simple and cost-effective tool could thus potentially aid in identifying patient groups for innovative therapeutic approaches.
CRIS-Team Scopus Importer:2024-11-01
Keywords: early breast cancer; hormone receptor-positive; IHC3; molecular marker; prognosis

Prognostic effect of Ki-67 in common clinical subgroups of patients with HER2-negative, hormone receptor-positive early breast cancer - Fasching, Peter; Gaß, Paul; Häberle, Lothar; Volz, Bernhard; Hein, Alexander; Hack, Carolin; Lux, Michael P.; Jud, Sebastian; Hartmann, Arndt; Beckmann, Matthias; Slamon, Dennis J.; Erber, Ramona (Breast Cancer Research and Treatment, 2019)
Purpose: Several clinical trials have investigated the prognostic and predictive usefulness of molecular markers. With limited predictive value, molecular markers have mainly been used to identify prognostic subgroups in which the indication for chemotherapy is doubtful and the prognosis is favorable enough for chemotherapy to be avoided. However, limited information is available about which groups of patients may benefit from additional therapy. This study aimed to describe the prognostic effects of Ki-67 in several common subgroups of patients with early breast cancer. Methods: This retrospective study analyzed a single-center cohort of 3140 patients with HER2−, hormone receptor-positive breast cancer. Five-year disease-free survival (DFS) rates were calculated for low (< 10%), intermediate (10–19%), and high (≥ 20%) Ki-67 expression levels, as assessed by immunohistochemistry, and for subgroups relative to age, body mass index, disease stage, tumor grade, and (neo-)adjuvant chemotherapy. It was also investigated whether Ki-67 had different effects on DFS in these subgroups. Results: The 5-year DFS rates for patients with low, intermediate, and high levels of Ki-67 expression were 0.90, 0.89, and 0.77, respectively. Ki-67 was able to further differentiate patients with an intermediate prognosis into different prognostic groups relative to common clinical parameters. Patients with stage II breast cancer had 5-year DFS rates of 0.84, 0.88, and 0.79 for low, intermediate, and high levels of Ki-67 expression. Ki-67 had different prognostic effects in subgroups defined by age and tumor grade. Conclusions: Ki-67 may help identify patients in intermediate prognostic groups with an unfavorable prognosis who may benefit from further therapy.
CRIS-Team Scopus Importer:2019-06-18
Keywords: Breast cancer; Ki-67; Molecular marker; Prognosis; Proliferation

Prognostic effect of low-level HER2 expression in patients with clinically negative HER2 status - Hein, Alexander; Hartkopf, Andreas D.; Emons, Julius; Lux, Michael P.; Volz, Bernhard; Taran, Florin Andrei; Overkamp, Friedrich; Hadji, Peyman; Tesch, Hans; Häberle, Lothar; Ettl, Johannes; Lüftner, Diana; et al. (European Journal of Cancer, 2021)
Purpose: Assessment of HER2 overexpression using immunohistochemistry (IHC) and/or in situ hybridisation (ISH) for the detection of HER2 amplifications is standard to identify patients for established HER2-directed treatments. Patients with lower HER2 expression levels have recently also become candidates for novel therapies targeting HER2. This study aimed to assess tumour and patient characteristics and prognosis in patients with advanced breast cancer (aBC), relative to low HER2 expression levels. Methods: PRAEGNANT is a prospective aBC registry (NCT02338167), focusing on molecular biomarkers. Patients in all therapy lines receiving any kind of treatment are eligible. This analysis includes patients with conventionally HER2-negative aBC. Clinical outcome was compared in the groups with no (IHC score 0) or with low HER2 expression (IHC 1+, or IHC 2+/ISH negative). Results: Low HER2 expression levels in triple-negative aBC patients did not influence progression-free survival. Overall survival appeared poorer in patients with IHC 2+ compared with patients with no HER2 expression in the unadjusted analysis (hazard ratio 2.24, 95% confidence interval 0.1.12–4.47). However, this effect was not maintained in the adjusted analysis. In HER2-negative, hormone receptor–positive patients, low HER2 expression appeared to have no effect on prognosis, neither progression-free survival nor overall survival. Conclusions: We could not demonstrate that HER2 expression at a low level and assessed in clinical routine can differentiate patients into prognostic groups. However, the prevalence of patients with a low expression makes this population interesting for clinical trials with potentially active treatments using HER2 as a target.
CRIS-Team Scopus Importer:2021-08-06
Keywords: Advanced breast cancer; Antihormone therapy; Chemotherapy; HER2; HER2/neu; Lapatinib; Metastatic; Pertuzumab; TDM-1; Trastuzumab

Prognostic gene expression signature for high-grade serous ovarian cancer - Millstein, J.; Budden, T.; Goode, E. L.; Anglesio, M. S.; Talhouk, A.; Intermaggio, M. P.; Leong, H. S.; Chen, S.; Elatre, W.; Gilks, B.; Nazeran, T.; Volchek, M.; et al. (Annals of Oncology, 2020)
Background: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC. Patients and methods: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies. Results: Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02–2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to –), 5.4 (4.6–7.0), 3.8 (3.3–4.6), 3.2 (2.9–3.7) and 2.3 (2.1–2.6) years. Conclusion: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.
CRIS-Team Scopus Importer:2020-07-17
Keywords: formalin-fixed paraffin-embedded; gene expression; high-grade serous ovarian cancer; overall survival; prognosis

Prognostic impact of selection criteria of current adjuvant endocrine therapy trials NATALEE and monarchE in postmenopausal HRpos/HER2neg breast cancer patients treated with upfront letrozole - Fasching, Peter; Hack, Carolin; Nabieva, Naiba; Maass, Nicolai; Aktas, Bahriye; Kümmel, Sherko; Thomssen, Christoph; Wolf, Christopher; Kolberg, Hans Christian; Brucker, Cosima; Janni, Wolfgang; Dall, Peter; et al. (European Journal of Cancer, 2024)
Background: The monarchE and NATALEE trials demonstrated the benefit of CDK4/6 inhibitor (CDK4/6i) therapy in adjuvant breast cancer (BC) treatment. Patient selection, based on clinical characteristics, delineated those at high (monarchE) and high/intermediate recurrence risk (NATALEE). This study employed a historical patient cohort to describe the proportion and prognosis of patients eligible for adjuvant CDK4/6i trials. Methods: Between 2009 and 2011, 3529 patients were enrolled in the adjuvant PreFace clinical trial (NCT01908556). Eligibility criteria included postmenopausal patients with hormone receptor-positive (HRpos) BC for whom a five-year upfront therapy with letrozole was indicated. Patients were categorized into prognostic groups according to monarchE and NATALEE inclusion criteria, and their invasive disease-free survival (iDFS) and overall survival (OS) were assessed. Results: Among 2891 HRpos patients, 384 (13.3 %) met the primary monarchE inclusion criteria. The majority (n = 261) qualified due to having ≥ 4 positive lymph nodes. For NATALEE, 915 out of 2886 patients (31.7 %) met the eligibility criteria, with 126 patients (13.7 %) being node-negative. Patients from monarchE with ≥ 4 positive lymph nodes and NATALEE with stage III BC exhibited the poorest prognosis (3-year iDFS rate 0.87). Patients ineligible for the trials demonstrated prognoses similar to the most favorable patient groups within the eligibility criteria. Conclusion: Patient populations eligible for monarchE and NATALEE trials differed. Nearly a third of the postmenopausal HRpos population, previously under upfront letrozole treatment, met the NATALEE prognostic eligibility criteria. As certain eligible groups had a prognosis similar to non-eligible patients, it might be interesting to explore additional patient groups for CDK4/6i therapy.
CRIS-Team Scopus Importer:2024-08-02
Keywords: Aromatase inhibitors; CDK4/6 inhibitors; Early breast cancer; Hormone therapy; Letrozole; Prognosis

Prognostic Impact of Weight Change During Adjuvant Chemotherapy in Patients With High-Risk Early Breast Cancer: Results From the ADEBAR Study - Mutschler, Nikola S.; Scholz, Christoph; Friedl, Thomas W. P.; Zwingers, Thomas; Fasching, Peter; Beckmann, Matthias; Fehm, Tanja; Mohrmann, Svjetlana; Salmen, Jessica; Ziegler, Carola; Jaeger, Bernadette; Widschwendter, Peter; et al. (Clinical Breast Cancer, 2018)
In addition to established prognostic factors, individual lifestyle-associated factors, such as obesity, physical activity, and diet, seem to modulate the course of breast cancer. The aim of this analysis was to evaluate the influence of weight changes during adjuvant chemotherapy on outcome in a large multicenter prospectively randomized trial.The ADEBAR trial compares a sequential chemotherapy consisting of epirubicin/cyclophosphamide followed by docetaxel to an epirubicin/5-fluorouracil/cyclophosphamide regimen in patients with lymph node-positive early breast cancer. Body weight was measured before each cycle of chemotherapy. According to the relative weight change (>= 5%) between the first and the last cycle, patients were categorized into the weight gain, weight loss, or stable weight group. Overall survival (OS) and disease-free survival were assessed by univariate Kaplan-Meier and multivariate Cox regression analyses.Concise data from 1080 of 1493 participants who completed all cycles of chemotherapy were available for analysis. Of 307 patients (24.8%) whose weight changed by >= 5%, 120 patients (11.1%) lost and 187 (17.3%) gained weight. Multivariate analysis showed a significant independent effect of weight change on OS (P = .039), but not on disease-free survival (P = .111). Both weight change groups had a worse OS compared to patients with stable weight (weight gain: hazard ratio, 1.55; 95% confidence interval, 1.01-2.40; P = .047; weight loss: hazard ratio, 1.55; 95% CI, 0.97-2.47; P = .067).Weight change of > 5% during adjuvant chemotherapy in patients with high-risk early breast cancer is associated with poor OS.
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Prognostic relevance of Ki-67 in the primary tumor for survival after a diagnosis of distant metastasis - Loehberg, Christian R.; Almstedt, Katrin; Jud, Sebastian; Haeberle, Lothar; Fasching, Peter; Hack, Carolin; Lux, Michael P.; Thiel, Falk; Schrauder, Michael G.; Brunner, Michaela; Bayer, Christian M.; Hein, Alexander; et al. (Breast Cancer Research and Treatment, 2013)
Prediction of the prognosis for metastatic breast cancer patients depends on molecular subtypes similar to those found in patients with primary breast cancer. Several studies have shown that estrogen receptor (ER) and progesterone receptor (PR) status determine the course of the disease and the prognosis. As Ki-67 helps to differentiate molecular subtypes in patients with primary breast cancer, the aim of this study was to assess the prognostic relevance of Ki-67 in the primary tumor in relation to its prognostic relevance for patients with metastatic breast cancer. A total of 467 patients with invasive breast cancer were identified in the database of a single breast cancer center, in whom Ki-67 had been assessed in tumor material from the breast at the time of the primary diagnosis and who had developed a metastasis at any time during the subsequent course. For these patients, tumor and patient characteristics were used to determine prognostic factors relative to overall survival after the diagnosis of distant metastases. Ki-67 was added to this model to investigate whether this might improve the prediction of overall survival. In the multivariate Cox model, age at diagnosis, body mass index, nodal status, tumor size, ER and PR status, and time from diagnosis to metastasis were identified as relevant prognostic factors. Adding Ki-67 to the model improved the prediction of overall survival. There was also a significant and relevant interaction with the PR status. In patients with a low-proliferation primary tumor, a high level of PR expression would indicate an extraordinarily good prognosis (HR 0.39; 95 % CI, 0.23-0.66). In patients with higher-proliferation primary tumors, PR status was not capable of differentiating prognostic groups. Ki-67 is useful in addition to known prognostic factors for breast cancer. It is able to indicate a group of women with a poorer prognosis, specifically in the group of patients with PR-positive breast cancer. © 2013 Springer Science+Business Media New York.
CRIS-Team Scopus Importer:2021-07-19
Keywords: Ki-67; Metastatic breast cancer; Progesterone receptor; Prognosis; Proliferation

Prognostic relevance of the HER2 status of circulating tumor cells in metastatic breast cancer patients screened for participation in the DETECT study program - Müller, V.; Banys-Paluchowski, M.; Friedl, T. W.P.; Fasching, Peter; Schneeweiss, A.; Hartkopf, A.; Wallwiener, D.; Rack, B.; Meier-Stiegen, F.; Huober, J.; Rübner, Matthias; Hoffmann, O.; et al. (ESMO Open, 2021)
Background: Circulating tumor cells (CTCs) have been reported to predict clinical outcome in metastatic breast cancer (MBC). Biology of CTCs may differ from that of the primary tumor and HER2-positive CTCs are found in some patients with HER2-negative tumors. Patients and methods: Patients with HER2-negative MBC were screened for participation in DETECT III and IV trials before the initiation of a new line of therapy. Blood samples were analyzed using CELLSEARCH. CTCs were labeled with an anti-HER2 antibody and classified according to staining intensity (negative, weak, moderate, or strong staining). Results: Screening blood samples were analyzed in 1933 patients with HER2-negative MBC. As many as 1217 out of the 1933 screened patients (63.0%) had ≥1 CTC per 7.5 ml blood; ≥5 CTCs were detected in 735 patients (38.0%; range 1-35 078 CTCs, median 8 CTCs). HER2 status of CTCs was assessed in 1159 CTC-positive patients; ≥1 CTC with strong HER2 staining was found in 174 (15.0%) patients. The proportion of CTCs with strong HER2 staining among all CTCs of an individual patient ranged between 0.06% and 100% (mean 15.8%). Patients with estrogen receptor (ER)- and progesterone receptor (PR)-positive tumors were more likely to harbor ≥1 CTC with strong HER2 staining. CTC status was significantly associated with overall survival (OS). Detection of ≥1 CTC with strong HER2 staining was associated with shorter OS [9.7 (7.1-12.3) versus 16.5 (14.9-18.1) months in patients with CTCs with negative-to-moderate HER2 staining only, P = 0.013]. In multivariate analysis, age, ER status, PR status, Eastern Cooperative Oncology Group performance status, therapy line, and CTC status independently predicted OS. Conclusion: CTC detection in patients with HER2-negative disease is a strong prognostic factor. Presence of ≥1 CTC with strong HER2 staining was associated with shorter OS, supporting a biological role of HER2 expression on CTCs.
CRIS-Team Scopus Importer:2021-12-17
Keywords: breast cancer; circulating tumor cell; HER2 status; liquid biopsy; survival

Prognostic relevance of the HER2 status of circulating tumor cells in metastatic breast cancer patients screened for participation in the DETECT study program - Muller, Volkmar; Banys-Paluchowski, Maggie; Friedl, Thomas W. P.; Fasching, Peter; Schneeweiss, Andreas; Hartkopf, Andreas; Wallwiener, Diethelm; Rack, Brigitte; Meier-Stiegen, Franziska; Huober, Jens; Rübner, Matthias; Hoffmann, Oliver; et al. (Cancer Research, 2021)
CRIS-Team WoS Importer:2021-03-26

Progression-free survival and overall survival in patients with advanced her2-positive breast cancer treated with trastuzumab emtansine (T-dm1) after previous treatment with pertuzumab - Michel, Laura L.; Hartkopf, Andreas D.; Fasching, Peter; Kolberg, Hans Christian; Hadji, Peyman; Tesch, Hans; Häberle, Lothar; Ettl, Johannes; Lüftner, Diana; Wallwiener, Markus; Müller, Volkmar; Beckmann, Matthias; et al. (Cancers, 2020)
The approval of trastuzumab emtansine (T-DM1) was conducted without pertuzumab as previous therapy. Efficacy data on T-DM1 following pertuzumab treatment are therefore limited. This study explores this issue in a real-world setting. Within the prospective PRAEGNANT (Prospective Academic Translational Research Network for the Optimization of the Oncological Health Care Quality in the Advanced Setting) metastatic breast cancer registry (NCT02338167), patients in all therapy lines receiving any kind of treatment were eligible for inclusion. This report describes patient characteristics and progression-free survival (PFS) in human epidermal growth factor receptor 2 (HER2)-positive patients receiving T-DM1 after pertuzumab treatment. Seventy-six patients were identified, 39 of whom received T-DM1 as second-line therapy, 25 as third-line, and 12 as fourth-line therapy or higher. Pertuzumab was mostly administered as a first-line treatment (n = 61; 80.3%). The median PFS in all patients was 3.5 months (95% CI: 2.8–7.8); in second-line treatment, 7.7 months (95% CI: 2.8–11.0); in third-line, 3.4 months (95% CI: 2.3–not reached (NR)); and in fourth-line therapy or higher, 2.7 months (95% CI: 1.2–NR). T-DM1 was mainly administered second-line after pertuzumab, but also in more heavily pretreated patients. The PFS in higher therapy lines appears to be shorter than in second-line.
CRIS-Team Scopus Importer:2020-10-30
Keywords: Advanced breast cancer; Chemotherapy; HER2 c-erbB2; HER2/neu; Metastatic; Pertuzumab; T-DM1; Trastuzumab

PROTAC Drugs in Cancer Care - Fasching, Peter (Clinical Advances in Hematology and Oncology, 2024)
CRIS-Team Scopus Importer:2024-05-24

PROTEIN SURFACE SIGNATURE ON SERUM EXTRACELLULAR VESICLES FOR NON-INVASIVE DETECTION OF TUMOR PROGRESSION IN GLIOBLASTOMA PATIENTS - Tzaridis, Theophilos; Weller, Johannes; Bachurski, Daniel; Shakheri, Farhad; Schaub, Christina; Hau, Peter; Buness, Andreas; Schlegel, Uwe; Steinbach, Joachim; Seidel, Clemens; Goldbrunner, Roland; Schaefer, Niklas; et al. (NEURO-ONCOLOGY, 2021)
CRIS-Team WoS Importer:2022-03-04

Prototypic (18)F-Labeled Argininamide-Type Neuropeptide Y Y1R Antagonists as Tracers for PET Imaging of Mammary Carcinoma - Keller, Max; Maschauer, Simone; Brennauer, Albert; Tripal, Philipp; Koglin, Norman; Dittrich, Ralf; Bernhardt, Guenther; Kuwert, Torsten; Wester, Hans-Juergen; Buschauer, Armin; Prante, Olaf (ACS Medicinal Chemistry Letters, 2017)
The neuropeptide Y (NPY) Y1 receptor (Y1R) selective radioligand (R)-N(?)-(2,2-diphenylacetyl)-N(?)-[4-(2-[(18)F]fluoropropanoylamino)butyl]aminocarbonyl-N-(4-hydroxybenzyl)argininamide ([(18)F]23), derived from the high-affinity Y1R antagonist BIBP3226, was developed for imaging studies of Y1R-positive tumors. Starting from the argininamide core bearing amine-functionalized spacer moieties, a series of fluoropropanoylated and fluorobenzoylated derivatives was synthesized and studied for Y1R affinity. The fluoropropanoylated derivative 23 displayed high affinity (Ki = 1.3 nM) and selectivity toward Y1R. Radiosynthesis was accomplished via (18)F-fluoropropanoylation, yielding [(18)F]23 with excellent stability in mice; however, the biodistribution study revealed pronounced hepatobiliary clearance with high accumulation in the gall bladder (>100 %ID/g). Despite the unfavorable biodistribution, [(18)F]23 was successfully used for imaging of Y1R positive MCF-7 tumors in nude mice. Therefore, we suggest [(18)F]23 as a lead for the design of PET ligands with optimized physicochemical properties resulting in more favorable biodistribution and higher Y1R-dependent enrichment in mammary carcinom
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Psychological Predictors of Acute Postoperative Pain after Hysterectomy for Benign Causes - Scheel, Jennifer; Sittl, Reinhard; Grießinger, Norbert; Strupf, Marion; Parthum, Andreas; Dimova, Violeta; Horn-Hofmann, Claudia; Thiel, Falk; Beckmann, Matthias; Lautenbacher, Stefan (Clinical Journal of Pain, 2016)
Psychological parameters have been shown to contribute significantly to the development of acute postoperative pain (APOP). For the prediction of APOP in chest malformation patients and cancer patients, we found pain-specific psychological predictors to be of higher relevance than general psychological predictors. The current study aims to further substantiate these findings.In a sample of 73 middle-aged hysterectomy patients, three predictor sets were assessed 1 day before surgery: attentional biases (towards pain-related, social threat, and positive words in a dot-probe task), pain-related emotions and cognitions (pain anxiety, pain catastrophizing, and pain hypervigilance), and affective state variables (depression and somatization). APOP intensity rated 2-3 days after surgery and analgesic consumption during the first 48 postoperative hours were used as outcome measures.APOP intensity ratings were significantly explained by their best single predictors in a multiple regression analysis: social threat words of the dot-probe task, pain anxiety, and somatization (14.7% of explained variance). When comparing standardized beta coefficients, pain-specific psychological predictors appeared to be of higher explanatory relevance than general psychological predictors. In contrast, analgesic consumption could not be significantly predicted by the psychological variables.Hysterectomy patients at risk for high APOP intensity could be characterized by the psychological variables used, whereas their predictive value for analgesic consumption was limited. The high predictive potency of pain-specific psychological variables should be considered for further improvement of pain management and prevention, because pain-specific variables like pain anxiety can be the target of focal psychological interventions when preparing for surgery.
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Psychooncological counseling and treatment as part of the Comprehensive Cancer Center (CCC): Multicenter study to detect the psycho-oncological needs, indications and using - Buettner-Teleaga, A.; Weis, J.; Goerling, U.; Hornemann, B.; Erim, Yesim; Beckmann, Matthias; Senf, B.; Gresch, C.; Schulz-Kindermann, K.; Friedrich, H. -C.; Albus, C.; Geiser, F.; et al. (2016)
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Psycho-Oncological Self-Help Groups in Bavaria: The Current Situation and Suggestions for Improvement - Lieb, Marietta; Madl, Martina; Vogelhuber, Martin; Beckmann, Matthias; Erim, Yesim (Oncology Research and Treatment, 2024)
BACKGROUND: Self-help groups (SHGs) are an important cornerstone of the German health care system. Especially collaborations of SHGs with cancer centers enable active patient involvement in cancer care. We investigated the current situation and unmet needs of Bavarian SHGs in order to point out possible options of action. METHODS: We conducted a cross-sectional study with Bavarian psycho-oncological SHGs. Via e-mail, an online survey was sent to 150 SHGs registered at the BZKF (Bavarian Cancer Research Center). We assessed activities and needs of the SHGs as well as the nature of collaborations with cancer centers. We focused on adaptations during the COVID-19 pandemic and the inclusion of migrants. RESULTS: 46 (33.66%) SHGs participated, while 39 (84.78%) completed the questionnaire. During the COVID-19 pandemic, 50% of the SHGs reported less meetings. 22.7% changed to online meetings or other formats (43.2%). 20.9% of the SHGs had regular meetings with the cancer center, and 23.1% with the psycho-oncology. 51.2% evaluated the psycho-oncological services as neutral to dissatisfying due to lack of information, availability, and long waiting times. The SHGs indicated needs concerning interventions (coping strategies, digital applications, etc.), information, and better communication. Efforts for overcoming inequalities seemed rare: only 13.6% of the SHGs and 16.2% of the cancer centers had services for migrants. CONCLUSIONS: This study gave an overview of current activities and needs of Bavarian SHGs. The implementation of patient guides, comprehensive information material, and low-threshold psycho-oncological services should be objectives in future care to increase patient satisfaction. The needs for services for migrants should be investigated in more detail.
CRIS-Team Scopus Importer:2024-05-17
Keywords: Cancer; Cancer centers; Collaborations; Psycho-oncology; Self-help groups

Q-TWiST analysis of pembrolizumab combined with chemotherapy as first-line treatment of metastatic TNBC that expresses PD-L1 - Fasching, Peter; Huang, M.; Haiderali, A.; Pan, W.; Hu, P.; Chaudhuri, M.; De Tilleghem, C. Le Bailly; Cappoen, N.; O'Shaughnessy, J. (ANNALS OF ONCOLOGY, 2022)
CRIS-Team WoS Importer:2022-06-03

Q-TWiST analysis of pembrolizumab combined with chemotherapy as first-line treatment of metastatic triple-negative breast cancer that expresses PD-L1 - Huang, Min; O'Shaughnessy, Joyce; Haiderali, Amin; Pan, Wilbur; Hu, Peter; Chaudhuri, Mitashri; Le Bailly De Tilleghem, Celine; Cappoen, Nicolas; Fasching, Peter (European Journal of Cancer, 2022)
Objective: In the KEYNOTE-355 (KN355) trial, pembrolizumab in combination with chemotherapy demonstrated superior efficacy and manageable safety compared with chemotherapy alone in patients with previously untreated locally recurrent inoperable and metastatic triple-negative breast cancer (mTNBC) with PD-L1 positive (Combined Positive Score [CPS]≥ 10) tumours. This study aimed to evaluate the clinical benefits and risks of pembrolizumab measured by quality-adjusted survival in the trial population. Methods: The study used data from the final analysis of KN355. The Quality-adjusted Time Without Symptoms of disease progression or Toxicity of treatment (Q-TWiST) analysis was used to compare treatments of pembrolizumab plus chemotherapy versus chemotherapy alone. Patients’ survival time was partitioned into three health states — toxicity before disease progression (TOX), time without symptoms or toxicity before disease progression (TWiST), and relapse (REL). Utilities for these health states were estimated using EuroQol-5 Dimensions, 3 Levels (EQ-5D-3L) data collected in KN355. Q-TWiST was derived as the utility-weighted sum of the mean health state durations. Results: Patients randomised to pembrolizumab plus chemotherapy had 3.7 months greater Q-TWiST (relative gain of 18%; P = 0.003) compared to those randomised to chemotherapy at the median follow-up of 44 months, and 4.3 months greater Q-TWiST (relative gain of 20%; P = 0.004) at the maximum follow-up of 52 months. The Q-TWiST gain increased with longer follow-up time. Conclusions: Pembrolizumab plus chemotherapy was associated with statistically significant and clinically important improvement in Q-TWiST compared to chemotherapy in previously untreated PD-L1–positive mTNBC.
CRIS-Team Scopus Importer:2022-11-25
Keywords: Metastatic triple-negative breast cancer; Pembrolizumab plus chemotherapy; Q-TWiST; Quality-adjusted survival

Qualitätssicherungsrichtlinie Früh- und Reifgeborene des Gemeinsamen Bundesausschusses als Qualitätsrisiko? Analyse zu Erfüllungsgrad und Konsequenzen in der Versorgung weiterer intensivpflichtiger Patienten sowie drohender Frühgeburten am Beispiel eines regionalen Verbund-Perinatalzentrums - Kleeberg, Markus; Beckmann, Matthias; Fusch, Christoph; Hanf, Volker; Kainer, Franz; Klinge, Jens; Koehler, Wolfgang; Morhart, Patrick; Schroth, Michael Andreas (Zeitschrift für Geburtshilfe und Neonatologie, 2020)
Background The quality guideline for care delivery to preterm and mature infants (QFR-RL) places high demands on perinatal centers. In this analysis, the degree of fulfillment was determined. Additionally, care delivery to further patient groups and sufficient nursing staff capacity for caredelivery to imminent preterm infants (FG) were evaluated. Methods A network of 4 perinatal centers (level 1) with about 10,000 births per year supplied the data on the ratio of 1:1/1:2-care infants,patients per nurse, and nursing staff capacity. This data was statistically evaluated by center, shift, and week day over a period of 5 months for compliance with QFR-RL and DGPM recommendations. Furthermore, imminent preterm infants were recorded and compared with available nursing staff capacity. Results In total, the QFR-RL was fulfilled in 88% of shifts (n=1,584). Only one center reached the required 95. The degree of fulfillment and the number of staff nurses declined from late to night shifts (p<0.001). The ratio of 1:1-care infants was significantly higher when demands were not fulfilled (p<0.001). Only 14.1 of imminent preterm infants could have been attended in accordance with the QFR-RL. Conclusion 1:1 care as well as lower nurse staffing in late and night shifts lead to non-fulfillment of requirements and poorer care delivery to other intensive care patients. This was also reflected in the lower degree of fulfillment of DGPM recommendations. Sufficient nursing staff capacity was rare with the consequence that it was almost impossible to deliver care to imminent preterm infants per the guideline.
CRIS-Team Scopus Importer:2020-11-06
Keywords: 1:1-Care; preterm infants care; quality guideline of care delivery of preterm and mature infants; quality of care; staffing ratio

Quality-adjusted survival with ribociclib plus fulvestrant (R plus F) versus placebo plus fulvestrant (P plus F) in postmenopausal women (PMW) HR+/HER2-advanced breast cancer (ABC) based on the MONALEESA-3 trial - Jerusalem, G.; Delea, T.; Martin Jimenez, M.; De Laurentiis, M.; Nusch, A.; Beck, J. T.; Chan, A.; Im, S-A.; Neven, P.; Lonshteyn, A.; Chandiwana, D.; Lanoue, B.; et al. (ANNALS OF ONCOLOGY, 2020)
CRIS-Team WoS Importer:2020-06-26

Quality-Adjusted Survival with Ribociclib Plus Fulvestrant Versus Placebo Plus Fulvestrant in Postmenopausal Women with HR±HER2− Advanced Breast Cancer in the MONALEESA-3 Trial - Jerusalem, Guy; Delea, Thomas E.; Martin, Migule; De Laurentiis, Michelino; Nusch, Arnd; Beck, J. Thaddeus; Chan, Arlene; Im, Seock Ah; Neven, Patrick; Lonshteyn, Alexander; Chandiwana, David; Lanoue, Brad; et al. (Clinical Breast Cancer, 2022)
Background: MONALEESA-3 demonstrated an overall survival (OS) benefit for ribociclib plus fulvestrant (R+F) in postmenopausal women with hormone receptor (HR) positive, HER2 negative advanced breast cancer (ABC). This study estimated quality-adjusted (QA) survival outcomes for patients receiving R+F vs. placebo (P)+F in MONALEESA-3. Methods: Kaplan-Meier OS was partitioned into health states: (1) toxicity (TOX)=time spent with grade 3 –4 adverse events before progression (DP); (2) progression (PROG)=time between DP and death; and (3) time without symptoms or toxicity (TWiST)=time not in TOX or PROG. QA time was calculated by combining estimated mean time in each health state with treatment-group specific health-state utility values estimated using EQ-5D-5L questionnaire. Outcomes included QA progression-free survival (QAPFS), QAOS, and QA TWiST (Q-TWiST). Q-TWiST was calculated with health-state utility values for TOX and PROG defined relative to TWiST. Results: Mean PFS and OS were significantly greater with R+F vs. P+F (difference 0.56 and 0.19 years). Mean time in TOX and TWiST were greater with R+F; mean time in PROG was greater with P+F. QAPFS was 0.45 years (95% CI 0.27 –0.63) greater with R+F than P+F (P <.001). QAOS was numerically greater with R+F vs. P+F (0.16 years, 95% CI 0.07 –0.45, P = .0569). Q-TWiST was 0.23 years greater with R+F (95% CI 0.07 –0.45, P = .0069). In a sensitivity analysis using an estimate of disutility for PROG, the difference in QAOS was 0.23 years (95% CI 0.08 –0.41, P = .0022). Conclusion: R+F in postmenopausal women with HR+/HER2- ABC improves QAPFS, resulting in clinically important improvements in Q-TWiST and may improve QAOS.
CRIS-Team Scopus Importer:2022-01-28
Keywords: Breast cancer; Fulvestrant; Postmenopausal; Quality of life; Ribociclib; Survival

Quality assurance and improvement in oncology using guideline-derived quality indicators - results of gynaecological cancer centres certified by the German cancer society (DKG) - Griesshammer, Ellen; Wesselmann, S.; Beckmann, Matthias; Dannecker, C.; Wagner, U.; Sibert, N. T.; Armbrust, R.; Sehouli, J. (Journal of Cancer Research and Clinical Oncology, 2022)
Purpose Based on the example of Gynaecological Cancer Centres (GCCs) certified by the German Cancer Society, this study evaluates the results of medical-guideline-derived quality indicators (QIs) for cervical cancer (CC) and ovarian cancer (OC), examines the development of indicator implementation over time as well as the status of guideline-compliant care and identifies improvement measures. Methods QI results for patients with CC and OC treated in GCCs between 2015 and 2019 are analysed. The median, overall proportion and standard deviation of each QI were calculated. Two-sided Cochran-Armitage tests were applied. Results QIs are divided into two categories: process-organization (PO-QIs) and treatment-procedures (TP-QIs), to allow a differentiated analysis for identifying improvement measures. PO-QIs that reflect the implementation of processes and structures show a high degree of application. PO-QIs have a tremendous influence on the quality of care and are easy to implement through SOPs. TP-QIs report on treatments that are performed in the GCC. TP-QIs that report on systemic therapies reach a plateau where the guideline is known, but patient-related-factors meaningfully prevent further increase. TP-QIs that report on surgical interventions fluctuate. The most relevant factors are practitioners' personal skills. Besides the discussion of results amongst peers during the audit, improvement measures could include surgical courses or coaching. Conclusion The analysis shows that a combination of different measures is necessary to anchor quality sustainably in health care and thus improve it.
CRIS-Team WoS Importer:2022-06-17
Keywords: Quality indicators; Quality assurance; Health service research; Certification

Quality assurance using quality indicators for prevention and early detection of cervical cancer in certified gynaecological dysplasia units and consultancies - Steinkasserer, Lena; Wesselmann, Simone; Quaas, Jens; Beckmann, Matthias; Dannecker, Christian; Hachenberg, Jens; Jentschke, Matthias; Hillemanns, Peter (Archives of Gynecology and Obstetrics, 2024)
Purpose: Cervical cancer is the fourth most common cancer in women worldwide. A successful screening concept for cervical cancer reduces the incidence and mortality of cervical cancer. Quality indicators (QIs) derived from the screening guidelines for cervical cancer and used by the certified dysplasia units and dysplasia consultancies are evaluated in this paper. The aim of this paper is to present the current data from the annual reports of these units and consultancies. Methods: The results of the basic data and indicators for the audit year 2022 in the gynaecological dysplasia consultancies and units are presented. In 2022, 84 dysplasia consultancies and 42 units were audited. 40 units and 84 consultancies are included in the annual report. QI outcomes for patients treated in certified dysplasia units and dysplasia consultancies are analysed. Median, overall proportion, and standard deviation were calculated for each QI. Results: The indicator year 2021 was analysed, which was audited in 2022 and evaluated in 2023. A total of nine QIs were analysed. Most target goals were met by the 84 certified dysplasia consultancies and by the 40 dysplasia units. The QIs evaluated are implemented to a very high degree. The targets for the three QIs were achieved by both the dysplasia consultancies and the units in at least 95% of the certified centres (QI 1: 100%, QI 2: 95%, QI 3: 100%; QI 1: 100%, QI 2: 97%, QI 3: 100%, respectively). The presentation of patients to the tumour board by the consultancies/units is working; the units are attending the tumour board more regularly than in previous years. Where the target was not met, the auditors issued deviations or reduced the duration of the certificate. The cases are discussed intensively in the sense of an individual case analysis and with the determination of measures on-site. Conclusions: The targets for the various indicators were largely met by the dysplasia consultancies and units in the 2022 audit year. The certification of gynaecological dysplasia consultancies/units which have to cooperate with certified gynaecological cancer centres, has for the first time ensured the continuity of healthcare from prevention and early diagnosis to treatment of gynaecological cancers.
CRIS-Team Scopus Importer:2024-09-06
Keywords: Cervical cancer; Dysplasia consultancy; Dysplasia unit; Prevention; Quality assurance; Quality indicators; Screening

Quality-Assured Analysis of PIK3CA Mutations in Hormone Receptor–Positive/Human Epidermal Growth Factor Receptor 2–Negative Breast Cancer Tissue: A Story About the Need for Proficiency Testing for High-Quality Molecular Biomarker Reporting in Precision Medicine - Schmidt, Carolin; Stöhr, Robert; Dimitrova, Lora; Beckmann, Matthias; Rübner, Matthias; Fasching, Peter; Denkert, Carsten; Lehmann, Ulrich; Vollbrecht, Claudia; Haller, Florian; Hartmann, Arndt; Erber, Ramona (Journal of Molecular Diagnostics, 2024)
In precision oncology, reliable testing of predictive molecular biomarkers is a prerequisite for optimal patient treatment. Interlaboratory comparisons are a crucial tool to verify diagnostic performance and reproducibility of one's approach. Herein is described the design and results of the first recurrent, internationally performed PIK3CA (phosphatidylinositol-4,5-bisphosphate 3 kinase catalytic subunit α) breast cancer tissue external quality assessment (EQA), organized by German Quality in Pathology GmbH and started in 2021. After the internal pretesting phase performed by the (lead) panel institutes, in both 2021 and 2022, each EQA test set comprised n = 10 tissue samples of hormone receptor–positive, human epidermal growth factor receptor 2–negative invasive breast cancer that had to be analyzed and reported by the participants. In 2021, the results were evaluated separately for German-speaking countries (part 1) and international laboratories (part 2). In 2022, the EQA was performed across the European Union. The EQA success rates were 84.6% (n = 11/13), 88.6% (n = 39/44), and 87.9% (n = 29/33) for EQA 2021 part 1, part 2, and EQA 2022, respectively. The most commonly used methods were next-generation sequencing and mutation-/allele-specific qualitative PCR-based assays. In summary, this recurrent PIK3CA EQA proved to be a suitable approach to obtain an international overview of methods used for PIK3CA mutation analysis, to evaluate them qualitatively, and identify the strengths and weaknesses of individual methods.
CRIS-Team Scopus Importer:2024-05-31

Quality of life and oncological outcome in endometrial cancer patients after vaginal brachytherapy: comparison of two dosing schemes - Papathemelis, Thomas; Scharl, Sophia; Hipp, Matthias; Scharl, Anton; Beckmann, Matthias; Lux, Michael P.; Koelbl, Oliver (Archives of Gynecology and Obstetrics, 2019)
Purpose: Vaginal brachytherapy reduces the risk of local recurrence and was shown to be equieffective in preventing vaginal vault recurrence, but less toxic compared to external-beam radiotherapy in a subset of high intermediate-risk endometrial cancer patients and is administered as single adjuvant treatment in those patients. Different radiotherapeutic approaches with various dosing schemes exist toward brachytherapy. The aim of this study was to compare the outcome and long-term quality of life after brachytherapy with two different high-dose-rate dosing schemes. Methods: Retrospective analysis was conducted of the recurrence and survival rates of 104 patients with endometrial cancer FIGO stage I–II that underwent adjuvant brachytherapy with three times 5 Gy or four times 5 Gy to the upper two-thirds of the vaginal vault in two different institutions between January 2010 and December 2013. Quality of life was assessed by EORTC QLQ-30 questionnaire and EN 24 module. Results: The vaginal vault recurrence rates were 4.9% and 5.0% for patients treated with 3 × 5 Gy and 4 × 5 Gy, respectively (p = 0.98). We did not observe a difference in pelvic recurrence (p = 0.96), overall survival (p = 0.33) or quality of life between the different radiotherapy regimens. Metastatic recurrence and the use of chemotherapy contribute to impairment on quality of life. Younger patients (< 70 years) reported worse emotional functioning (p = 0.02) and higher symptom scales of diarrhea (p = 0.01) and financial problems (p = 0.03). Sexual activity was lower in patients younger than 70 years (p = 0.05). Conclusions: Further prospective studies are needed to evaluate the effect of dosing schemes on recurrence rates and quality of life. Younger patients (< 70 years) seem to experience greater reduction in quality of life due to endometrial cancer diagnosis.
CRIS-Team Scopus Importer:2019-05-21
Keywords: Adjuvant treatment; Brachytherapy; Endometrial cancer; Radiotherapy

Quality of Life and Treatment-Related Side Effects in Patients With HR+/HER2- Advanced Breast Cancer: Findings From a Multicountry Survey - Cardoso, Fatima; Rihani, Julie; Harmer, Victoria; Harbeck, Nadia; Casas, Ana; Rugo, Hope S.; Fasching, Peter; Moore, Adam; de Courcy, Joanna; Pathak, Purnima; Haftchenary, Sina; Aubel, Dawn; et al. (Oncologist, 2023)
BACKGROUND: Quality of life (QOL) is a critical factor in decision-making for advanced breast cancer (ABC). There is a need to improve how QOL and treatment-related side effects (SEs) that impact it are clinically assessed. We examined healthcare professionals' (HCPs') and patients' perspectives on the importance of QOL discussions and the impact of SEs on QOL in clinical settings. PATIENTS AND METHODS: A cross-sectional online survey was conducted (7/2020-5/2021) among oncologists, nurses, and patients with HR+/HER2- ABC in 7 countries. RESULTS: The survey was completed by 502 HCPs and 467 patients. Overall, 88% of oncologists and 49% of patients recalled QOL discussions at follow-up. In the first- through fourth-line (1L, 2L, 3L, and 4L) settings, respectively, 48%, 57%, 79%, and 85% of oncologists reported QOL was very important; 73% and 45% of patients receiving 1L and 2L treatment and 40% receiving 3L+ treatment indicated QOL was important. Patients reported that insomnia, anxiety, back pain, fatigue, diarrhea, hot flashes, low sexual interest, and loss of appetite had a moderate/severe impact on QOL. Of patients experiencing certain SEs, ≥64% did not discuss them with HCPs until there was a moderate/severe impact on QOL. In patients receiving a CDK4/6 inhibitor, SEs, including insomnia, diarrhea, back pain, and fatigue, had a moderate/severe impact on QOL. CONCLUSIONS: This survey discovered disconnects between HCPs and patients with ABC on the importance of QOL discussions and the impact of SEs on QOL. These data support the use of ABC-specific QOL questionnaires that closely monitor SEs impacting QOL.
CRIS-Team Scopus Importer:2023-10-20
Keywords: advanced breast cancer; physician/patient communication; qualitative research; quality of life; survey

Quality of life with talazoparib after platinum or multiple cytotoxic non-platinum regimens in patients with advanced breast cancer and germline BRCA1/2 mutations: patient-reported outcomes from the ABRAZO phase 2 trial - Hurvitz, S. A.; Quek, R. G. W.; Turner, N. C.; Telli, M. L.; Rugo, H. S.; Mailliez, A.; Ettl, J.; Grischke, E.; Mina, L. A.; Balmana, Judith; Fasching, Peter; Bhattacharyya, H.; et al. (European Journal of Cancer, 2018)
BACKGROUND: Talazoparib (1 mg/day) exhibited promising efficacy and safety in patients with advanced breast cancer during ABRAZO (NCT02034916); this study evaluated patient-reported outcomes (PROs). PATIENTS AND METHODS: ABRAZO is a two-cohort, two-stage, phase 2 study of talazoparib in patients with advanced breast cancer after a response to prior platinum-based therapy (cohort 1 [C1], n = 49) or ≥3 platinum-free cytotoxic-based regimens (cohort 2 [C2], n = 35). PROs were assessed on day 1 (baseline), every 6 weeks for an initial 24 weeks, and every 12 weeks thereafter until progression, using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) and its breast cancer module, QLQ-BR23. RESULTS: Global health status/quality of life (GHS/QoL) was maintained from baseline across all time points for both C1 and C2. For C1 and C2, median time to deterioration (TTD) of GHS/QoL (95% confidence interval [CI]) was 2.8 (2.1, 3.0) and 5.5 (4.2, 5.7) months, respectively. Median TTD for all QLQ-C30 functional scales for C1 and C2 ranged 2.1-3.1 months and 4.2-5.6 months, respectively; median TTD for all QLQ-BR23 symptom scales ranged 2.6-4.0 months and 4.2-5.6 months, respectively. There were no statistically significant differences in estimated overall change from baseline in the GHS/QoL scale for both cohorts (C1: -2.6 [95% CI, -7.8, 2.5]; C2: 1.2 [95% CI, -5.5, 8.0]). Significant overall improvements in the breast symptoms and arm symptoms and the future perspective of patients in C1 and C2 were observed, despite the statistically significant and clinically meaningful overall deterioration among patients regarding their role functioning (in C1) and dyspnoea symptoms (in C2). CONCLUSION: Despite the statistically significant and clinically meaningful overall deterioration among patients regarding their role functioning (in C1) and dyspnoea symptoms (in C2), patients in both C1 and C2 reported significant overall improvements in their breast symptoms, arm symptoms and future perspective, and their GHS/QoL was maintained from baseline.
EVALuna2:202806

Quantification of thyroid volume using 3-D ultrasound imaging - Kollorz, Eva Nicole Karin; Hahn, Dieter; Linke, Rainer; Goecke, Tamme W.; Hornegger, Joachim; Kuwert, Torsten (IEEE Transactions on Medical Imaging, 2008)
Ultrasound (US) is among the most popular diagnostic techniques today. It is non-invasive, fast, comparably cheap, and does not require ionizing radiation. US is commonly used to examine the size, and structure of the thyroid gland. In clinical routine, thyroid imaging is usually performed by means of 2-D US. Conventional approaches for measuring the volume of the thyroid gland or its nodules may therefore be inaccurate due to the lack of 3-D information. This work reports a semi-automatic segmentation approach for the classification, and analysis of the thyroid gland based on 3-D US data. The images are scanned in 3-D, pre-processed, and segmented. Several pre-processing methods, and an extension of a commonly used geodesic active contour level set formulation are discussed in detail. The results obtained by this approach are compared to manual interactive segmentations by a medical expert in five representative patients. Our work proposes a novel framework for the volumetric quantification of thyroid gland lobes, which may also be expanded to other parenchymatous organs. © 2006 IEEE.

RAD51B in Familial Breast Cancer - Pelttari, Liisa M.; Khan, Sofia; Vuorela, Mikko; Kiiski, Johanna I.; Vilske, Sara; Nevanlinna, Viivi; Ranta, Salla; Schleutker, Johanna; Winqvist, Robert; Kallioniemi, Anne; Doerk, Thilo; Bogdanova, Natalia V.; et al. (PLoS ONE, 2016)
Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11-1.19, P = 8.88 x 10-16) and among familial cases (OR: 1.24, 95% CI: 1.16-1.32, P = 6.19 x 10-11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.
EVALuna2:33327

RAD51 Testing in Patients with Early HER2-Negative Breast Cancer and Homologous Recombination Deficiency: A Post Hoc Analysis of the GeparOLA Trial - Villacampa, Guillermo; Llop-Guevara, Alba; Filmann, Natalie; Herencia-Ropero, Andrea; Fasching, Peter; Karn, Thomas; Marmé, Frederik; Klare, Peter; Müller, Volkmar; Stefek, Andrea; Schem, Christian; Uleer, Christoph; et al. (Clinical Cancer Research, 2025)
PURPOSE: The randomized GeparOLA trial reported comparable pathologic complete response (pCR) rates with neoadjuvant treatment containing olaparib versus carboplatin. In this study, we evaluate the association between functional homologous recombination deficiency (HRD) by RAD51 foci and pCR and the potential of improving patient selection by combining RAD51 and stromal tumor-infiltrating lymphocytes. PATIENTS AND METHODS: This is a post hoc blinded biomarker analysis from the randomized GeparOLA trial. Patients with early-stage HER2-negative breast cancer and HRD assessed by Myriad MyChoice or BRCA1/BRCA2 mutations were randomized 1:1 to receive (i) paclitaxel plus olaparib or (ii) paclitaxel plus carboplatin, both followed by epirubicin/cyclophosphamide. Functional HRD was predefined as a RAD51 score ≤10% (RAD51-low). RESULTS: Overall, 90 of 97 (92.8%) samples were evaluable for RAD51 testing, and 72 of 90 (80.0%) were RAD51-low. The pCR rate in patients with RAD51-low tumors was 66.7% (48/72), whereas it decreased to 22.2% (4/18) in those with RAD51-high. In the multivariable model including clinicopathologic factors and treatment, the RAD51 score remained significantly associated with pCR (OR = 12.03; 95% confidence interval, 2.60-55.73; P = 0.002). Patients with RAD51-low and high stromal tumor-infiltrating lymphocytes in their tumors achieved a pCR rate of 75.0% (27/36). Similar results were observed for olaparib or carboplatin. In the exploratory disease-free survival analysis, no differences were observed between RAD51 groups (high vs. low: HR = 0.85; 95% confidence interval, 0.25-2.97). CONCLUSIONS: In a preselected population with HRD, according to a genetic test, RAD51 testing identifies patients with different pCR rates under PARP inhibitor-based or platinum-based therapies. Future biomarker-driven studies should consider this information to refine stratification factors and to improve patient selection.
CRIS-Team Scopus Importer:2025-03-28

Radiotherapy statements of the 18th St. Gallen International Breast Cancer Consensus Conference—a German expert perspective - Krug, David; Banys-Paluchowski, Maggie; Brucker, Sara Y.; Denkert, Carsten; Ditsch, Nina; Fasching, Peter; Haidinger, Renate; Harbeck, Nadia; Heil, Jörg; Huober, Jens; Jackisch, Christian; Janni, Wolfgang; et al. (Strahlentherapie und Onkologie, 2024)
Purpose: To summarize the radiotherapy-relevant statements of the 18th St. Gallen Breast Cancer Consensus Conference and interpret the findings in light of German guideline recommendations. Methods: Statements and voting results from the 18th St. Gallen International Breast Cancer Consensus Conference were collected and analyzed according to their relevance for the radiation oncology community. The voting results were discussed in two hybrid meetings among the authors of this manuscript on March 18 and 19, 2023, in light of the German S3 guideline and the 2023 version of the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) guidelines. Results and conclusion: There was a high level of agreement between the radiotherapy-related statements of the 18th St. Gallen International Breast Cancer Consensus Conference and the German S3 and AGO guidelines. Discrepancies include the impact of number of lymph node metastases for the indication for postmastectomy radiotherapy.
CRIS-Team Scopus Importer:2024-05-17
Keywords: Breast-conserving surgery; Ductal carcinoma in situ; Guideline; Hypofractionation; Radiation oncology

Randomised, open-label, phase II study comparing the efficacy and the safety of cabazitaxel versus weekly paclitaxel given as neoadjuvant treatment in patients with operable triple-negative or luminal B/HER2-negative breast cancer (GENEVIEVE) - Kuemmel, Sherko; Paepke, Stefan; Huober, Jens; Schem, Christian; Untch, Michael; Blohmer, Jens Uwe; Eiermann, Wolfgang; Gerber, Bernd; Hanusch, Claus; Hilfrich, Joern; Jackisch, Christian; Schneeweiss, Andreas; et al. (European Journal of Cancer, 2017)
BACKGROUND: The GENEVIEVE study compared the pathological complete response (pCR) rate (ypT0/is ypN0/+) in patients with operable human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC) treated with either cabazitaxel or paclitaxel. METHODS: GENEVIEVE was a prospective, multicentre, randomised, open-label, phase II study comparing the efficacy and the safety of four 3-weekly cycles cabazitaxel versus 12 weeks of paclitaxel given as neoadjuvant treatment. Primary end-point was the pCR rate defined as the complete absence of invasive carcinoma on histological examination of the breast irrespective of lymph node involvement (ypT0/is, ypN0/+) after the taxane treatment. Patients could receive an anthracycline-based therapy thereafter. RESULTS: Overall, 333 patients were randomised and started treatment with 74.7% and 83.2% of patients completing treatment in the cabazitaxel and paclitaxel arms, respectively. Patients in cabazitaxel arm had a significantly lower pCR rate compared to the paclitaxel arm (1.2% versus 10.8%; p = 0.001). A total of 42 (25.3%) patients in the cabazitaxel arm and 17 (10.2%) in the paclitaxel arm had at least one serious adverse event (p < 0.001). Dose reductions were observed in 9.6% patients in the cabazitaxel arm compared to 11.4% in the paclitaxel arm (p = 0.721). Main reason for dose reductions was non-haematological toxicities in 3.0% versus 7.8% (p = 0.087), respectively. CONCLUSIONS: The GENEVIEVE study showed no short-term effect of cabazitaxel in triple-negative or luminal B/HER2-negative primary BC, while there seemed to be no differences in drug exposure and patient compliance between the two arms. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT01779479.
EVALuna2:36185

Randomized, open-label, phase II study comparing the efficacy and the safety of cabazitaxel versus weekly paclitaxel given as neoadjuvant treatment in patients with operable triple negative or luminal B/HER2 normal breast cancer (GENEVIEVE) - Paepke, S.; Huober, J.; Sherko, K.; Eidtmann, H.; Untch, M.; Costa, S. Dan; Blohmer, J. U.; Eiermann, W.; Gerber, B.; Hanusch, C.; Hilfrich, J.; Jackisch, C.; et al. (2016)
EVALuna2:33541

RANK and RANKL Expression in Tumors of Patients with Early Breast Cancer - Behrens, Annika; Wurmthaler, Lena; Heindl, Felix; Gaß, Paul; Häberle, Lothar; Volz, Bernhard; Hack, Carolin; Emons, Julius; Erber, Ramona; Hartmann, Arndt; Beckmann, Matthias; Rübner, Matthias; et al. (Geburtshilfe und Frauenheilkunde, 2023)
Introduction The receptor activator of nuclear factor-κB (RANK) pathway was associated with the pathogenesis of breast cancer. Several studies attempted to link the RANK/RANKL pathway to prognosis; however, with inconsistent outcomes. We aimed to further contribute to the knowledge about RANK/RANKL as prognostic factors in breast cancer. Within this study, protein expression of RANK and its ligand, RANKL, in the tumor tissue was analyzed in association with disease-free survival (DFS) and overall survival (OS) in a study cohort of patients with early breast cancer. Patients and Methods 607 samples of female primary and early breast cancer patients from the Bavarian Breast Cancer Cases and Controls Study were analyzed to correlate the RANK and RANKL expression with DFS and OS. Therefore, expression was quantified using immunohistochemical staining of a tissue microarray. H-scores were determined with the cut-off value of 8.5 for RANK and 0 for RANKL expression, respectively. Results RANK and RANKL immunohistochemistry were assessed by H-score. Both biomarkers did not correlate (ρ = -0.04). According to molecular subtypes, triple-negative tumors and HER2-positive tumors showed a higher number of RANK-positive tumors (H-score ≥ 8.5), however, no subtype-specific expression of RANKL could be detected. Higher RANKL expression tended to correlate with a better prognosis. However, RANK and RANKL expression could not be identified as statistically significant prognostic factors within the study cohort. Conclusions Tumor-specific RANK and RANKL expressions are not applicable as prognostic factors for DFS and OS, but might be associated with subtype-specific breast cancer progression.
CRIS-Team Scopus Importer:2023-12-22
Keywords: breast cancer; immunohistochemistry; prognosis; RANK; RANKL

RANK Expression as an Independent Predictor for Response to Neoadjuvant Chemotherapy in Luminal-Like Breast Cancer: A Translational Insight from the GeparX Trial - Link, Theresa; Blohmer, Jens Uwe; Schmitt, Wolfgang D.; Kuhlmann, Jan Dominik; Just, Marianne; Untch, Michael; Stoetzer, Oliver J.; Fasching, Peter; Thill, Marc; Reinisch, Mattea; Schneeweiss, Andreas; Wimberger, Pauline; et al. (Clinical Cancer Research, 2023)
Purpose: The GeparX study investigated whether denosumab as add-on treatment to nab-paclitaxel–based neoadjuvant chemotherapy (NACT) with two different schedules (125 mg/m2 weekly vs. day 1, 8 every 22 days) may increase pathologic complete response (pCR) rate. The addition of denosumab to NACT did not improve pCR rates as recently published. In this study, we investigated whether receptor activator of nuclear factor-kappa B (RANK) expression, as part of the denosumab target pathway: (i) may retrospectively identify a subgroup of patients with additional clinical benefit of denosumab or (ii) may predict response to nab-paclitaxel NACT. Experimental Design: RANK protein was IHC-stained on pre-therapeutic core biopsies from patients of the GeparX study (n ¼ 667) with the antibody RANK/Envision System HRP (DAB) and was analyzed for the percentage of membranous RANK tumor cell staining (>5% RANKhigh vs. ≤5% RANKlow). Results: We could not identify any patient subgroup with differential response under denosumab add-on treatment in patients with RANKhigh expression [139/667, 20.8%; OR, 0.86; 95% confidence interval (CI), 0.44–1.68; P ¼ 0.667] or RANKlow expression (528/667 (79.2%) OR, 1.10; 95% CI, 0.78–1.56; P ¼ 0.589; Pinteraction ¼ 0.528). However, the pCR rate was higher in the RANKhigh subgroup compared with RANKlow (50% vs. 39%; OR, 1.52; 95% CI, 1.04–2.21; P ¼ 0.037). RANK expression constituted an independent predictor of response to NACT frequently in patients with luminal-like subtype (HRþ/HER2−; OR, 2.98; 95% CI, 1.30–6.79; P ¼ 0.010). No predictive value of RANK expression among the different nab-paclitaxel regimens was observed. Conclusion: We report RANK expression to be an independent predictive biomarker for response to NACT in patients with luminal-like breast cancer.
CRIS-Team Scopus Importer:2023-12-08

RANKL and OPG and their influence on breast volume changes during pregnancy in healthy women - Wunderle, Marius; Rübner, Matthias; Häberle, Lothar; Schwenke, Eva; Hack, Carolin; Bayer, Christian M.; Koch, Martin; Schwitulla, Judith; Schulz-Wendtland, Rüdiger; Kozieradzki, Ivona; Lux, Michael P.; Beckmann, Matthias; et al. (Scientific Reports, 2020)
Breast cancer risk is reduced by number of pregnancies and breastfeeding duration, however studies of breast changes during or after pregnancy are rare. Breast volume changes - although not linked to breast cancer risk - might be an interesting phenotype in this context for correlative studies, as changes of breast volume vary between pregnant women. Serum receptor activator of nuclear factor kappa B ligand (RANKL) and its antagonist osteoprotegerin (OPG) were measured prospectively before gestational week 12, and three-dimensional breast volume assessments were performed. A linear regression model including breast volume at the start of pregnancy, RANKL, OPG, and other factors was used to predict breast volume at term. The mean breast volume was 413 mL at gestational week 12, increasing by a mean of 99 mL up to gestational week 40. In addition to body mass index and breast volume at the beginning of pregnancy, RANKL and OPG appeared to influence breast volume with a mean increase by 32 mL (P = 0.04) and a mean reduction by 27 mL (P = 0.04), respectively. Linking the RANKL/RANK/OPG pathway with breast volume changes supports further studies aiming at analysing breast changes during pregnancy with regard to breast cancer risk.
CRIS-Team Scopus Importer:2020-03-31

Rare Case Report - Mucoepidermoid Carcinoma (MEC) of the Vulva - Dietl, Anna; Stübs, Frederik; Schulmeyer, Carla; Behrens, Annika; Hartmann, Arndt; Agaimy, Abbas; Beckmann, Matthias; Gaß, Paul (GEBURTSHILFE UND FRAUENHEILKUNDE, 2022)
CRIS-Team WoS Importer:2022-11-04

Rare germline copy number variants (CNVs) and breast cancer risk - Dennis, Joe; Tyrer, Jonathan P.; Walker, Logan C.; Michailidou, Kyriaki; Dorling, Leila; Bolla, Manjeet K.; Wang, Qin; Ahearn, Thomas U.; Andrulis, Irene L.; Anton-Culver, Hoda; Antonenkova, Natalia N.; Arndt, Volker; et al. (Communications Biology, 2022)
Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.
CRIS-Team Scopus Importer:2022-02-04

Rationale and trial design of NATALEE: a Phase III trial of adjuvant ribociclib + endocrine therapy versus endocrine therapy alone in patients with HR+/HER2− early breast cancer - Slamon, Dennis J.; Fasching, Peter; Hurvitz, Sara; Chia, Stephen; Crown, John; Martín, Miguel; Barrios, Carlos H.; Bardia, Aditya; Im, Seock Ah; Yardley, Denise A.; Untch, Michael; Huang, Chiun Sheng; et al. (Therapeutic Advances in Medical Oncology, 2023)
Background: Ribociclib has demonstrated a statistically significant overall survival benefit in pre- and postmenopausal patients with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) advanced breast cancer. New Adjuvant Trial with Ribociclib [LEE011] (NATALEE) is a trial evaluating the efficacy and safety of adjuvant ribociclib plus endocrine therapy (ET) versus ET alone in patients with HR+/HER2− early nonmetastatic breast cancer (EBC). Methods/design: NATALEE is a multicenter, randomized, open-label, Phase III trial in patients with HR+/HER2− EBC. Eligible patients include women, regardless of menopausal status, and men aged ⩾18 years. Select patients with stage IIA, stage IIB, or stage III disease (per the anatomic classification in the AJCC Cancer Staging Manual, 8th edition) with an initial diagnosis ⩽18 months prior to randomization are eligible. Patients receiving standard (neo)adjuvant ET are eligible if treatment was initiated ⩽12 months before randomization. Patients undergo 1:1 randomization to ribociclib 400 mg/day (3 weeks on/1 week off) +ET (letrozole 2.5 mg/day or anastrozole 1 mg/day [investigator’s discretion] plus goserelin [men or premenopausal women]) or ET alone. Ribociclib treatment duration is 36 months; ET treatment duration is ⩾60 months. The primary end point is invasive disease-free survival. Discussion: The 36-month treatment duration of ribociclib in NATALEE is extended compared with that in other adjuvant cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor trials and is intended to maximize efficacy due to longer duration of CDK4/6 inhibition. Compared with the 600-mg/day dose used in advanced breast cancer, the reduced ribociclib dose used in NATALEE may improve tolerability while maintaining efficacy. NATALEE includes the broadest population of patients with HR+/HER2− EBC of any Phase III trial currently evaluating adjuvant CDK4/6 inhibitor treatment. Trial registration: ClinicalTrials.gov identifier: NCT03701334 (https://clinicaltrials.gov/ct2/show/NCT03701334)
CRIS-Team Scopus Importer:2023-06-30
Keywords: adjuvant therapy; CDK4/6 inhibitors; HR+/HER2– early breast cancer; NATALEE; ribociclib

Real-world effectiveness of ribociclib 1 aromatase inhibitor, or endocrine monotherapy, or chemotherapy as first-line treatment in postmenopausal women with HR-positive, HER2-negative locally advanced or metastatic breast cancer: The RIBANNA study - Fasching, Peter; Decker, T.; Guderian, G.; Heim, J.; Jackisch, C.; Lueck, H-J.; Lueftner, D.; Marme, F.; Reimer, T.; Woeckel, A. (ANNALS OF ONCOLOGY, 2018)
CRIS-Team WoS Importer:2019-03-08

Real-world efficacy of ribociclib plus aromatase inhibitor/fulvestrant, or endocrine monotherapy, or chemotherapy as first-line treatment in women with HR-positive, HER2-negative locally advanced or metastatic breast cancer: Third interim analysis from the RIBANNA study - Wockel, Achim; Brucker, Cosima; Decker, Thomas; Falbrede, Jorg; Forstbauer, Helmut; Gohler, Thomas; Hoffmann, Oliver; Jackisch, Christian; Janssen, Jan; Kohler, Andreas; Ludtke-Heckenkamp, Kerstin; Luftner, Diana; et al. (CANCER RESEARCH, 2021)
CRIS-Team WoS Importer:2021-03-26

Reconstructing tumor history in breast cancer: signatures of mutational processes and response to neoadjuvant chemotherapy☆ - Denkert, C.; Untch, M.; Benz, S.; Schneeweiss, A.; Weber, K. E.; Schmatloch, S.; Jackisch, C.; Sinn, H. P.; Golovato, J.; Karn, T.; Marmé, F.; Link, T.; et al. (Annals of Oncology, 2021)
Background: Different endogenous and exogenous mutational processes act over the evolutionary history of a malignant tumor, driven by abnormal DNA editing, mutagens or age-related DNA alterations, among others, to generate the specific mutational landscape of each individual tumor. The signatures of these mutational processes can be identified in large genomic datasets. We investigated the hypothesis that genomic patterns of mutational signatures are associated with the clinical behavior of breast cancer, in particular chemotherapy response and survival, with a particular focus on therapy-resistant disease. Patients and methods: Whole exome sequencing was carried out in 405 pretherapeutic samples from the prospective neoadjuvant multicenter GeparSepto study. We analyzed 11 mutational signatures including biological processes such as APOBEC-mutagenesis, homologous recombination deficiency (HRD), mismatch repair deficiency and also age-related or tobacco-induced alterations. Results: Different subgroups of breast carcinomas were defined mainly by differences in HRD-related and APOBEC-related mutational signatures and significant differences between hormone-receptor (HR)-negative and HR-positive tumors as well as correlations with age, Ki-67 and immunological parameters were observed. We could identify mutational processes that were linked to increased pathological complete response rates to neoadjuvant chemotherapy with high significance. In univariate analyses for HR-positive tumors signatures, S3 (HRD, P < 0.001) and S13 (APOBEC, P = 0.001) as well as exonic mutation rate (P = 0.002) were significantly correlated with increased pathological complete response rates. The signatures S3 (HRD, P = 0.006) and S4 (tobacco, P = 0.011) were prognostic for reduced disease-free survival of patients with chemotherapy-resistant tumors. Conclusion: The results of this investigation suggest that the clinical behavior of a tumor, in particular, response to neoadjuvant chemotherapy and disease-free survival of therapy-resistant tumors, could be predicted by the composition of mutational signatures as an indicator of the individual genomic history of a tumor. After additional validations, mutational signatures might be used to identify tumors with an increased response rate to neoadjuvant chemotherapy and to define therapy-resistant subgroups for future therapeutic interventions.
CRIS-Team Scopus Importer:2021-03-05
Keywords: breast cancer; mutational signatures; neoadjuvant therapy; prognosis; response; whole exome sequencing

Reconstructive and Aesthetic Surgeries on the Female GenitaliaGuideline of the DGGG, DGPRAC, OEGGG and SGGG (S2k-Level, AWMF Registry No. 009/019, May 2022) - Beckmann, Matthias; Borkenhagen, Ada; Fahlbusch, Christine; Gold, Daniela; Hoffmann, Juergen; Löhrs, Bettina; Luze, Hanna; Mirastschijski, Ursula; O'Dey, Dan M.; Pöschke, Patrik; Remmel, Eugenia; Schaefer, Dirk; et al. (Geburtshilfe und Frauenheilkunde, 2023)
Aim This official guideline was coordinated and published by the German Society for Gynaecology and Obstetrics (DGGG), the German Society for Plastic, Reconstructive and Aesthetic Surgery (DGPRAC), the Austrian Society for Gynaecology and Obstetrics (OEGGG), and the Swiss Society for Gynaecology and Obstetrics (SGGG). The guideline aims to provide a consensus-based overview of reconstructive and aesthetic surgeries on female genitalia based on an evaluation of the relevant literature. Methods This S2k-guideline was developed by representative members from different medical professions on behalf of the guidelines commission of the DGGG, DGPRAC, OEGGG and SGGG using a structured consensus process. Recommendations Statements and recommendations on the epidemiology, aetiology, classification, symptoms, diagnosis, and treatment of acquired changes of the external genitalia are presented and special situations are discussed.
CRIS-Team Scopus Importer:2023-07-21
Keywords: aesthetic surgeries; female genital mutilation (FGM); female genitalia; guideline; reconstructive surgeries

Recording of the regional Origin Areas of Patients from the Molecular Tumor Board to Identify the "white Spots" in the Service Area - A joint Initiative of the Bavarian CCC WERA Alliance - Lueke, F.; Haller, F.; Utpatel, K.; Krebs, M.; Meidenbauer, Norbert; Scheiter, A.; Spörl, Silvia; Heudobler, D.; Keil, F.; Schubart, Christoph; Tögel, Lars; Einhell, S.; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2022)
CRIS-Team WoS Importer:2022-11-18

Recurrent KAT6B/A::KANSL1 Fusions Characterize a Potentially Aggressive Uterine Sarcoma Morphologically Overlapping With Low-grade Endometrial Stromal Sarcoma. - Agaimy, Abbas; Clarke, Blaise A.; Kolin, David L.; Lee, Cheng-Han; Lee, Jen-Chieh; Mccluggage, W. Glenn; Pöschke, Patrik; Stöhr, Robert; Swanson, David; Turashvili, Gulisa; Beckmann, Matthias; Hartmann, Arndt; et al. (American Journal of Surgical Pathology, 2022)
With the widespread application of next-generation sequencing, the genetic landscape of uterine mesenchymal neoplasms has been evolving rapidly to include several recently identified fusion genes. Although chromosomal rearrangements involving the 10q22 and 17q21.31 loci have been reported in occasional uterine leiomyomas decades ago, the corresponding KAT6B::KANSL1 fusion has been only recently identified in 2 uterine tumors diagnosed as leiomyoma and leiomyosarcoma. We herein describe 13 uterine stromal neoplasms carrying a KAT6B::KANSL1 (n=11) and KAT6A::KANSL1 (n=2) fusion. Patient ages ranged from 33 to 81 years (median, 49 y). Tumor size was 2.6 to 23.5 cm (median, 8.2 cm). Nine tumors were myometrium-centered, and 3 had an intracavitary component. Original diagnoses were mostly low-grade endometrial stromal sarcoma (LG-ESS; 10 cases) with atypical features (limited CD10 expression, sex cord-like features, pericytic vasculature, and frequent myxoid changes). Treatment was hysterectomy±bilateral salpingo-oophorectomy (10), myomectomy (1), and curettage (2). Five patients were disease-free at 6 to 34 months, 3 (27%) died of disease at 2 to 47 months, and 3 were alive with disease at 2, 17, and 17 years. Histologically, most tumors showed variable overlap with LG-ESS, but they were generally well-circumscribed lacking the extensive permeative and angioinvasive growth typical of LG-ESS. They were composed of monotonous medium-sized oval and spindle cells arranged into diffuse sheets with prominent spiral-type arterioles and frequent pericytoma-like vascular pattern. Variable myxoid stromal changes were frequent. Mitotic activity ranged from 1 to >20 in 10 HPFs. Immunohistochemistry showed variable expression of CD10 (12/13), estrogen receptor (8/11), progesterone receptor (8/11), smooth muscle actin (9/11), desmin (4/12), h-caldesmon (2/10), calretinin (3/8), inhibin (1/7), WT1 (4/7), cyclin D1 (5/11; diffuse in only 1 case), and pankeratin (5/10). This series characterizes a KAT6B/A::KANSL1 fusion-positive uterine stromal neoplasm within the morphologic spectrum of LG-ESS but with atypical features. The relationship of these neoplasms to genuine LG-ESS remains unclear. This molecular subtype of uterine endometrial stromal sarcoma has the potential for an unfavorable clinical course despite the absence of widely invasive growth; nevertheless, analysis of more cases is necessary to delineate the phenotypic spectrum and biological potential of this tumor.
EVALuna2:504168

Reduction of Serious Adverse Events (SAE) under palbociclib treatment in patients using an interactive eHealth system - Schmidt, M.; Degenhardt, T.; Fasching, Peter; Lueftner, D.; Mueller, V.; Thomssen, C.; Schem, C.; Witzel, I.; Decker, T.; Tesch, H.; Kuemmel, S.; Uleer, C.; et al. (EUROPEAN JOURNAL OF CANCER, 2020)
CRIS-Team WoS Importer:2020-11-13

Reduction of Serious Adverse Events (SAE) under palbociclib treatment in patients using an interactive eHealth system - Schmidt, M.; Degenhardt, T.; Fasching, Peter; Lüftner, D.; Müller, V.; Thomssen, C.; Schem, C.; Witzel, I.; Decker, T.; Tesch, H.; Kümmel, S.; Uleer, C.; et al. (European Journal of Cancer, 2020)
CRIS-Team Scopus Importer:2020-10-16

Refined cut-off for TP53 immunohistochemistry improves prediction of TP53 mutation status in ovarian mucinous tumors: implications for outcome analyses - Kang, Eun Young; Cheasley, Dane; LePage, Cecile; Wakefield, Matthew J.; da Cunha Torres, Michelle; Rowley, Simone; Salazar, Carolina; Xing, Zhongyue; Allan, Prue; Bowtell, David D.L.; Mes-Masson, Anne Marie; Provencher, Diane M.; et al. (Modern Pathology, 2021)
TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5-14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MBOT with a higher risk of mortality.
CRIS-Team Scopus Importer:2021-02-05

Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia - Spurdle, Amanda B.; Couch, Fergus J.; Parsons, Michael T.; Mcguffog, Lesley; Barrowdale, Daniel; Bolla, Manjeet K.; Wang, Qin; Healey, Sue; Schmutzler, Rita Katharina; Wappenschmidt, Barbara; Rhiem, Kerstin; Hahnen, Eric; et al. (Breast Cancer Research, 2014)
The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling.Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach.ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)).These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.
EVALuna2:9304

Regulation of murine placentogenesis by the retroviral genes Syncytin-A, Syncytin-B and Peg10 - Henke, Christine; Ruebner, Matthias; Faschingbauer, Florian; Stolt, Claus; Schäfer, Natascha; Lang, Nadine; Beckmann, Matthias; Strissel, Pamela; Strick, Reiner (Differentiation, 2013)
The murine placenta has a trichorial structure with two multinucleated syncytiotrophoblast (SCT) layers representing a barrier between the maternal and fetal blood system. Genes of endogenous retroviruses and retrotransposon-derived paternally expressed genes (Peg), remnants of past infections and integrations in the genome, have essential functions in placentogenesis. Previous studies showed that the envelope genes Syncytin-A and Syncytin-B were essential for cell-cell fusion of the SCT. The goal of this study was to analyze the temporal localization and expression of nine genes throughout placental development from embryonic day (E)8.5 to E18.5 using in situ-hybridization and absolute RNA-quantification. These included a comparison of previously characterized genes from the labyrinth Syncytin-A, Syncytin-B, Gcm1, the junctional zone PL-1, PL-2, Plf, Tpbpa with two further characterized genes Peg10 and Tpbpb. Syncytin-A and Syncytin-B RNA localized to SCT-I and SCT-II, respectively. Peg10 RNA localized to all extraembryonic tissues, specifically to the parietal and sinusoidal TGC of the labyrinth layer, which is in contact with SCT-I and the maternal blood. All three retroviral/retrotransposon-derived genes showed the highest expression at E16.5, but Peg10 with 188,917.1 molecules/ng cDNA was 208-fold and 106.8-fold higher expressed than Syncytin-A and Syncytin-B, respectively. Tpbpb localized to the junctional zone and showed the highest expression at E16.5 along with PL-2, Plf, Tpbpa, but not PL-1, which decreased in expression at E10.5. To investigate a role of Syncytin-A, Syncytin-B and Peg10 in cell-cell fusion, we established a cell culture system with fractionated primary trophoblasts from murine placentae. Culturing trophoblasts for up to 72h partly resembled trophoblast development in vivo according to the nine marker genes. Knockdown of Syncytin-A demonstrated a functional regulation of cell-cell fusion, where knockdown of Peg10 showed no involvement in cell fusion. Due to the expression of Peg10 in TGCs, we propose an essential functional role in the fetal-maternal blood system.
EVALuna2:4934

Re-irradiation of the chest wall for local breast cancer recurrence : Results of salvage brachytherapy with hyperthermia - Auoragh, A.; Strnad, Vratislav; Ott, O. J.; Beckmann, Matthias; Fietkau, Rainer (Strahlentherapie und Onkologie, 2016)
Following mastectomy and adjuvant external beam radiation therapy in patients with breast cancer, the incidence of local or locoregional recurrence is approximately 9 % (2-20 %). Alongside the often limited possibilities of surgical treatment, radiation therapy combined with superficial hyperthermia is the most effective local therapy. In the present work, a retrospective analysis of salvage brachytherapy combined with superficial hyperthermia for chest wall recurrences is presented.Between 2004 and 2011, 18 patients with a total of 23 target volumes resulting from chest wall recurrences after previously mastectomy and external beam radiation therapy (median 56 Gy, range 50-68 Gy) were treated with superficial brachytherapy as salvage treatment: 8 patients (44 %) had macroscopic tumor, 3 (17 %) had microscopic tumor (R1), and 7 (39 %) had undergone R0 resection and were treated due to risk factors. A dose of 50 Gy was given (high-dose rate [HDR] and pulsed-dose rate [PDR] procedures). In all, 5 of 23 patients (22 %) received additional concurrent chemotherapy, and in 20 of 23 (87 %) target volumes additional superficial hyperthermia was carried out twice weekly.The 5-year local recurrence-free survival was 56 %, the disease-free survival was 28 %, and a 5-year overall survival was 22 %. Late side effects Common Toxicity Criteria (CTC) grade 3 were reported in 17 % of the patients: 2 of 18 (11 %) had CTC grade 3 fibrosis, and 1 of 18 (6 %) had a chronic wound healing disorder.Re-irradiation as salvage brachytherapy with superficial hyperthermia for chest wall recurrences is a feasible and safe treatment with good local control results and acceptable late side effects.
EVALuna2:18364

Relevance of tumour-infiltrating lymphocytes, PD-1 and PD-L1 in patients with high-risk, nodal-metastasised breast cancer of the German Adjuvant Intergroup Node–positive study - Noske, Aurelia; Möbus, Volker; Weber, Karsten; Schmatloch, Sabine; Weichert, Wilko; Köhne, Claus Henning; Solbach, Christine; Ingold Heppner, Barbara; Steiger, Katja; Müller, Volkmar; Fasching, Peter; Karn, Thomas; et al. (European Journal of Cancer, 2019)
Background: Immune cell infiltration in breast cancer is important for the patient's prognosis and response to systemic therapies including immunotherapy. We sought to investigate the prevalence of tumour-infiltrating lymphocytes (TILs)and their association with immune checkpoints such as programmed cell death 1 (PD-1)and programmed cell death ligand 1 (PD-L1)in high-risk, node-positive breast cancer of the adjuvant German Adjuvant Intergroup Node–positive (GAIN-1)trial. Patients and methods: We evaluated TILs by haematoxylin and eosin staining and PD-1 and PD-L1 (SP263 assay)expression by immunohistochemistry in 1318 formalin-fixed, paraffin-embedded breast carcinomas. The association of TILs with PD-1, PD-L1, molecular intrinsic subtypes, outcome and therapy regimens (dose-dense [dd]epirubicin, paclitaxel and cyclophosphamide [EPC]and dd epirubicin, cyclophosphamide, paclitaxel and capecitabine [EC-PwX])was statistically tested. Results: Overall TILs density was significantly associated with the expression of PD-1 and PD-L1 in immune cells (each p < 0.0001)and PD-L1 in tumour cells (p = 0.0051). TILs were more common in triple-negative breast cancer (TNBC)and human epidermal growth factor receptor 2 (HER2)HER2-positive tumours (each p < 0.0001). On multivariate Cox regression analyses, patients with breast cancer without TILs had an unfavourable disease-free survival (DFS)in the EPC arm compared with the EC-PwX arm (hazard ratio [HR]= 0.69 [0.44–1.06], p = 0.0915); but no differences were seen in tumours with TILs (HR = 1.24 [0.92–1.67], p = 0.1566, interaction p = 0.0336). PD-1–positive immune cells in TNBC were associated with a significantly better DFS (HR = 0.50 [0.25–0.99], p = 0.0457). PD-L1 expression had no impact on patient outcome. Conclusions: TILs predict the benefit of intensified ddEPC compared with ddEC-PwX therapy in node-positive, high-risk breast cancer. TILs, PD-1 and PD-L1 are linked to each other indicating tumour immunogenicity. Moreover, PD-1–positive immune cells have a positive prognostic impact in TNBC. Clinical trial: NCT00196872.
CRIS-Team Scopus Importer:2019-05-17
Keywords: Adjuvant; Breast cancer; PD-1; PD-L1; Prognosis; Therapy prediction; TILs

Reliability of an e-PRO Tool of EORTC QLQ-C30 for Measurement of Health-Related Quality of Life in Patients With Breast Cancer: Prospective Randomized Trial - Wallwiener, Markus; Matthies, Lina; Simoes, Elisabeth; Keilmann, Lucia; Hartkopf, Andreas D.; Sokolov, Alexander N.; Walter, Christina B.; Sickenberger, Nina; Wallwiener, Stephanie; Feisst, Manuel; Gaß, Paul; Fasching, Peter; et al. (Journal of Medical Internet Research, 2017)
BACKGROUND: Breast cancer represents the most common malignant disease in women worldwide. As currently systematic palliative treatment only has a limited effect on survival rates, the concept of health-related quality of life (HRQoL) is gaining more and more importance in the therapy setting of metastatic breast cancer. One of the major patient-reported outcomes (PROs) for measuring HRQoL in patients with breast cancer is provided by the European Organization for Research and Treatment of Cancer (EORTC). Currently, paper-based surveys still predominate, as only a few reliable and validated electronic-based questionnaires are available. Facing the possibilities associated with evolving digitalization in medicine, validation of electronic versions of well-established PRO is essential in order to contribute to comprehensive and holistic oncological care and to ensure high quality in cancer research. OBJECTIVE: The aim of this study was to analyze the reliability of a tablet-based measuring application for EORTC QLQ-C30 in German language in patients with adjuvant and (curative) metastatic breast cancer. METHODS: Paper- and tablet-based questionnaires were completed by a total of 106 female patients with adjuvant and metastatic breast cancer recruited as part of the e-PROCOM study. All patients were required to complete the electronic- (e-PRO) and paper-based versions of the HRQoL EORTC QLQ-C30 questionnaire. A frequency analysis was performed to determine descriptive sociodemographic characteristics. Both dimensions of reliability (parallel forms reliability [Wilcoxon test] and test of internal consistency [Spearman rho and agreement rates for single items, Pearson correlation and Kendall tau for each scale]) were analyzed. RESULTS: High correlations were shown for both dimensions of reliability (parallel forms reliability and internal consistency) in the patient's response behavior between paper- and electronic-based questionnaires. Regarding the test of parallel forms reliability, no significant differences were found in 27 of 30 single items and in 14 of 15 scales, whereas a statistically significant correlation in the test of consistency was found in all 30 single items and all 15 scales. CONCLUSIONS: The evaluated e-PRO version of the EORTC QLQ-C30 is reliable for patients with both adjuvant and metastatic breast cancer, showing a high correlation in almost all questions (and in many scales). Thus, we conclude that the validated paper-based PRO assessment and the e-PRO tool are equally valid. However, the reliability should also be analyzed in other prospective trials to ensure that usability is reliable in all patient groups. TRIAL REGISTRATION: ClinicalTrials.gov NCT03132506; https://clinicaltrials.gov/ct2/show/NCT03132506 (Archived by WebCite at http://www.webcitation.org/6tRcgQuou).
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Reliability of prenatal detection of X-linked hypohidrotic ectodermal dysplasia by tooth germ sonography - Hammersen, Johanna; Wohlfart, Sigrun; Goecke, Tamme W.; Köninger, Angela; Stepan, Holger; Gallinat, Ralph; Morris, Susan; Bücher, Katharina; Clarke, Angus; Wünsche, Stephanie; Beckmann, Matthias; Schneider, Holm; et al. (Prenatal Diagnosis, 2019)
Objective: In X-linked hypohidrotic ectodermal dysplasia (XLHED), dysfunction of ectodysplasin A1 (EDA1) due to EDA mutations results in malformation of hair, teeth, and sweat glands. Hypohidrosis, which can cause life-threatening hyperthermia, is amenable to intrauterine therapy with recombinant EDA1. This study aimed at evaluating tooth germ sonography as a noninvasive means to identify affected fetuses in pregnant carrier women. Methods: Sonography, performed at 10 study sites between gestational weeks 18 and 28, led to the diagnosis of XLHED if fewer than six tooth germs were detected in mandible or maxilla. The assessment was verified postnatally by EDA sequencing and/or clinical findings. Estimated fetal weights and postnatal weight gain of boys with XLHED were assessed using appropriate growth charts. Results: In 19 of 38 sonographic examinations (23 male and 13 female fetuses), XLHED was detected prenatally. The prenatal diagnosis proved to be correct in 37 cases; one affected male fetus was missed. Specificity and positive predictive value were both 100%. Tooth counts obtained by clinical examination corresponded well with findings on panoramic radiographs. We observed no weight deficits of subjects with XLHED in utero but occasionally during infancy. Conclusion: Tooth germ sonography is highly specific and reliable in detecting XLHED prenatally.
CRIS-Team Scopus Importer:2019-08-27

Repetitive Maturation of Oocytes From Non-Stimulated Xenografted Ovarian Tissue From a Prepubertal Patient Indicating the Independence of Human Ovarian Tissue - Raffel, Nathalie; Lotz, Laura; Hoffmann, Inge; Liebenthron, Jana; Söder, Stephan; Beckmann, Matthias; Dittrich, Ralf (Geburtshilfe und Frauenheilkunde, 2017)
Introduction: Modern anti-cancer strategies have distinctly increased survival rates; nevertheless, often accompanied by sterility. Currently, the only option for preserving fertility in prepubertal females is to cryopreserve ovarian tissue and re-transplant frozen-thawed tissue to restore fertility after treatment. Our aim was to report the occurrence of repetitive antral follicle formation and oocyte maturation in a prepubescent ovarian tissue xenograft without exogenous hormone stimulation. Material and Methods: Frozen-thawed ovarian tissue from a 6-year-old patient suffering from nephroblastoma was xenotransplanted in oophorectomized severe combined immunodeficiency (SCID) mice to evaluate follicle development. Ergebnisse: Repetitive follicle development to the antral stage occurred in the same xenograft of prepubertal ovarian tissue without exogenous hormone administration; 37 days after retrieving a maturing oocyte (this first retrieval has been previously published), another, completely mature oocyte was harvested from the xenograft. Subsequent histological evaluation of the grafted tissue showed primordial follicles, nearly all stages of developing follicles, as well as large atretic ones. Many clusters with dormant primordial follicles were also present. Conclusion: Xenotransplanted prepubertal ovarian tissue has the potential for repetitive oocyte retrieval cycles without administering exogenous hormones. The results indicate that the human ovarian tissue might be able to synchronize the hypothalamus-hypophysis-axes of the mouse to the physiological human cycle; this should be investigated in future studies.
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Replication of Epigenetic Postpartum Depression Biomarkers and Variation with Hormone Levels - Osborne, Lauren; Clive, Makena; Kimmel, Mary; Gispen, Fiona; Guintivano, Jerry; Brown, Tori; Cox, Olivia; Judy, Jennifer; Meilman, Samantha; Braier, Aviva; Beckmann, Matthias; Kornhuber, Johannes; et al. (Neuropsychopharmacology, 2016)
DNA methylation variation at HP1BP3 and TTC9B is modified by estrogen exposure in the rodent hippocampus and was previously shown to be prospectively predictive of postpartum depression (PPD) when modeled in antenatal blood. The objective of this study was to replicate the predictive efficacy of the previously established model in women with and without a previous psychiatric diagnosis and to understand the effects of changing hormone levels on PPD biomarker loci. Using a statistical model trained on DNA methylation data from N=51 high-risk women, we prospectively predicted PPD status in an independent N=51 women using first trimester antenatal gene expression levels of HP1BP3 and TTC9B, with an area under the receiver operator characteristic curve (AUC) of 0.81 (95% CI: 0.69-0.92, p<5 × 10(-4)). Modeling DNA methylation of these genes in N=240 women without a previous psychiatric diagnosis resulted in a cross-sectional prediction of PPD status with an AUC of 0.81 (95% CI: 0.68-0.93, p=0.01). TTC9B and HP1BP3 DNA methylation at early antenatal time points showed moderate evidence for association to the change in estradiol and allopregnanolone over the course of pregnancy, suggesting that epigenetic variation at these loci may be important for mediating hormonal sensitivity. In addition both loci showed PPD-specific trajectories with age, possibly mediated by age-associated hormonal changes. The data add to the growing body of evidence suggesting that PPD is mediated by differential gene expression and epigenetic sensitivity to pregnancy hormones and that modeling proxies of this sensitivity enable accurate prediction of PPD.
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