State-of-the-Art Treatment and Novel Agents in Local and Distant Recurrences of Cervical Cancer - Tempfer, Clemens B.; Beckmann, Matthias (Oncology Research and Treatment, 2016)
Depending on the stage at initial presentation, cervical cancer will recur in 25-61% of women. Typical manifestations of recurrent cervical cancer include the central pelvis and the pelvic side walls as well as retroperitoneal lymph node basins in the pelvis and the para-aortic region, and - more rarely - supraclavicular lymph nodes. There are no typical symptoms of recurrent cervical cancer. Women with suspected recurrence after cervical cancer based on gynecological examination or organ-specific symptoms must undergo imaging studies and - if technically feasible - biopsy with histological verification, especially in cases of distant metastases, in order to rule out a second primary. Radiotherapy-naïve women should be treated with salvage radiochemotherapy with curative intention. For women with previous radiotherapy, surgery in the form of hysterectomy, local resection, or pelvic exenteration is the treatment of choice. Pelvic exenteration can lead to cure in selected patients, but at the price of a high rate of complications and significant morbidity and mortality. If complete surgical resection is not feasible or if the woman is not a candidate for surgery, chemotherapy with palliative intent should be offered. Patients with recurrent disease outside the pelvis are candidates for systemic chemotherapy. Several agents have shown to be active in this situation, either in single-agent or combination regimens. Platinum-containing regimens have a superior efficacy over non-platinum regimens and bevacizumab may be added to chemotherapy.
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Status quo and future directions of digitalization in gynecology and obstetrics in Germany: a survey of the commission Digital Medicine of the German Society for Gynecology and Obstetrics - Pfob, André; Hillen, Christoph; Seitz, Katharina; Griewing, Sebastian; Becker, Sven; Bayer, Christian; Wagner, Uwe; Fasching, Peter; Wallwiener, Markus (Archives of Gynecology and Obstetrics, 2024)
Purpose: Digitalization plays a critical role and is beginning to impact every part of the patient journey, from drug discovery and data collection to treatment and patient-reported outcomes. We aimed to evaluate the status quo and future directions of digital medicine in the specialty of gynecology and obstetrics in Germany. Methods: An anonymous questionnaire was distributed via the German Society of Gynecology and Obstetrics newsletter in December 2022. The questionnaire covered the domains baseline demographic information, telemedicine, digital health applications (DIGAs), and future expectations. Results: In all, 91 participants completed the survey. Median age was 34 years; 67.4% (60 of 89) were female and 32.6% (29 of 89) were male. About 10% (9 of 88) have prescribed DIGAs to date and 14% (12 of 86) offer telemedical appointments. Among those who do not use digital medicine, very few plan to do so in the near future. Reasons include missing software interfaces, lack of time to try out new things, lack of knowledge, lack of monetary compensation (66.3%), and employee concerns. A majority agreed that digitalization will help to save time and improve patient care and that intelligent algorithms will aid clinicians in providing patient care to women. Conclusions: The status quo and future directions of digital medicine in gynecology and obstetrics in Germany are characterized by contradicting expectations regarding the benefits of digital medicine and its actual implementation in clinical routine. This represents an important call to action to meet the requirements of modern patient care.
CRIS-Team Scopus Importer:2023-12-08
Keywords: Artificial intelligence; Digital health; eHealth; Gynecology and obstetrics; Implementation

Stellenwert der Vakzine gegen humane Papillomaviren in der Prävention von Krebserkrankungen - Schulmeyer, Carla; Knöll, Antje; Iro, Heinrich; Müller, Susanna; Beckmann, Matthias (Onkologe, 2021)
Background: Human papillomaviruses (HPV) are the most common causes of genital viral infections. HPV infections usually heal, but can also persist and thus cause lesions of different grades. Infections with high-risk HPV types (hrHPV) 16, 18, 31, 33, 45, 52, and 58 are responsible for causing 90% of cervical cancer cases in Europe. Head and neck cancer, vaginal and vulvar cancer and their precursors, as well as penile or anal cancer may also be associated with hrHPV. Objectives: The aim of this work is to demonstrate the importance of HPV vaccines in the prevention of genital as well as head and neck cancers. Materials and methods: This work is based on a selective literature search in the PubMed database on the correlation between HPV vaccines and HPV-associated cancer. Results: HPV vaccination ensures a high level of protection against precancerous lesions and cancer of the cervix, vagina, vulva, anus, and genital warts. Conclusions: Results of HPV vaccination and its positive effects on head and neck tumors is expected within the next few decades.
CRIS-Team Scopus Importer:2021-11-05
Keywords: Condylomata acuminata; HPV; Oropharyngeal neoplasms; Sexually transmitted diseases; Uterine cervical neoplasms

Stellungnahme des Präsidenten und des Leitlinien-Beauftragten der DGGG - Absence of Evidence Is Not Evidence of Absence - Carl Edward Sagan (911.1934-20.12.1996, US-amerikanischer Astronom, Astrophysiker, Exobiologe) - Scharl, Anton; Beckmann, Matthias (Geburtshilfe und Frauenheilkunde, 2021)
CRIS-Team Scopus Importer:2021-08-27

Strong hypoxia reduces leptin synthesis in purified primary human trophoblasts - Nuesken, E.; Herrmann, Y.; Wohlfarth, M.; Goecke, Tamme W.; Appel, S.; Schneider, Holm; Doetsch, J.; Nuesken, K. D. (Placenta, 2015)
Introduction Oxygen availability severely affects placental function. During placental hypoxia, stabilization of hypoxia inducible factors (HIFs) affects transcription, and leptin gene expression concomitantly increases in vivo and in vitro. However, a causal relationship is uncertain.
CRIS-Team Scopus Importer:2020-07-01
Keywords: Hypoxia; Leptin/leptin receptor; Placenta; Trophoblast

STUDY OF TELOMERE LENGTH AND DIFFERENT MARKERS OF OXIDATIVE STRESS IN PATIENTS WITH PARKINSON'S DISEASE - Watfa, Ghassan; Dragonas, C.; Brosche, Thorolf; Dittrich, Ralf; Sieber, Cornel; Alecu, C.; Benetos, A.; Nzietchueng, R. (Journal of Nutrition, Health & Aging, 2011)
Background: Many studies have shown that short telomere length (TL) is associated with high oxidative stress and various age-related diseases. Parkinson's disease (PD) is an age-related disease, and although its pathogenic mechanism is uncertain, oxidative stress is believed to be implicated in this pathology. The aim of this case-control study was to assess both TL and the different markers of oxidative stress in elderly patients with PD compared to age control subjects. Methods: 20 PD patients and 15 age-matched controls, >65 years were studied. TL was measured by Southern blotting from DNA samples extracted from white blood cells. Superoxide dismutase (SOD) activity and plasma levels of total glutathione and protein carbonyls were determined. Results: There was a trend for lower TL in PD patients: 6.06 +/- 0.81 kb in PD versus 6.45 +/- 0.73 kb in controls (p = 0.08). No significant difference was found between the two groups in terms of oxidative stress markers. In controls, age was the main determinant of telomere shortening (r = -0.547; p = 0.03) whereas, in PD patients, telomere shortening was mainly dependent on plasmatic concentrations of carbonyl proteins (r= -0.544; p=0.044). In PD patients, a negative association was observed between plasma carbonyl protein levels and SOD activity (r= -0.622, p=0.004). Conclusions: In PD, TL is shorter in presence of high oxidative stress as measured by carbonyl protein levels. The absence of telomere attrition with age among patients with PD could reflect a telomere regulation by mechanisms other than age.
Keywords: Aging; Parkinson's disease; oxidative stress; telomere length

Superpixel Pre-segmentation of HER2 Slides for Efficient Annotation - Öttl, Mathias; Mönius, Jana; Marzahl, Christian; Rübner, Matthias; Geppert, Carol-Immanuel; Hartmann, Arndt; Beckmann, Matthias; Fasching, Peter; Maier, Andreas; Erber, Ramona; Breininger, Katharina (Informatik aktuell, 2022)
Supervised deep learning has shown state-of-the-art performance for medical image segmentation across different applications, including histopathology and cancer research; however, the manual annotation of such data is extremely laborious. In this work, we explore the use of superpixel approaches to compute a pre-segmentation of HER2 stained images for breast cancer diagnosis that facilitates faster manual annotation and correction in a second step. Four methods are compared: standard simple linear iterative clustering (SLIC) as a baseline, a domain adapted SLIC, and superpixels based on feature embeddings of a pretrained ResNet-50 and a denoising autoencoder. To tackle oversegmentation, we propose to hierarchically merge superpixels, based on their content in the respective feature space. When evaluating the approaches on fully manually annotated images, we observe that the autoencoder-based superpixels achieve a 23% increase in boundary F1 score compared to the baseline SLIC superpixels. Furthermore, the boundary F1 score increases by 73% when hierarchical clustering is applied on the adapted SLIC and the autoencoder-based superpixels. These evaluations show encouraging first results for a pre-segmentation for efficient manual refinement without the need for an initial set of annotated training data.<br
CRIS-Team Scopus Importer:2022-05-06

Supportive Infusions in Integrative Breast and Gynecological Oncology - Report on Patients' Satisfaction and Self-reported Effects and Side Effects - Hack, Carolin; Antoniadis, Sophia; Beckmann, Matthias; Brandl, Anna; Fasching, Peter; Hackl, Janina; Langemann, Hanna; Stock, Katja; Weber, Natalie; Theuser, Anna-Katharin (Geburtshilfe und Frauenheilkunde, 2018)
Background During cancer therapy, many patients suffer from malnutrition or vitamin deficiency. Treatment for nutrition-related deficiencies should therefore include nutritional therapy and possibly oral or intravenous substitution of micronutrients. Little information exists on multinutrient infusion therapies. The aim of this study was to develop standardized infusion protocols for integrative medicine infusions with micronutrients (IMed infusions) and to report on side effects of the treatment and patients' satisfaction with it. Methods For the IMed consultancy service, four special formulas for intravenous use were developed in cooperation with the pharmacy at Erlangen University Hospital. A retrospective cross-sectional study was conducted between October 2015 and January 2018 in which 45 patients with gynecological or breast cancer (BC) and IMed infusion therapy were included. Follow-up data were obtained from 20 patients using a standardized questionnaire on IMed infusions. Results A total of 280 IMed infusions were administered in the study period. The majority of the patients received an IMed regeneration infusion (78%). The majority of the patients had BC and were receiving chemotherapy. Most patients reported a high or very high level of satisfaction with the organization (60%), general treatment (65%) and counseling (85%). Subjective improvement in their disease-related and therapy-induced symptoms, such as fatigue, polyneuropathy and physical efficiency, was reported by 70% of the patients, while 75% reported a subjective increase in quality of life. Side effects were rare and minor. Conclusions Therapy with IMed infusions in women with BC or gynecological cancer requires the same standards set for drug therapy. Although vitamins represent dietary supplements, appropriate assessment of the patient's medical history is needed and patients must receive appropriate information. For this purpose, standardized processes, as in the context of an IMed consultancy service, are helpful.
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Surgical Aspects of Ovarian Tissue Removal and Ovarian Tissue Transplantation for Fertility Preservation - Beckmann, Matthias; Dittrich, Ralf; Findeklee, S.; Lotz, Laura (Geburtshilfe und Frauenheilkunde, 2016)
Introduction: The removal of ovarian tissue prior to starting oncologic treatment and the subsequent transplantation of this tissue after completing therapy have become increasingly important surgical fertility-preserving techniques. The aim of this review was to investigate the different surgical techniques used for this method reported in the literature to date and to discuss the advantages and disadvantages of the respective techniques.Review:A search was done in MEDLINE using a defined algorithm to find studies published between January 2004 and December 2015. All study designs were included in our review if they contained statements on the surgical technique used. We found 16 publications (8 retrospective cohort studies, 6 case reports and 2 systematic reviews) with a total of 1898 female patients which reported on the surgical technique used for ovarian biopsy and 15 publications (7 retrospective cohort studies, 6 case reports and 2 systematic reviews) with a total of 455 women which mentioned the surgical technique used for ovarian transplantation. Different surgical techniques can be used both for ovarian biopsy and for the transplantation of ovarian tissue. A number of different surgical routes have been used, and the amount of tissue extracted, the instruments used, the treatment of the ovary, the transplantation site, the blood supply to the transplanted ovarian tissue and the procedure used for simultaneous surgical interventions vary.Conclusion:In future, one of the tasks will be to establish a standard surgical method for ovarian extraction and transplantation which will have a low rate of complications and a high pregnancy and birth rate while ensuring that the transplanted tissue is fully functional.
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Surgical outcome after neoadjuvant chemotherapy and bevacizumab: results from the GeparQuinto study (GBG 44) - Gerber, Bernd; Von Minckwitz, Gunter; Eidtmann, Holger; Rezai, Mahdi; Fasching, Peter; Tesch, Hans; Eggemann, Holm; Schrader, Iris; Kittel, Kornelia; Hanusch, Claus; Solbach, Christine; Jackisch, Christian; et al. (Annals of Surgical Oncology, 2014)
Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, has shown increased pathological complete response rates when added to neoadjuvant chemotherapy. In various cancer types, bevacizumab treatment was accompanied by an increased risk of bleedings and other surgical complications. We assessed associated surgical complications.In the GeparQuinto trial, 1,948 patients were randomized to receive four cycles epirubicin/cyclophosphamide (EC, 90/600 mg/m(2) q3w) followed by four cycles docetaxel (D, 100 mg/m(2) q3w) each with (ECB-DB) or without (EC-D) bevacizumab (B, 15 mg/kg q3w) concurrent with chemotherapy. Surgery had to be performed not earlier than 28 days after the last bevacizumab infusion, but within days 21 and 35 after the last chemotherapy.In 743 (38.1 %) patients, a surgical complication (bleedings, hematomas, necrosis, wound infections, abscess) was documented prospectively. Baseline characteristics of the patients were well balanced between both arms. The breast-conserving surgery (BCS) rate (N = 502) was 69.1 % (EC-D) and 71.9 % (ECB-DB; p = 0.464). The first surgical procedure was performed at a median of 29 (EC-D) and 34 days (ECB-DB) after last chemotherapy with or without bevacizumab infusion (p < 0.001). Surgical complications were documented in 38 (10.9 %; EC-D) and 59 (15.0 %; ECB-DB) patients (p = 0.103). Surgical complications were significantly higher after ECD-DB only in patients treated with BCS (N = 53; p = 0.029) or in those requiring repeat surgery in order achieve clear margins (N = 23; p = 0.037) compared to the EC-D group.Addition of bevacizumab to neoadjuvant chemotherapy might be associated with an increased risk for surgical complications in patients treated with BCS or after repeated surgeries.
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Surgical treatment of cervical cancer Operative Therapie des Zervixkarzinoms - Fehm, Tanja; Gantert, Daniel; Martignoni, Franca; Koch, Martin; Beckmann, Matthias (Onkologe, 2020)
Background: Surgery represents the first choice for treatment of early cervical carcinoma (FIGO IA1 to FIGO IIa according to Fédération Internationale de Gynécologie et d’Obstétrique). The extent of surgical therapy for the patient should be determined based on the patient’s age and tumor spread, particularly if fertility preservation is desired. More recently, less radical surgical procedures and concepts for sentinel lymph node biopsy are increasingly used in order to reduce mortality and morbidity. Controversy is currently emerging in the context of new studies regarding the choice of surgical approach. Objective: In this article, surgical options for the treatment of cervical cancer are reviewed. Materials and methods: An overview of the current study situation and literature is provided, taking into consideration the current German S3 guideline on cervical carcinoma. Results: Localized cervical cancer (≤FIGO IIA) is primarily treated by surgery. Recent studies, e.g. SHAPE, are investigating whether less radical surgical procedures can provide adequate oncological safety. A fertility-preserving approach is possible up to stage IB1 depending on the presence of risk factors. After the study results of the LACC trial were published with increased recurrence and mortality rate in the group undergoing laparoscopic surgery compared to the laparotomy group, patients must be informed about these data prior to decision making regarding the route of hysterectomy. Conclusion: The treatment of cervical cancer should be conducted according to the stage. Surgery is key in the treatment of early cervical carcinoma. Even less radical procedures seem to provide adequate oncological safety.
CRIS-Team Scopus Importer:2020-04-28
Keywords: Fertility preservation; Hysterectomy; Sentinel lymph node biopsy; Trachelectomy; Uterine cervical neoplasms

Surgical treatment of endometrial cancer - Emons, G.; Brucker, S. Y.; Fleisch, M. C.; Mueller, M.; Juhasz-Boess, E.; Kiesel, L.; Runnebaum, I. B.; Friedrich, M.; Mustea, A.; Erdogan, S.; Beckmann, Matthias (Die Gynäkologie, 2022)
In July 2022, the first update (Version 2.0) of the German S3 guideline on the diagnosis, treatment and follow-up of patients with endometrial cancer was published, supported by the Leitlinienprogramm Onkologie (Oncology Guideline Program). This article is the summary of Chap. 6: "Surgical Treatment". Relevant innovations compared to version 1.0 include the introduction of molecular classification and sentinel node biopsy, as well as the option of neoadjuvant chemotherapy for advanced cases where primary cytoreductive surgery is not possible.
CRIS-Team WoS Importer:2022-07-29

Surprising prenatal toxicity of epidermal lipoxygenase-3 - Vierling, F.; Dick, Angela; Wahlbuhl, Mandy; Krieg, P.; Henke, Christine; Ruebner, M.; Schneider, Holm (Placenta, 2014)
Metabolites of the epidermal lipoxygenase-3 (eLOX-3) are involved in various metabolic pathways. Most unexpectedly, intra-amniotic delivery of eLOX-3 to mice at gestational day 14.5, both via an adenoviral vector and as recombinant protein, resulted in fetal growth restriction and intrauterine death. Periodic acid-Schiff staining and RT-PCR analysis of placentae from fetuses exposed to eLOX-3 indicated a lack of glycogen trophoblasts in the junctional zone. Placenta-specific gene expression was altered. Thus, the observed prenatal toxicity of eLOX-3 could be due to a strong effect on placental development.
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Survival after adding capecitabine and trastuzumab to neoadjuvant anthracycline-taxane-based chemotherapy for primary breast cancer (GBG 40–GeparQuattro) - Von Minckwitz, G.; Rezai, M.; Fasching, Peter; Huober, J.; Tesch, H.; Bauerfeind, I.; Hilfrich, J.; Eidtmann, H.; Gerber, B.; Hanusch, C.; Blohmer, J. U.; Costa, S. D.; et al. (Annals of Oncology, 2014)
The GeparQuattro study showed that adding capecitabine or prolonging the duration of anthracycline-taxane-based neoadjuvant chemotherapy from 24 to 36 weeks did not increase pathological complete response (pCR) rates. Trastuzumab-treated patients with HER2-positive disease showed a higher pCR rate than patients with HER2-negative disease treated with chemotherapy alone. We here present disease-free (DFS) and overall survival (OS) analyses.Patients (n = 1495) with cT >= 3 tumors, or negative hormone-receptor status, or positive hormone-receptor and clinically node-positive disease received four times epirubicin/cyclophosphamide and were thereafter randomly assigned to four times docetaxel (Taxotere), or four times docetaxel/capecitabine over 24 weeks, or four times docetaxel followed by capecitabine over 36 weeks. Patients with HER2-positive tumors received 1 year of trastuzumab, starting with the first chemotherapy cycle. Follow-up was available for a median of 5.4 years.Outcome was not improved for patients receiving capecitabine (HR 0.92; P = 0.463 for DFS and HR 93; P = 0.618 for OS) as well as for patients receiving 36 weeks of chemotherapy (HR 0.97; P = 0.818 for DFS and HR 0.97; P = 0.825 for OS). Trastuzumab-treated patients with HER2-positive disease showed similar DFS (P = 0.305) but a significantly better adjusted OS (P = 0.040) when compared with patients with HER2-negative disease treated with chemotherapy alone. Recorded long-term cardiac toxicity was low.Long-term results, similar to the results of pCR, do not support the use of capecitabine in the neoadjuvant setting in addition to an anthracycline-taxane-based chemotherapy. However, the results support previous data showing a benefit of trastuzumab as predicted by higher pCR rates.
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Survival after neoadjuvant chemotherapy with or without bevacizumab or everolimus for HER2-negative primary breast cancer (GBG 44-GeparQuinto)+ - Von Minckwitz, G.; Loibl, S.; Untch, M.; Eidtmann, H.; Rezai, M.; Fasching, Peter; Tesch, H.; Eggemann, H.; Schrader, I.; Kittel, K.; Hanusch, C.; Huober, J.; et al. (Annals of Oncology, 2014)
The GeparQuinto study showed that adding bevacizumab to 24 weeks of anthracycline-taxane-based neoadjuvant chemotherapy increases pathological complete response (pCR) rates overall and specifically in patients with triple-negative breast cancer (TNBC). No difference in pCR rate was observed for adding everolimus to paclitaxel in nonearly responding patients. Here, we present disease-free (DFS) and overall survival (OS) analyses.Patients (n = 1948) with HER2-negative tumors of a median tumor size of 4 cm were randomly assigned to neoadjuvant treatment with epirubicin/cyclophosphamide followed by docetaxel (EC-T) with or without eight infusions of bevacizumab every 3 weeks before surgery. Patients without clinical response to EC ± Bevacizumab were randomized to 12 weekly cycles paclitaxel with or without everolimus 5 mg/day. To detect a hazard ratio (HR) of 0.75 (? = 0.05, ? = 0.8) 379 events had to be observed in the bevacizumab arms.With a median follow-up of 3.8 years, 3-year DFS was 80.8% and 3-year OS was 89.7%. Outcome was not different for patients receiving bevacizumab (HR 1.03; P = 0.784 for DFS and HR 0.974; P = 0.842 for OS) compared with patients receiving chemotherapy alone. Patients with TNBC similarly showed no improvement in DFS (HR = 0.99; P = 0.941) and OS (HR = 1.02; P = 0.891) when treated with bevacizumab. No other predefined subgroup (HR+/HER2-; locally advanced (cT4 or cN3) or not; cT1-3 or cT4; pCR or not) showed a significant benefit. No difference in DFS (HR 0.997; P = 0.987) and OS (HR 1.11; P = 0.658) was observed for nonearly responding patients receiving paclitaxel with or without everolimus overall as well as in subgroups.Long-term results, in opposite to the results of pCR, do not support the neoadjuvant use of bevacizumab in addition to an anthracycline-taxane-based chemotherapy or everolimus in addition to paclitaxel for nonearly responding patients.NCT 00567554, www.clinicaltrials.gov.
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Survival Analysis After Neoadjuvant Chemotherapy With Trastuzumab or Lapatinib in Patients With Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer in the GeparQuinto (G5) Study (GBG 44) - Untch, Michael; Von Minckwitz, Gunter; Gerber, Bernd; Schem, Christian; Rezai, Mahdi; Fasching, Peter; Tesch, Hans; Eggemann, Holm; Hanusch, Claus; Huober, Jens; Solbach, Christine; Jackisch, Christian; et al. (Journal of Clinical Oncology, 2018)
Purpose The GeparQuinto phase III trial demonstrated a lower pathologic complete response (pCR; pT0 ypN0) rate when lapatinib was added to standard anthracycline-taxane chemotherapy compared with trastuzumab in patients with human epidermal growth factor receptor 2 (HER2) -positive breast cancer. Here, we report the long-term outcomes. Methods Patients with HER2-positive tumors (n = 615) received neoadjuvant treatment with epirubicin (E) plus cyclophosphamide (C), followed by docetaxel (T) in combination with either lapatinib (L) or trastuzumab (H; ECH-TH arm: n = 307; ECL-TL arm: n = 308). All patients received adjuvant trastuzumab for a total of 12 months and 18 months in the ECH-TH and ECL-TL arms, respectively. Median follow-up was 55 months. Results Three-year disease-free survival (DFS), distant DFS (DDFS), and overall survival (OS) were not significantly different between the two treatment arms. Long-term outcomes correlated with pCR (DFS: hazard ratio [HR], 0.63; P = .042; DDFS: HR, 0.55; P = .021; and OS: HR, 0.31; P = .004). A benefit only for OS was observed in patients who were treated with trastuzumab and achieved pCR versus no pCR (HR, 0.15; P = .010), whereas no difference was found in patients with pCR versus without pCR in the lapatinib arm. DFS and DDFS remained unchanged in both treatment arms according to hormone receptor status, whereas OS was significantly better in hormone receptor-positive patients who were treated with neoadjuvant lapatinib (HR, 0.32; P = .019), followed by adjuvant trastuzumab. No difference was observed in hormone receptor-negative patients; however, the small number of events limits this interpretation. Within the hormone receptor-negative cohort, pCR was significantly associated with DFS, DDFS, and OS ( P = .002, .005, and .002, respectively). Conclusion pCR correlated with long-term outcome. In patients with hormone receptor-positive tumors, prolonged anti-HER2 treatment-neoadjuvant lapatinib for 6 months, followed by adjuvant trastuzumab for 12 months-significantly improved survival compared with anti-HER2 treatment with trastuzumab alone.
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Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response-final results from GeparSixto - Loibl, S.; Weber, K. E.; Timms, K. M.; Elkin, E. P.; Hahnen, E.; Fasching, Peter; Lederer, Bianca; Denkert, C.; Schneeweiss, A.; Braun, S.; Salat, C. T.; Rezai, M.; et al. (Annals of Oncology, 2018)
Background: In the neoadjuvant GeparSixto study, adding carboplatin to taxane- and anthracycline-based chemotherapy improved pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Here, we present survival data and the potential prognostic and predictive role of homologous recombination deficiency (HRD). Patients and methods: Patients were randomized to paclitaxel plus nonpegylated liposomal doxorubicin (Myocet®) (PM) or PM plus carboplatin (PMCb). The secondary study end points disease-free survival (DFS) and overall survival (OS) were analyzed. Median follow-up was 47.3 months. HRD was among the exploratory analyses in GeparSixto and was successfully measured in formalin-fixed, paraffin-embedded tumor samples of 193/315 (61.3%) participants with TNBC. Homologous recombination (HR) deficiency was defined as HRD score ≥42 and/or presence of tumor BRCA mutations (tmBRCA). Results: A significantly better DFS (hazard ratio 0.56, 95% CI 0.34-0.93; P = 0.022) was observed in patients with TNBC when treated with PMCb. The improvement of OS with PMCb was not statistically significant. Additional carboplatin did not improve DFS or OS in patients with HER2-positive tumors. HR deficiency was detected in 136 (70.5%) of 193 triple-negative tumors, of which 82 (60.3%) showed high HRD score without tmBRCA. HR deficiency independently predicted pCR (ypT0 ypN0) [odds ratio (OR) 2.60, 95% CI 1.26-5.37, P = 0.008]. Adding carboplatin to PM significantly increased the pCR rate from 33.9% to 63.5% in HR deficient tumors (P = 0.001), but only marginally in HR nondeficient tumors (from 20.0% to 29.6%, P = 0.540; test for interaction P = 0.327). pCR rates with carboplatin were also higher (63.2%) than without carboplatin (31.7%; OR 3.69, 1.46-9.37, P = 0.005) in patients with high HRD score but no tmBRCA. DFS rates were improved with addition of carboplatin, both in HR nondeficient (hazard ratio 0.44, 0.17-1.17, P = 0.086) and HR deficient tumors (hazard ratio 0.49, 0.23-1.04, P = 0.059). Conclusions: The addition of carboplatin to neoadjuvant PM improved DFS significantly in TNBC. Long-term survival analyses support the neoadjuvant use of carboplatin in TNBC. HR deficiency in TNBC and HRD score in non-tmBRCA TNBC are predictors of response. HRD does not predict for carboplatin benefit.
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Survival analysis of the randomised phase III GeparOcto trial comparing neoadjuvant chemotherapy of intense dose-dense epirubicin, paclitaxel, cyclophosphamide versus weekly paclitaxel, liposomal doxorubicin (plus carboplatin in triple-negative breast cancer) for patients with high-risk early breast cancer - Schneeweiss, Andreas; Michel, Laura L.; Möbus, Volker; Tesch, Hans; Klare, Peter; Hahnen, Eric; Denkert, Carsten; Kast, Karin; Pohl-Rescigno, Esther; Hanusch, Claus; Link, Theresa; Untch, Michael; et al. (European Journal of Cancer, 2021)
Background: GeparOcto demonstrated that pathological complete response (pCR) of intense dose-dense epirubicin, paclitaxel and cyclophosphamide (iddEPC) was comparable to weekly paclitaxel/non-pegylated liposomal doxorubicin (plus carboplatin (PM(Cb) in triple-negative breast cancer [TNBC]) in high-risk early breast cancer (BC). Here, we report time-to-event secondary end-points. Patients and methods: Patients were randomised to receive 18 weeks of E (150 mg/m2) followed by P (225 mg/m2) followed by C (2000 mg/m2), each q2w or weekly P (80 mg/m2) plus M (20 mg/m2) plus, in TNBC, Cb (AUC 1.5). Patients with human epidermal growth factor receptor 2-positive (HER2+)BC received trastuzumab (6[loading dose 8]mg/kg q3w) and pertuzumab (420[840]mg q3w) with P and C cycles. Results: 945 patients started treatment (iddEPC n = 470; PM(Cb) n = 475). After a median follow-up of 47.0 (range 1.6–61.5) months, 162 (75 in iddEPC; 87 in PM(Cb)) invasive disease-free survival (iDFS) events and 79 (41 in iddEPC; 38 in PM(Cb)) deaths were reported. No significant difference was observed in 4-year iDFS (81.9% iddEPC versus 79.7% PM(Cb), HR = 1.16 [95%CI 0.85–1.59], log-rank p = 0.334) or 4-year overall survival (OS) (90.3% iddEPC versus 90.6% PM(Cb), HR = 0.90 [95%CI 0.58–1.40], log-rank p = 0.637) overall and in HER2+ and TNBC subgroups. HR+/HER2- BC patients, however, had significantly better 4-year iDFS (77.9% iddEPC versus 62.5% PM, HR = 2.11 [95%CI 1.08–4.10], log-rank p = 0.025) and 4-year OS with iddEPC (94.7% iddEPC versus 80.1% PM, HR = 3.26 [95%CI 1.06–10.00], log-rank p = 0.029). Conclusion: While there was no difference in survival for the entire cohort, the HR+/HER2-subgroup significantly benefits from iddEPC. This supports the concept of an additional effect of NACT beyond pCR in patients with HR+/HER2- BC. ClinicalTrials.gov identifier: NCT02125344.
CRIS-Team Scopus Importer:2021-11-26
Keywords: Breast cancer; Dose-dense; Neoadjuvant chemotherapy; Survival

Survival analysis of the randomized phase III GeparOcto trial comparing neoadjuvant chemotherapy (NACT) of iddEPC versus weekly paclitaxel, liposomal doxorubicin (plus carboplatin in triplenegative breast cancer, TNBC) (PM(Cb)) for patients (pts) with highrisk early breast cancer (BC) - Schneeweiss, A.; Moebus, V.; Tesch, H.; Klare, P.; Denkert, C.; Kast, K.; Hanusch, C.; Link, T.; Untch, M.; Jackisch, C.; Blohmer, J-U.; Fasching, Peter; et al. (ANNALS OF ONCOLOGY, 2020)
CRIS-Team WoS Importer:2020-10-30

Systemic Therapy of Premenopausal Patients with Early Stage Hormone Receptor-Positive, HER2-Negative Breast Cancer - Controversies and Standards in Healthcare - Müller, Volkmar; Fasching, Peter; Nabieva, Naiba; Fehm, Tanja N.; Thill, Marc; Schmidt, Marcus; Kühn, Thorsten; Banys-Paluchowski, Maggie; Belleville, Erik; Juhasz-Böss, Ingolf; Untch, Michael; Kolberg, Hans Christian; et al. (Geburtshilfe und Frauenheilkunde, 2023)
In patients with existing ovarian function, there are some special aspects to adjuvant endocrine therapy in premenopausal patients with hormone receptor-positive, HER2-negative (HR pos./HER2 neg.) breast cancer. Treatment options include tamoxifen with or without a GnRH analog, and aromatase inhibitors with a GnRH analog. Furthermore, ovarian function is affected by previous chemotherapy. Both aromatase inhibitors (+GnRH analogs) and GnRH analogs in combination with tamoxifen are supposed to be indicated for patients at increased risk of recurrence. However, national and international guidelines and therapy recommendations do not provide a clear definition of intermediate or high risk; as a result, therapy decisions are often made for each patient on an individual basis. This is also reflected in the considerable variability at national and international levels, e.g., with regard to the use of aromatase inhibitors + GnRH analogs. This review summarizes the data on completed studies (e.g., SOFT, TEXT, EBCTCG meta-analyses) and the current multigene testing studies (TailorX, RxPonder, ADAPT), discusses the rationale for current studies (e.g., CLEAR-B), and looks ahead to future questions.
CRIS-Team Scopus Importer:2023-06-23
Keywords: aromatase inhibitor; breast cancer; GnRH; premenopausal therapy; tamoxifen

Targeted Intraoperative Radiation Therapy Tumor Bed Boost During Breast-Conserving Surgery After Neoadjuvant Chemotherapy in TNBC and HER2 Positive Breast Cancer - Kolberg, H. C.; Loevey, G.; Akpolat-Basci, L.; Stephanou, M.; Fasching, Peter; Untch, M.; Liedtke, C.; Bulsara, M.; Vaidya, J. S. (2016)
EVALuna2:33059

Targeted Intraoperative Radiotherapy Tumour Bed Boost during Breast-Conserving Surgery after Neoadjuvant Chemotherapy - a Subgroup Analysis of Hormone Receptor-Positive HER2-Negative Breast Cancer - Kolberg, Hans-Christian; Loevey, Gyoergy; Akpolat-Basci, Leyla; Stephanou, Miltiades; Fasching, Peter; Untch, Michael; Hoffmann, Oliver; Bulsara, Max; Vaidya, Jayant S.; Liedtke, Cornelia (Breast Care, 2017)
Introduction: In a previous study our group showed a beneficial effect of targeted intraoperative radiotherapy (TARGIT-IORT) as an intraoperative boost on overall survival after neoadjuvant chemotherapy (NACT) compared to an external boost (EBRT). In this study we present the results of a detailed subgroup analysis of the hormone receptor (HR)-positive HER2-negative patients. Methods: In this cohort study involving 46 patients with HR-positive HER2-negative breast cancer after NACT, we compared the outcomes of 21 patients who received an IORT boost to those of 25 patients treated with an EBRT boost. All patients received whole breast radiotherapy. Results: Median follow-up was 49 months. Whereas disease-free-survival and breast cancer-specific mortality were not significantly different between the groups, the 5-year Kaplan-Meier estimate of overall mortality was significantly lower by 21% with IORT, p = 0.028. Non-breast cancer-specific mortality was significantly lower by 16% with IORT, p = 0.047. Conclusion: Although our results have to be interpreted with caution, we have shown that the improved overall survival demonstrated previously could be reproduced in the HR-positive HER2-negative subgroup. These data give further support to the inclusion of such patients in the TARGIT-B (Boost) randomised trial that is testing whether IORT boost is superior to EBRT boost.
EVALuna2:36209

Targeted intraoperative radiotherapy tumour bed boost during breast-conserving surgery after neoadjuvant chemotherapy - Kolberg, Hans-Christian; Loevey, Gyoergy; Akpolat-Basci, Leyla; Stephanou, Miltiades; Fasching, Peter; Untch, Michael; Liedtke, Cornelia; Bulsara, Max; Vaidya, Jayant S. (Strahlentherapie und Onkologie, 2017)
INTRODUCTION: The use of targeted intraoperative radiotherapy (TARGIT-IORT) as a tumour bed boost during breast-conserving surgery (BCS) for breast cancer has been reported since 1998. We present its use in patients undergoing breast conservation following neoadjuvant therapy (NACT). METHOD: In this retrospective study involving 116 patients after NACT we compared outcomes of 61 patients who received a tumour bed boost with IORT during lumpectomy versus 55 patients treated in the previous 13 months with external (EBRT) boost. All patients received whole breast radiotherapy. Local recurrence-free survival (LRFS), disease-free survival (DFS), distant disease-free survival (DDFS), breast cancer mortality (BCM), non-breast cancer mortality (NBCM) and overall mortality (OS) were compared. RESULTS: Median follow up was 49 months. The differences in LRFS, DFS and BCM were not statistically significant. The 5‑year Kaplan-Meier estimate of OS was significantly better by 15% with IORT: IORT 2 events (96.7%, 95%CI 87.5-99.2), EBRT 9 events (81.7%, 95%CI 67.6-90.1), hazard ratio (HR) 0.19 (0.04-0.87), log rank p = 0.016, mainly due to a reduction of 10.1% in NBCM: IORT 100%, EBRT 89.9% (77.3-95.7), HR (not calculable), log rank p = 0.015. The DDFS was as follows: IORT 3 events (95.1%, 85.5-98.4), EBRT 12 events (69.0%, 49.1-82.4), HR 0.23 (0.06-0.80), log rank p = 0.012. CONCLUSION: IORT during lumpectomy after neoadjuvant chemotherapy as a tumour bed boost appears to give results that are not worse than external beam radiotherapy boost. These data give further support to the inclusion of such patients in the TARGIT-B (boost) randomised trial that is testing whether IORT boost is superior to EBRT boost.
EVALuna2:36210

Targeted sequencing of FH-deficient uterine leiomyomas reveals biallelic inactivating somatic fumarase variants and allows characterization of missense variants - Popp, Bernt; Erber, Ramona; Kraus, Cornelia; Vasileiou, Georgia; Hoyer, Juliane; Burghaus, Stefanie; Hartmann, Arndt; Beckmann, Matthias; Reis, André; Agaimy, Abbas (Modern Pathology, 2020)
Uterine leiomyomas (ULs) constitute a considerable health burden in the general female population. The fumarate hydratase (FH) deficient subtype is found in up to 1.6% and can occur in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. We sequenced 13 FH deficient ULs from a previous immunohistochemical screen using a targeted panel and identified biallelic FH variants in all. In eight, we found an FH point mutation (two truncating, six missense) with evidence for loss of the second allele. Variant allele-frequencies in all cases with a point mutation pointed to somatic variants. Spatial clustering of the identified missense variants in the lyase domain indicated altered fumarase oligomerization with subsequent degradation as explanation for the observed FH deficiency. Biallelic FH deletions in five tumors confirm the importance of copy number loss as mutational mechanism. By curating all pathogenic FH variants and calculating their population frequency, we estimate a carrier frequency of up to 1/2,563. Comparing with the prevalence of FH deficient ULs, we conclude that most are sporadic and estimate 2.7–13.9% of females with an FH deficient UL to carry a germline FH variant. Further prospective tumor/normal sequencing studies are needed to develop a reliable screening strategy for HLRCC in women with ULs.
CRIS-Team Scopus Importer:2020-07-10

TGFB-induced factor homeobox 1 (TGIF) expression in breast cancer - Stuerken, Christine; Moebus, Volker; Milde-Langosch, Karin; Schmatloch, Sabine; Fasching, Peter; Rueschoff, Josef; Stickeler, Elmar; Henke, Rolf-Peter; Denkert, Carsten; Hanker, Lars; Schem, Christian; Vladimirova, Valentina; et al. (BMC Cancer, 2021)
Background: Breast cancer (BC) is the most frequent female cancer and preferentially metastasizes to bone. The transcription factor TGFB-induced factor homeobox 1 (TGIF) is involved in bone metabolism. However, it is not yet known whether TGIF is associated with BC bone metastasis or patient outcome and thus of potential interest.
CRIS-Team WoS Importer:2021-09-10

The association between prenatal alcohol consumption and preschool child stress system disturbance - Grimm, Jennifer; Stemmler, Mark; Golub, Yulia; Schwenke, Eva; Goecke, Tamme W.; Fasching, Peter; Beckmann, Matthias; Kratz, Oliver; Moll, Gunther; Kornhuber, Johannes; Eichler, Anna (Developmental Psychobiology, 2021)
Background: Drinking alcohol during pregnancy is considered a risk factor for child development; however, child biomarkers of prenatal alcohol exposure have been rarely studied. We examined whether a meconium alcohol metabolite (ethyl glucuronide, EtG) was associated with child cortisol concentrations at primary school age. Methods: For 137 children, prenatal alcohol exposure was operationalized by the meconium biomarker EtG and by maternal self-reports during pregnancy. Two EtG cut-offs (EtG ≥10 ng/g and EtG ≥112 ng/g) were applied. Cortisol concentrations were measured in saliva and hair samples. Results: Children with EtG ≥10 ng/g showed significantly reduced hair cortisol concentrations (HCCs) (p =.050, (Formula presented.) = 0.042). For children with EtG ≥112 ng/g, the cortisol awakening response (CAR) was significantly decreased (p =.025, (Formula presented.) = 0.070). These effects were also present in correlational analyses with continuous EtG data, speaking for partly dose-dependent effects. Especially, within the EtG ≥112 ng/g group, the basal (CAR: rp = −.642, p =.120) and cumulative (HCC: rp = −.660, p =.107) cortisol parameters were associated with child emotional symptoms at medium effect size. Conclusions: The present study showed both the biological association of intrauterine alcohol exposure with the cortisol stress system, partly dose-dependent, and the functional association with emotional and behavioral symptoms.
CRIS-Team Scopus Importer:2020-10-16
Keywords: alcohol; biomarker; child; cortisol stress system; ethyl glucuronide; hypothalamus-pituitary-adrenal axis; intrauterine alcohol exposure; meconium; pregnancy

The association of prenatal attachment and perinatal factors with pre- and postpartum depression in first-time mothers - Goecke, T.; Voigt, F.; Faschingbauer, F.; Spangler, Gottfried; Beckmann, Matthias; Beetz, Andrea (Archives of Gynecology and Obstetrics, 2012)
Purpose: This prospective study investigated associations between prenatal attachment of adult first-time mothers to the unborn child, perinatal factors and levels of depression before and up to 18 months after delivery. Method: Primiparas (N = 161) without specific risk factors answered the following questionnaires during the last term of pregnancy (t1): Edinburgh Postnatal Depression Scale (EPDS), Maternal Antenatal Attachment Scale (MAAS), questionnaire on the schema of the unborn child, and a questionnaire about the pregnancy. Perinatal data were taken from the patients' files. The EPDS was answered 3 weeks (t2, N = 157), 6 months (t3, N = 159), and 18 months (t4, N = 132) postpartum. Results: During pregnancy, 16.9 % of the women indicated mild depressive symptoms, and 7.5 %, medium to severe symptoms of depression. Mild symptoms of depression were found in 25.5 % at t2, 10.1 % at t3, and 12.2 % at t4; medium to severe symptoms were reported by 7.6, 1.9 and 5.6 %, respectively. Women with low control during delivery (emergency Caesarean) showed a tendency for higher levels (p = 0.067) of depression at t3 than women with elective Caesarean did. The quality of prenatal attachment to the unborn child correlated negatively with depressive symptoms at t1-t4. Conclusions: The closer the prenatal attachment of a mother to her unborn child, the less symptoms of depression she reports during the last term of pregnancy and postpartum. Therefore, promoting good mother-child attachment during pregnancy might influence the level of postpartum depression. © Springer-Verlag 2012.

The Benefit of a Retrospective Pregnancy Anamnesis in Child and Adolescent Psychiatry: The Reliability of Maternal Self-Report during Childhood Development - Mestermann, Stefan; Fasching, Peter; Beckmann, Matthias; Gerlach, Jennifer; Kratz, Oliver; Moll, Gunther; Kornhuber, Johannes; Eichler, Anna (Children, 2023)
Pregnancy anamnesis is a crucial part of child and adolescent psychiatry diagnostics. In previous works, the reliability of retrospective maternal self-report on perinatal characteristics was heterogeneous. This prospective longitudinal study aimed to evaluate women’s recall of prenatal events in a within-subject design. A sample of 241 women gave a self-report on prenatal alcohol, smoking, partnership quality, pregnancy satisfaction, and obstetric complications during the 3rd trimester (t0), childhood (t1, 6–10 y), and adolescence (t2, 12–14 y). The intra-individual agreement was examined. The t0–t1–(t2) agreement was poor to substantial; this was highest for smoking and worst for obstetric complications, followed by alcohol (Fleiss’ κ = 0.719 to −0.051). There were significant t0–t1–(t2) differences for all pregnancy variables (p < 0.017), except for 3rd trimester satisfaction (p = 0.256). For alcohol (t0 25.8%, t1 17.4%, t2 41.0%) and smoking (t0 11.9%, t1 16.4%, t2 22.6%), the highest self-reported rates were found during adolescence. During childhood, fewer obstetric complications (t0 84.9%, t1 42.2%) and worse partnerships were reported (t0 M = 8.86, t1 M = 7.89). Thought to be due to social stigmata and memory effects, pregnancy self-reports cannot be precisely reproduced. Creating a respectful and trusting atmosphere is essential for mothers to give honest self-reports that are in the best interest of their children.
CRIS-Team Scopus Importer:2023-06-30
Keywords: alcohol; partnership; pregnancy; pregnancy satisfaction; prenatal; retrospective; risk perceptions; self-report; smoking

The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity - Colombo, Mara; Lopez-Perolio, Irene; Meeks, Huong D.; Caleca, Laura; Parsons, Michael T.; Li, Hongyan; De Vecchi, Giovanna; Tudini, Emma; Foglia, Claudia; Mondini, Patrizia; Manoukian, Siranoush; Behar, Raquel; et al. (Human Mutation, 2018)
Although the spliceogenic nature of the BRCA2 c.68-7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real-time PCR and digital PCR (dPCR), the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case-control analysis in 83,636 individuals. Co-occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5-fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68-7T > A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 × 10-115 . There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86-1.24) nor for a deleterious effect of the variant when co-occurring with pathogenic variants. Our data provide for the first time robust evidence of the nonpathogenicity of the BRCA2 c.68-7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants.
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The Chorioallantoic Membrane Xenograft Assay as a Reliable Model for Investigating the Biology of Breast Cancer - Ranjan, Raphela A.; Muenzner, Julienne K.; Kunze, Philipp; Geppert, Carol-Immanuel; Rübner, Matthias; Hübner, Hanna; Fasching, Peter; Beckmann, Matthias; Bäuerle, Tobias; Hartmann, Arndt; Walther, Wolfgang; Eckstein, Markus; et al. (Cancers, 2023)
The chorioallantoic membrane (CAM) assay is an alternative in vivo model that allows for minimally invasive research of cancer biology. Using the CAM assay, we investigated phenotypical and functional characteristics (tumor grade, mitosis rate, tumor budding, hormone receptor (HR) and HER2 status, Ki-67 proliferation index) of two breast cancer cell lines, MCF-7 and MDA-MB-231, which resemble the HR+ (luminal) and triple-negative breast cancer (TNBC) subgroups, respectively. Moreover, the CAM results were directly compared with murine MCF-7- and MDA-MB-231-derived xenografts and human patient TNBC tissue. Known phenotypical and biological features of the aggressive triple-negative breast cancer cell line (MDA-MB-231) were confirmed in the CAM assay, and mouse xenografts. Furthermore, the histomorphological and immunohistochemical variables assessed in the CAM model were similar to those in human patient tumor tissue. Given the confirmation of the classical biological and growth properties of breast cancer cell lines in the CAM model, we suggest this in vivo model to be a reliable alternative test system for breast cancer research to reduce murine animal experiments.
CRIS-Team Scopus Importer:2023-04-14
Keywords: 3R; alternative in vivo model; CAM model; hormone receptor; HTB-26; MCF-7; MDA-MB-231; mouse xenograft; tumor aggressiveness

The clinical data intelligence project - Sonntag, Daniel; Tresp, Volker; Zillner, Sonja; Hammon, Matthias; Reis, André; Fasching, Peter; Sedlmayr, Martin; Ganslandt, Thomas; Prokosch, Hans-Ulrich; Budde, Clemens; Schmidt, Danilo; Hinrichs, Carl; et al. (Informatik-Spektrum, 2015)
UnivIS-Import:2017-12-18:Pub.2015.tech.IMMD.infome.thecli

The clinical relevance of serum vascular endothelial growth factor (VEGF) in correlation to circulating tumor cells and other serum biomarkers in patients with metastatic breast cancer - Banys-Paluchowski, Malgorzata; Witzel, Isabell; Riethdorf, Sabine; Pantel, Klaus; Rack, Brigitte; Janni, Wolfgang; Fasching, Peter; Aktas, Bahriye; Kasimir-Bauer, Sabine; Hartkopf, Andreas; Solomayer, Erich-Franz; Fehm, Tanja; et al. (Breast Cancer Research and Treatment, 2018)
VEGF is one of the most important angiogenesis-stimulating cytokines and has been previously shown to be overexpressed in several solid cancers. The aim of the present study was to assess the clinical relevance of serum VEGF (sVEGF) in a large cohort of metastatic breast cancer patients and to explore the relationship between sVEGF and other blood-based biomarkers.Two hundred fifty-three patients with metastatic breast cancer were enrolled in this prospective, multicentre study. Blood samples were collected before start of first-line or later-line treatment. sVEGF was quantified by a commercially available ELISA. Circulating tumor cells (CTCs) were detected using CellSearch and other biomarkers (EGFR, HER2, RAS p21, TIMP1, CAIX) by ELISA.Levels of sVEGF were determined in all patients, with a median concentration of 231 pg/ml. After a median follow-up of 19 months, median overall survival (OS) was 10.2 months in patients with sVEGF levels above the upper quartile (i.e. 367 pg/ml), while median OS has not been reached in patients with sVEGF < 367 pg/ml (p < 0.001). Median progression-free survival (PFS) was 4.8 months for patients with sVEGF >= 367 pg/ml versus 9.1 months with sVEGF levels < 367 pg/ml (p < 0.001). Patients with sVEGF levels >= 367 pg/ml and >= 5 CTCs had the shortest OS, while those with sVEGF < 367 pg/ml and non-elevated CTCs had the longest OS. CTCs, grading, line of therapy and RAS p21 were independent predictors of OS. sVEGF, line of therapy and CTCs were independent predictors of PFS in the multivariate analysis.Metastatic breast cancer patients with elevated levels of sVEGF have significantly worse clinical outcome. This finding supports the biological role of VEGF in breast cancer.Current Controlled Trials ISRCTN59722891 (DETECT).
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The concept of the certification system of the German Cancer Society and its impact on gynecological cancer care - Wesselmann, Simone; Beckmann, Matthias; Winter, A. (Archives of Gynecology and Obstetrics, 2014)
This article describes the status of gynecological cancer care in Germany and gives an overview of the certification of gynecological cancer care by the German Cancer Society (Deutsche Krebsgesellschaft DKG). The DKG certifies cancer centers to promote a high-quality level in the treatment of oncological patients.Searches were conducted in PubMed and ScienceDirect to identify the relevant literature. Catalog of requirements for centers certification as well as benchmark reports were used to characterize cancer care in centers certified by DKG.The certification system of the DKG has been developed to ensure comprehensive care for cancer patients in Germany. The criteria for certification are based on interdisciplinary and inter-professional care conforming to guidelines and specialist expertise. These requirements have been shown to improve structural and process quality, and thus satisfaction and health outcomes in patients.
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The contributions of breast density and common genetic variation to breast cancer risk - Vachon, Celine M.; Pankratz, V. Shane; Scott, Christopher G.; Häberle, Lothar; Ziv, Elad; Jensen, Matthew R.; Brandt, Kathleen R.; Whaley, Dana H.; Olson, Janet E.; Heusinger, Katharina; Hack, Carolin; Jud, Sebastian; et al. (Journal of the National Cancer Institute, 2015)
We evaluated whether a 76-locus polygenic risk score (PRS) and Breast Imaging Reporting and Data System (BI-RADS) breast density were independent risk factors within three studies (1643 case patients, 2397 control patients) using logistic regression models. We incorporated the PRS odds ratio (OR) into the Breast Cancer Surveillance Consortium (BCSC) risk-prediction model while accounting for its attributable risk and compared five-year absolute risk predictions between models using area under the curve (AUC) statistics. All statistical tests were two-sided. BI-RADS density and PRS were independent risk factors across all three studies (P interaction = .23). Relative to those with scattered fibroglandular densities and average PRS (2(nd) quartile), women with extreme density and highest quartile PRS had 2.7-fold (95% confidence interval [CI] = 1.74 to 4.12) increased risk, while those with low density and PRS had reduced risk (OR = 0.30, 95% CI = 0.18 to 0.51). PRS added independent information (P < .001) to the BCSC model and improved discriminatory accuracy from AUC = 0.66 to AUC = 0.69. Although the BCSC-PRS model was well calibrated in case-control data, independent cohort data are needed to test calibration in the general population.
EVALuna2:14513

The DETECT Study Concept - Metastatic breast cancer and circulating tumor cells - Schramm, A.; Friedl, T.; Rack, B.; Trapp, E.; Fasching, Peter; Taran, F-A.; Hartkopf, A.; Schneeweiss, A.; Mueller, V.; Aktas, B.; Pantel, K.; Meier-Stiegen, F.; et al. (2016)
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The Diagnosis, Treatment, and Aftercare of Cervical Carcinoma. - Beckmann, Matthias; Stübs, Frederik; Vordermark, Dirk; Koch, Martin Christoph; Horn, Lars Christian; Fehm, Tanja (Deutsches Ärzteblatt international, 2021)
BACKGROUND: Approximately 4380 cases of cervical carcinoma were diagnosed in Germany in 2016. In women who had not participated in early detection programs, cervical carcinoma was usually already in an advanced stage at the time of diagnosis. Certified structures for care in conformity with the existing guidelines are available. METHODS: The new German clinical practice guideline was revised with the participation of 50 medical societies under the expert guidance of the Guideline Program in Oncology, which includes the German Association of the Scientific Medical Societies (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF). A systematic literature review was conducted. Systematic reviews, meta-analyses, and randomized controlled trials (RCTs) were considered. RESULTS: The histologic tumor stage and lymph-node stage are essential determinants of the treatment strategy. The main innovation regarding surgical treatment is the revival of open hysterectomy (overall survival [minimally invasive vs open hysterectomy]: 94.04% vs 99.4%; hazard ratio [HR]: 6.00; 95% confidence interval [1.77; 20.30]). In addition, for tumors measuring 2 cm or less, sentinel node biopsy is recommended rather than radical pelvic lymphadenectomy. MRI-guided brachytherapy is an oblig atory component of radiochemotherapy (overall survival [radiochemotherapy with vs without brachytherapy]: 58.2% vs 46.2%, p<0.001). The standard palliative treatment consists of bevacizumab combined with a platinum-containing agent (overall survival: HR: 0.77 [0.62; 0.95]; p = 0.007). CONCLUSION: Despite the introduction of new treatments, the outcome of patients with advanced cervical carcinoma has not much improved. In the surgical treatment of cervical carcinoma, the open approach is now favored. The sentinel node biopsy technique has become well established for the surgical staging of small tumors. Controlled trials are needed so that the outcome of women with cervical carcinoma, particularly in its advanced and metastatic stages, can be improved.
EVALuna2:506686

The effect of bpV(HOpic) on in vitro activation of primordial follicles in cultured swine ovarian cortical strips - Raffel, Nathalie; Klemm, Katrin; Dittrich, Ralf; Hoffmann, Inge; Söder, Stefan; Beckmann, Matthias; Lotz, Laura (Reproduction in Domestic Animals, 2019)
The vanadate-derivative dipotassium bisperoxo (5-hydroxy-pyridine-2-carboxylic) oxovanadate (V) (bpV(HOpic)), a pharmacological inhibitor of phosphatase and tensin homolog (PTEN), has been used in ovarian follicle culture systems for activation of follicular growth in vitro and suggested to be responsible for primordial follicle survival through indirect Akt activation. For pig ovarian tissue, it is still not clear which culture medium needs to be used, as well as which factors and hormones could influence follicular development; this also applies to bpV(HOpic) exposure. Therefore, ovarian cortical strips from pigs were cultured in 1 µM bpV(HOpic) (N = 24) or control medium (N = 24) for 48 hr. Media were then replaced with control medium and all tissue pieces incubated for additional 4 days. The strips were embedded in paraffin for histological determination of follicle proportions at the end of the culture period and compared to histological sections from tissue pieces without cultivation, which had been embedded right after preparation; comparison of healthy follicles for each developmental stage was performed to quantify follicle survival and activation. After 6-day culture, follicle activation occurred in tissue samples from both cultured groups but significantly more follicles showed progression of follicular development in the presence of 1 µM bpV(HOpic). The amount of non-vital follicles was not significantly increased during cultivation. BpV(HOpic) affects pig ovarian follicle development by promoting the initiation of follicle growth and development, similar as in rodent species and humans.
CRIS-Team Scopus Importer:2019-06-28
Keywords: bpV (HOpic); fertiprotekt; follicle activation follicle reserve; in vitro culture; ovarian cortical tissue

The effect of participation in neoadjuvant clinical trials on outcomes in patients with early breast cancer - Brennan, Meghan; Gaß, Paul; Häberle, Lothar; Wang, Daidong; Hartmann, Arndt; Lux, Michael P.; Beckmann, Matthias; Untch, Michael; Fasching, Peter (Breast Cancer Research and Treatment, 2018)
BACKGROUND: Clinical trials can offer novel and more advanced and/or novel treatments to cancer patients in advance of them being approved and available for all patients. While several studies have examined the effect of clinical trial participation on prognosis, there has been no clear conclusion from these studies. Therefore, we chose to test the influence of trial participation on pathological complete response (pCR) and mastectomy rates after neoadjuvant chemotherapy. METHODS: In this retrospective study, all patients treated with neoadjuvant chemotherapy from 2001 to 2014 were selected. A total of 1038 patients with complete treatment, patient, and tumor characteristics were included. A total of 260 of those were treated in clinical trials. We examined whether study participation status in addition to commonly known predictors for pCR improves prediction of pCR. Similar analyses were conducted for the mastectomy rate outcome measure. Finally, survival analyses were also conducted as part of an exploratory analysis. RESULTS: Study participation was an independent predictor of pCR in addition to commonly known predictors. Adjusted odds ratio (OR) for trial participants versus non-participants was 1.53 (95% CI 1.03-2.28). Additionally, study participation improved the prediction of mastectomy risk. The adjusted OR for trial participants versus non-participants was 0.62 (95% CI 0.42-0.90). Subgroup-specific differences concerning the impact of study participation could not be shown for either pCR or mastectomy rate. Survival comparisons could not be conducted due to large differences in follow-up data in patients participating in clinical trials versus those who did not participate; however, pCR was a predictor of prognosis in both groups. CONCLUSION: Patients taking part in neoadjuvant chemotherapy clinical trials have a higher pCR rate and a lower mastectomy risk than patients not participating in clinical trials for their cancer care. This finding is a supporting factor for trial participation in neoadjuvant chemotherapy trials.
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The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer - Figlioli, Gisella; Bogliolo, Massimo; Catucci, Irene; Caleca, Laura; Lasheras, Sandra Viz; Pujol, Roser; Kiiski, Johanna I.; Muranen, Taru A.; Barnes, Daniel R.; Dennis, Joe; Michailidou, Kyriaki; Bolla, Manjeet K.; et al. (npj Breast Cancer, 2019)
Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.
CRIS-Team Scopus Importer:2019-11-12

The Father’s Part: Influences of Paternal Psychopathology and Parenting Behavior on Child and Adolescent Well-Being - Mestermann, Stefan; Arndt, Marie; Fasching, Peter; Beckmann, Matthias; Kratz, Oliver; Moll, Gunther; Kornhuber, Johannes; Eichler, Anna (Healthcare, 2023)
Family influences on child quality of life (QoL) are increasingly understood. Parenting behavior and parent individual psychopathology are among the established predictors of offspring mental health. However, literature often addresses these factors as ‘parental’, lacking further gender-specific differentiation while predominantly studying maternal aspects. Social and biological fathers are still underrepresented in family research. The aim of this study was to analyze paternal contributions to child well-being. A total of 197 father/mother-dyads gave a standardized self-report on parenting behavior and their own psychopathology at child primary school age (t1; 6–10 y). Ratings were compared mutually and associated with child self-rated QoL at t1 and adolescence (t2; 12–14 y). Fathers and mothers differed in psychopathology and most parenting behavior dimensions (positive parenting, involvement, responsible parenting, poor monitoring, and corporal punishment). Father psychopathology made a relevant predictive contribution to girls’ QoL at t2. Boys’ t1 QoL was significantly influenced by maternal parenting factors (positivity and corporal punishment). Compared to mothers, fathers are faced with different individual stressors; paternal parenting behavior is different, while fathers’ influences are significant, particularly for daughters. Father-addressed pre- and intervention programs in child psychotherapeutic treatment are of high relevance.
CRIS-Team Scopus Importer:2023-08-25
Keywords: child development; father; parent-child-relations; parental influence; parenting; parenting behavior; resilience

The genetic interplay between body mass index, breast size and breast cancer risk: a Mendelian randomization analysis - Ooi, Brandon Nick Sern; Loh, Huiwen; Ho, Peh Joo; Milne, Roger L.; Giles, Graham; Gao, Chi; Kraft, Peter; John, Esther M.; Swerdlow, Anthony; Brenner, Hermann; Wu, Anna H.; Haiman, Christopher; et al. (International Journal of Epidemiology, 2019)
BACKGROUND: Evidence linking breast size to breast cancer risk has been inconsistent, and its interpretation is often hampered by confounding factors such as body mass index (BMI). Here, we used linkage disequilibrium score regression and two-sample Mendelian randomization (MR) to examine the genetic associations between BMI, breast size and breast cancer risk. METHODS: Summary-level genotype data from 23andMe, Inc (breast size, n = 33 790), the Breast Cancer Association Consortium (breast cancer risk, n = 228 951) and the Genetic Investigation of ANthropometric Traits (BMI, n = 183 507) were used for our analyses. In assessing causal relationships, four complementary MR techniques [inverse variance weighted (IVW), weighted median, weighted mode and MR-Egger regression] were used to test the robustness of the results. RESULTS: The genetic correlation (rg) estimated between BMI and breast size was high (rg = 0.50, P = 3.89x10-43). All MR methods provided consistent evidence that higher genetically predicted BMI was associated with larger breast size [odds ratio (ORIVW): 2.06 (1.80-2.35), P = 1.38x10-26] and lower overall breast cancer risk [ORIVW: 0.81 (0.74-0.89), P = 9.44x10-6]. No evidence of a relationship between genetically predicted breast size and breast cancer risk was found except when using the weighted median and weighted mode methods, and only with oestrogen receptor (ER)-negative risk. There was no evidence of reverse causality in any of the analyses conducted (P > 0.050). CONCLUSION: Our findings indicate a potential positive causal association between BMI and breast size and a potential negative causal association between BMI and breast cancer risk. We found no clear evidence for a direct relationship between breast size and breast cancer risk.
CRIS-Team Scopus Importer:2019-09-17
Keywords: body mass index; breast cancer risk; Breast size; genetic correlation; genetic epidemiology; LDSC regression; Mendelian randomization

The HER2 phenotype of circulating tumor cells in HER2-positive early breast cancer: A translational research project of a prospective randomized phase III trial - Jaeger, B. A. S.; Neugebauer, J.; Andergassen, U.; Melcher, C.; Schochter, F.; Mouarrawy, D.; Ziemendorff, G.; Clemens, M.; Abel, E. V.; Heinrich, G.; Schueller, K.; Schneeweiss, A.; et al. (PLoS ONE, 2017)
BACKGROUND: HER2 is one of the predominant therapeutic targets in breast cancer. The metastatic selection process may lead to discrepancies between the HER2 status of the primary tumor and circulating tumor cells (CTCs). This study analyzed the HER2 status of CTCs in patients with HER2-positive primary breast cancer at the time of diagnosis. Aim of the study was to assess potential discordance of HER2 status between primary tumor and CTCs, as this may have important implications for the use of HER2-targeted therapy. METHODS: The number and HER2 status of CTCs out of 30ml peripheral blood were assessed in 642 patients using the CellSearch System (Janssen Diagnostics, USA). The cutoff for CTC positivity was the presence of at least 1 CTC, and the cutoff for HER2 positivity of CTCs was the presence of at least 1 CTC with a strong HER2 staining. RESULTS: 258 (40.2%) of the 642 patients were positive for CTCs (median 2; range 1-1,689). 149 (57.8%) of these 258 patients had at least 1 CTC with strong HER2 staining. The presence of HER2-positive CTCs was not associated with tumor size (p = 0.335), histopathological grading (p = 0.976), hormone receptor status (ER: p = 0.626, PR: p = 0.263) or axillary lymph node involvement (p = 0.430). Overall, 83 (32.2%) of the CTC-positive patients exclusively had CTCs with strong HER2 staining, whereas 31 (12.0%) had only CTCs with negative HER2 staining. Within-sample variation in the HER2 status of CTCs was found in 86 (57.8%) of the 149 patients with more than 1 CTC. CONCLUSION: This study demonstrated that discordance between the HER2 expression of CTCs and that of the primary tumor frequently occurs in early breast cancer. Future follow-up evaluation will assess whether this discrepancy may contribute to trastuzumab resistance.
EVALuna2:36134

The impact of anthracyclines in intermediate and high-risk HER2-negative early breast cancer-a pooled analysis of the randomised clinical trials PlanB and SUCCESS C - De Gregorio, Amelie; Janni, Wolfgang; Friedl, Thomas W. P.; Nitz, Ulrike; Rack, Brigitte; Schneeweiss, Andreas; Kates, Ronald; Fehm, Tanja; Kreipe, Hans; Christgen, Matthias; Kuemmel, Sherko; Trapp, Elisabeth; et al. (British Journal of Cancer, 2022)
Background Anthracycline/cyclophosphamide-taxane-containing chemotherapy (AC-T) is the standard of care in the adjuvant treatment of HER2-negative early breast cancer (EBC), but recent studies suggest omission of anthracyclines for reduced toxicity without compromising efficacy. Methods Based on individual patient data (n = 5924) pooled from the randomised Phase III trials PlanB and SUCCESS C, we compared disease-free survival (DFS) and overall survival (OS) between intermediate to high-risk HER2-negative EBC-patients treated with either six cycles of docetaxel/cyclophosphamide (TC6) or an AC-T regime using univariable and adjusted multivariable Cox regression models. Results AC-T conferred no significant DFS or OS advantage in univariable (DFS: hazard ratio (HR) for TC vs. AT 1.05, 95% confidence interval (CI): 0.89-1.24, P = 0.57; OS: HR 1.00, 95% CI: 0.80-1.26, P = 1.00) and adjusted multivariable analysis (DFS: HR 1.01, 95% CI: 0.86-1.19, P = 0.91; OS: HR 0.97, 95% CI: 0.77-1.22, P = 0.79). Patients receiving TC6 had significantly fewer grade 3-4 adverse events. Exploratory subgroup analysis showed that AC-T was associated with significantly better DFS and OS in pN2/3 patients, specifically in those with lobular histology. Conclusion For most patients with HER2-negative EBC, AC-T is not associated with a survival benefit compared to TC6. However, patients with lobular pN2/pN3 tumours seem to benefit from anthracycline-containing chemotherapy.
CRIS-Team WoS Importer:2022-03-18

The impact of mammalian target of rapamycin inhibition on bone health in postmenopausal women with hormone receptor-positive advanced breast cancer receiving everolimus plus exemestane in the phase IIIb 4EVER trial - Hadji, Peyman; Stoetzer, Oliver; Decker, Thomas; Kurbacher, Christian M.; Marme, Frederik; Schneeweiss, Andreas; Mundhenke, Christoph; Distelrath, Andrea; Fasching, Peter; Lux, Michael P.; Lueftner, Diana; Janni, Wolfgang; et al. (Journal of Bone Oncology, 2019)
Background: Breast cancer and its treatments are associated with a detrimental effect on bone health. Here we report the results of an exploratory analysis assessing changes in levels of biomarkers of bone metabolism in patients enrolled in the phase IIIb 4EVER study.
CRIS-Team WoS Importer:2019-03-20

The influence of obesity on survival in early, high-risk breast cancer: results from the randomized SUCCESS A trial - Widschwendter, Peter; Friedl, Thomas W. P.; Schwentner, Lukas; Degregorio, Nikolaus; Jaeger, Bernadette; Schramm, Amelie; Bekes, Inga; Deniz, Miriam; Lato, Krisztian; Weissenbacher, Tobias; Kost, Bernd; Andergassen, Ulrich; et al. (Breast Cancer Research, 2015)
Obese breast cancer patients have worse prognosis than normal weight patients, but the level at which obesity is prognostically unfavorable is unclear.This retrospective analysis was performed using data from the SUCCESS A trial, in which 3754 patients with high-risk early breast cancer were randomized to anthracycline- and taxane-based chemotherapy with or without gemcitabine. Patients were classified as underweight/normal weight (body mass index (BMI) < 25.0), overweight (BMI 25.0-29.9), slightly obese (BMI 30.0-34.9), moderately obese (BMI 35.0-39.9) and severely obese (BMI >= 40.0), and the effect of BMI on disease-free survival (DFS) and overall survival (OS) was evaluated (median follow-up 65 months). In addition, subgroup analyses were conducted to assess the effect of BMI in luminal A-like, luminal B-like, HER2 (human epidermal growth factor 2)-positive and triple-negative tumors.Multivariate analyses revealed an independent prognostic effect of BMI on DFS (p = 0.001) and OS (p = 0.005). Compared with underweight/normal weight patients, severely obese patients had worse DFS (hazard ratio (HR) 2.70, 95 % confidence interval (CI) 1.71-4.28, p < 0.001) and OS (HR 2.79, 95 % CI 1.63-4.77, p < 0.001), while moderately obese, slightly obese and overweight patients did not differ from underweight/normal weight patients with regard to DFS or OS. Subgroup analyses showed a similar significant effect of BMI on DFS and OS in patients with triple-negative breast cancer (TNBC), but not in patients with other tumor subtypes.Severe obesity (BMI >= 40) significantly worsens prognosis in early breast cancer patients, particularly for triple-negative tumors.Clinicaltrials.gov NCT02181101 . Registered September 2005.
EVALuna2:17573

The influence of prenatal risks on attachment, emotion regulation and emotional and behavioral problems in middle childhood: A prospective longitudinal study - Ziegler, Clara; Zalan, Vera; Eichler, Anna; Heinrich, Hartmut; Moll, Gunther; Fasching, Peter; Beckmann, Matthias; Kornhuber, Johannes; Lenz, Bernd; Spangler, Gottfried (International Attachment Conference, 2017)

The integrative epigenomic-transcriptomic landscape of ER positive breast cancer - Gao, Yang; Jones, Allison; Fasching, Peter; Rübner, Matthias; Beckmann, Matthias; Widschwendter, Martin; Teschendorff, Andrew E. (Clinical Epigenetics, 2015)
While recent integrative analyses of copy number and gene expression data in breast cancer have revealed a complex molecular landscape with multiple subtypes and many oncogenic/tumour suppressor driver events, much less is known about the role of DNA methylation in shaping breast cancer taxonomy and defining driver events.Here, we applied a powerful integrative network algorithm to matched DNA methylation and RNA-Seq data for 724 estrogen receptor (ER)-positive (ER+) breast cancers and 111 normal adjacent tissue specimens from The Cancer Genome Atlas (TCGA) project, in order to identify putative epigenetic driver events and to explore the resulting molecular taxonomy. This revealed the existence of nine functionally deregulated epigenetic hotspots encompassing a total of 146 genes, which we were able to validate in independent data sets encompassing over 1000 ER+ breast cancers. Integrative clustering of the matched messenger RNA (mRNA) and DNA methylation data over these genes resulted in only two clusters, which correlated very strongly with the luminal-A and luminal B subtypes. Overall, luminal-A and luminal-B breast cancers shared the same epigenetically deregulated hotspots but with luminal-B cancers exhibiting increased aberrant DNA methylation patterns relative to normal tissue. We show that increased levels of DNA methylation and mRNA expression deviation from the normal state define a marker of poor prognosis. Our data further implicates epigenetic silencing of WNT signalling antagonists and bone morphogenetic proteins (BMP) as key events underlying both luminal subtypes but specially of luminal-B breast cancer. Finally, we show that DNA methylation changes within the identified epigenetic interactome hotspots do not exhibit mutually exclusive patterns within the same cancer sample, instead exhibiting coordinated changes within the sample.Our results indicate that the integrative DNA methylation and transcriptomic landscape of ER+ breast cancer is surprisingly homogeneous, defining two main subtypes which strongly correlate with luminal-A/B subtype status. In particular, we identify WNT and BMP signalling as key epigenetically deregulated tumour suppressor pathways in luminal ER+ breast cancer, with increased deregulation seen in luminal-B breast cancer.
EVALuna2:17561

The International Endometriosis Evaluation Program (IEEP Study) - A Systematic Study for Physicians, Researchers and Patients - Burghaus, Stefanie; Fehm, T.; Fasching, Peter; Blum, Simon; Renner, Stefan; Baier, F.; Brodkorb, T.; Fahlbusch, C.; Findeklee, S.; Häberle, Lothar; Heusinger, K.; Hildebrandt, T.; et al. (Geburtshilfe und Frauenheilkunde, 2016)
INTRODUCTION: Endometriosis is a heterogeneous disease characterized by a range of different presentations. It is usually diagnosed when patients present with pain and/or infertility, but it has also been diagnosed in asymptomatic patients. Because of the different diagnostic approaches and diverse therapies, time to diagnosis can vary considerably and the definitive diagnosis may be delayed, with some cases not being diagnosed for several years. Endometriosis patients have many unmet needs. A systematic registration and follow-up of endometriosis patients could be useful to obtain an insight into the course of the disease. The validation of biomarkers could contribute to the development of diagnostic and predictive tests which could help select patients for surgical assessment earlier and offer better predictions about patients who might benefit from medical, surgical or other interventions. The aim is also to obtain a better understanding of the etiology, pathogenesis and progression of the disease. MATERIAL AND METHODS: To do this, an online multicenter documentation system was introduced to facilitate the establishment of a prospective multicenter case-control study, the IEEP (International Endometriosis Evaluation Program) study. We report here on the first 696 patients with endometriosis included in the program between June 2013 and June 2015. RESULTS: A documentation system was created, and the structure and course of the study were mapped out with regard to data collection and the collection of biomaterials. CONCLUSION: The documentation system permits the history and clinical data of patients with endometriosis to be recorded. The IEEP combines this information with biomaterials and uses it for scientific studies. The recorded data can also be used to evaluate clinical quality control measures such as the certification parameters used by the EEL (European Endometriosis League) to assess certified endometriosis centers.
EVALuna2:32966

The PI3K Pathway: Background and Treatment Approaches - Lux, Michael P.; Fasching, Peter; Schrauder, Michael G.; Hein, Alexander; Jud, Sebastian; Rauh, Claudia; Beckmann, Matthias (Breast Care, 2016)
Two-thirds of all breast cancer patients with metastases have a hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative subtype. Endocrine therapy is the treatment of choice in these patients since in addition to its effectiveness it can also maintain the patients' quality of life over a longer term. However, 44-62% of postmenopausal patients with metastatic breast carcinoma have primary tamoxifen resistance. After 3-5 years, 30-40% of the patients receiving tamoxifen treatment develop secondary resistance. Understanding the way in which resistance develops is therefore essential for developing treatment approaches that can prevent or reverse endocrine resistance. The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway plays a central role here. As a result of the numerous interactions involved, complex issues arise that need to be taken into account in the development and use of therapeutic agents. In addition, this signaling pathway is the one that most frequently undergoes mutations in breast cancer. The prognostic and predictive significance of individual mutations has not yet been fully explained, but it might provide a basis for patient selection in clinical studies. Initial research results on the use of PI3K inhibitors suggest that this may be a highly promising therapeutic approach, with an acceptable side effect profile.
EVALuna2:33003

The placental mTOR-pathway: correlation with early growth trajectories following intrauterine growth restriction? - Fahlbusch, F. B.; Menendez-Castro, C.; Nögel, Stephanie; Marek, I.; Beckmann, Matthias; Schleussner, E.; Ruebner, M.; Huebner, H.; Dörr, Helmuth-Günther; Schild, R. L.; Doetsch, J.; Rascher, Wolfgang; et al. (Journal of Developmental Origins of Health and Disease, 2015)
Idiopathic intrauterine growth restriction (IUGR) is a result of impaired placental nutrient supply. Newborns with IUGR exhibiting postnatal catch-up growth are of higher risk for cardiovascular and metabolic co-morbidities in adult life. Mammalian target of rapamycin (mTOR) was recently shown to function as a placental nutrient sensor. Thus, we determined possible correlations of members of the placental mTOR signaling cascade with auxologic parameters of postnatal growth. The protein expression and activity of mTOR-pathway signaling components, Akt, AMP-activated protein kinase ?, mTOR, p70S6kinase1 and insulin receptor substrate-1 were analysed via western blotting in IUGR v. matched appropriate-for-gestational age (AGA) placentas. Moreover, mTOR was immunohistochemically stained in placental sections. Data from western blot analyses were correlated with retrospective auxological follow-up data at 1 year of age. We found significant catch-up growth in the 1st year of life in the IUGR group. MTOR and its activated form are immunohistochemically detected in multiple placental compartments. We identified correlations of placental mTOR-pathway signaling components to auxological data at birth and at 1 year of life in IUGR. Analysis of the protein expression and phosphorylation level of mTOR-pathway components in IUGR and AGA placentas postpartum, however, did not reveal pathognomonic changes. Our findings suggest that the level of activated mTOR correlates with early catch-up growth following IUGR. However, the complexity of signals converging at the mTOR nexus and its cellular distribution pattern seem to limit its potential as biomarker in this setting.
EVALuna2:17439

The prognostic relevance of urokinase-type plasminogen activator (uPA) in the blood of patients with metastatic breast cancer - Banys-Paluchowski, Malgorzata; Witzel, Isabell; Aktas, Bahriye; Fasching, Peter; Hartkopf, Andreas; Janni, Wolfgang; Kasimir-Bauer, Sabine; Pantel, Klaus; Schoen, Gerhard; Rack, Brigitte; Riethdorf, Sabine; Solomayer, Erich-Franz; et al. (Scientific Reports, 2019)
In breast cancer (BC), elevated levels of urokinase-type plasminogen activator (uPA) in tumor tissue have been confirmed as a strong prognostic factor in level-of-evidence-1 studies. The aim of the present study was to evaluate the clinical relevance of uPA levels in serum of metastatic BC patients and to compare uPA with other blood-based biomarkers. 252 patients were enrolled in this prospective, multicentre study. Blood samples were collected before begin of first-line or later-line systemic treatment. Serum uPA was quantified by a commercially available ELISA. Circulating tumor cells (CTCs) were detected using CellSearch; other biomarkers (EGFR, VEGF, HER2, RAS p21, TIMP1, CAIX) by ELISA. Using the ROC analysis, the optimal cut-off value (determined by the Youden index) of serum uPA was 2.52 ng/ml. Using this value, 26% of patients had elevated uPA levels. Patients with visceral metastasis and more than one metastatic site were significantly more likely to present with elevated uPA levels. CTC status, serum HER2, RAS p21, CAIX, TIMP1 and VEGF correlated significantly with uPA levels. Elevated uPA levels predicted shorter overall and progression-free survival in univariate analysis (median OS: 7.5 months [95%-CI 4.5-10.5 months] vs. not reached, p < 0.001; PFS:4.8 [95%CI: 3.1-6.5] vs. 9.1 [7.4-10.8] months, p < 0.001). In multivariate analysis, elevated uPA, presence of >= 5 CTCs, elevated RAS p21, higher grading and higher line of therapy were independent predictors of shorter OS, while elevated CTC counts, higher line of therapy and negative estrogen receptor status were independent predictors of shorter PFS. In conclusion, elevated uPA levels independently predict reduced overall survival and improved prognostication in patients with known CTC status. Whether high serum uPA might identify patients most likely to benefit from therapies targeting uPA, remains to be evaluated in future trials.
CRIS-Team WoS Importer:2019-03-06

The Randomized AMBORA Trial: Impact of Pharmacological/Pharmaceutical Care on Medication Safety and Patient-Reported Outcomes During Treatment With New Oral Anticancer Agents - Dürr, Pauline; Schlichtig, Katja; Kelz, Carolin; Deutsch, Birgit; Maas, Renke; Eckart, Michael J.; Wilke, Jochen; Wagner, Harald; Wolff, Kerstin; Preuß, Caroline; Brückl, Valeska; Meidenbauer, Norbert; et al. (Journal of Clinical Oncology, 2021)
PURPOSE: Oral anticancer drugs (eg, kinase inhibitors) play an important role in cancer therapy. However, considerable challenges regarding medication safety of oral anticancer drugs have been reported. Randomized, controlled, multicenter studies on the impact of intensified clinical pharmacological/pharmaceutical care on patient safety and patient treatment perception are lacking. METHODS: Patients were eligible for the randomized, multicenter AMBORA study, if they were newly started on any of the oral anticancer drugs approved in 2001 or later without restriction to certain tumor entities. Patients were randomly assigned to receive either standard of care (control group) or an additional, intensified clinical pharmacological/pharmaceutical care, which included medication management and structured patient counseling, over a period of 12 weeks (intervention group). Primary end points were the number of antitumor drug-related problems (ie, side effects and unresolved medication errors) and patient treatment satisfaction with the oral anticancer therapy after 12 weeks measured with the Treatment Satisfaction Questionnaire for Medication, category convenience. RESULTS: Two hundred two patients were included. Antitumor drug-related problems were significantly lower in the intervention compared with the control group (3.85 v 5.81 [mean], P < .001). Patient treatment satisfaction was higher in the intervention group (Treatment Satisfaction Questionnaire for Medication, convenience; 91.6 v 74.4 [mean], P < .001). The hazard ratio for the combined end point of severe side effects (Common Terminology Criteria for Adverse Events ≥ 3), treatment discontinuation, unscheduled hospital admission, and death was 0.48 (95% CI, 0.32 to 0.71, P < .001) in favor of the intervention group. CONCLUSION: Treatment with oral anticancer drugs is associated with a broad range of medication errors and side effects. An intensified clinical pharmacological/pharmaceutical care has considerable, positive effects on the number of medication errors, patient treatment perception, and severe side effects.
CRIS-Team Scopus Importer:2021-07-02

Therapierelevante Biomarker in der gynäkologischen Onkologie - Ditsch, Nina; Fasching, Peter (Best Practice Onkologie, 2022)
The first biomarkers were discovered decades ago. Their prognostic and predictive value is still the subject of current research. Biomarker-based treatments represent the basis of the current and future trial landscape in gynecologic oncology, as was clearly demonstrated at this year’s ASCO Annual Meeting. The all-important question is founded in the quality of diagnostics at the immunohistochemical or molecular level. In breast cancer therapy, a HER‑2 (human epidermal growth factor receptor 2) finding was previously considered therapeutically relevant if there was an immunohistochemical (IHC) evaluation of 3+ or a fluorescence in situ hybridization (FISH)- or chromogenic in situ hybridization (CISH)-positive value. Use of the antibody–drug conjugate trastuzumab–deruxtecan, also in HER-2-low forms (IHC1+ or 2+, even if FISH/CISH negative), is now celebrated as practice changing, since significantly improved progression-free survival (PFS) and overall survival (OS) were also shown in this situation. With the accelerating use of newer therapeutics, attention should be paid to the side effects and the cost–benefit ratio. The following article provides an overview of the currently most important prognostic and predictive markers in breast, ovarian, endometrial, and cervical cancer.
CRIS-Team Scopus Importer:2022-11-11
Keywords: Her-2; Immune checkpoint inhibitors; Immunoconjugates; Microsatellite instability; Prognosis; Trastuzumab

Therapy landscape in patients with metastatic HER2-positive breast cancer: Data from the PRAEGNANT real-world breast cancer registry - Lux, Michael P.; Nabieva, Naiba; Hartkopf, Andreas D.; Huober, Jens; Volz, Bernhard; Taran, Florin-Andrei; Overkamp, Friedrich; Kolberg, Hans-Christian; Hadji, Peyman; Tesch, Hans; Häberle, Lothar; Ettl, Johannes; et al. (Cancers, 2019)
This study presents comprehensive real-world data on the use of anti-human epidermal growth factor receptor 2 (HER2) therapies in patients with HER2-positive metastatic breast cancer (MBC). Specifically, it describes therapy patterns with trastuzumab (H), pertuzumab + trastuzumab (PH), lapatinib (L), and trastuzumab emtansine (T-DM1). The PRAEGNANT study is a real-time, real-world registry for MBC patients. All therapy lines are documented. This analysis describes the utilization of anti-HER2 therapies as well as therapy sequences. Among 1936 patients in PRAEGNANT, 451 were HER2-positive (23.3%). In the analysis set (417 patients), 53% of whom were included in PRAEGNANT in the first-line setting, 241 were treated with H, 237 with PH, 85 with L, and 125 with T-DM1 during the course of their therapies. The sequence PH ! T-DM1 was administered in 51 patients. Higher Eastern Cooperative Oncology Group (ECOG) scores, negative hormone receptor status, and visceral or brain metastases were associated with more frequent use of this therapy sequence. Most patients received T-DM1 after treatment with pertuzumab. Both novel therapies (PH and T-DM1) are utilized in a high proportion of HER2-positive breast cancer patients. As most patients receive T-DM1 after PH, real-world data may help to clarify whether the efficacy of this sequence is similar to that in the approval study.
CRIS-Team Scopus Importer:2019-05-14
Keywords: Advanced breast cancer; Antihormone therapy; Chemotherapy; Her2 c-ERBB2; Her2/neu; Lapatinib; Metastatic; Pertuzumab; T-DM1; Trastuzumab

Therapy response and prognosis of patients with early breast cancer with low positivity for hormone receptors – An analysis of 2765 patients from neoadjuvant clinical trials - Villegas, Sonia L.; Nekljudova, Valentina; Pfarr, Nicole; Engel, Jutta; Untch, Michael; Schrodi, Simone; Holms, Frank; Ulmer, Hans U.; Fasching, Peter; Weber, Karsten E.; Albig, Christian; Heinrichs, Clemens; et al. (European Journal of Cancer, 2021)
Aim: To evaluate HER2-negative breast cancer (BC) with a low hormone receptor (HR) expression, with regard to pathological complete response (pCR) and survival, in comparison to triple-negative BC (TNBC) and strong HR-positive BC. Methods: We compared negative [oestrogen (ER) and progesterone receptor (PR) <1%], low-positive (ER and/or PR 1–9%) and strong-positive (ER or PR 10–100%) HR-expression in neoadjuvant clinical trial cohorts (n = 2765) of BC patients. End-points were disease-free survival (DFS), distant-disease free survival (DDFS) and overall survival (OS). We performed RNA sequencing on available tumour tissue samples from patients with low-HR expression (n = 38). Results: Ninety-four (3.4%) patients had low HR-positive tumours, 1769 (64.0%) had strong HR-positive tumours, and 902 (32.6%) had TNBC. There were no significant differences in pCR rates between women with low HR-positive tumours (27.7%) and women with TNBC (35.5%). DFS and DDFS were also not different [for DFS, hazard ratio 1.26, 95%-CI (confidence interval) : 0.87–1.83, log-rank test p = 0.951; for DDFS, hazard ratio 1.17, 95%-CI: 0.78–1.76, log-rank test p = 0.774]. Patients with strong HR-positive tumours had a significantly lower pCR rate (pCR 9.4%; odds ratio 0.38, 95%-CI: 0.23–0.63), but better DFS (hazard ratio 0.48, 95%-CI: 0.33–0.70) and DDFS (hazard ratio 0.49, 95%-CI: 0.33–0.74) than patients with low HR-positive tumours. Molecular subtyping (RNA sequencing) of low HR-positive tumours classified these predominantly into a basal subtype (86.8%). Conclusion: Low HR-positive, HER2-negative tumours have a similar clinical behaviour to TNBC showing high pCR rates and poor survival and also a basal-like gene expression signature. Patients with low HR-positive tumours should be regarded as candidates for therapy strategies targeting TNBC.
CRIS-Team Scopus Importer:2021-03-26
Keywords: Breast cancer; Breast neoplasms; Cancer biomarkers; ER-negative PR-negative HER2-negative breast cancer; Hormone-dependent neoplasms; Mammary cancer; Neoadjuvant therapy; Oestrogen receptors; Progesterone receptors; Triple-negative breast cancer

The safety and satisfaction of ovarian tissue cryopreservation in prepubertal and adolescent girls - Lotz, Laura; Barbosa, Patricia Reis; Knorr, Christian; Hofbeck, Louisa; Hoffmann, Inge; Beckmann, Matthias; Antoniadis, Sophia; Dittrich, Ralf (Reproductive Biomedicine Online, 2020)
Research question: Is ovarian tissue cryopreservation (OTC) for fertility preservation in prepubertal and adolescent girls safe, and who would benefit most from the procedure? Design: Survey and retrospective study including patients who had OTC under the age of 18 years in a single centre for fertility preservation. Serum anti-Müllerian hormone levels were measured as a marker for detection of diminished ovarian reserve. Results: Fifty-three from 102 women participated in the survey (12 deceased, 19 declined, 17 unreachable, 1 palliative). The average age at OTC was 14.8 ± 2.3 (range: 6–17) years and at survey 21.9 ± 4.3 (range: 16–33) years. Ovarian tissue retrieval (laparoscopy: n = 45, laparotomy: n = 8) was without complications in 52 cases. In 23 (53.5%) of the 43 women who were post-menarchal at OTC, transient amenorrhoea occurred. At survey, 15 women reported a regular menstrual cycle, 25 used oral contraceptives, 9 women reported hormone replacement therapy due to primary ovary insufficiency and 4 had amenorrhoea. Two patients reported the birth of a healthy child after IVF, while 51 patients are still childless, mostly due to their young age (mean: 21.2 years). To date, one patient has had transplantation of the ovarian tissue (17 years at cryopreservation). Forty-nine of the interviewees would again decide on OTC, while three argued against it on the basis of the previous financial cost; one woman was unsure. Conclusions: Children with cancer may be at risk for gonadal insufficiency. OTC is practically the only technique that can be offered to young girls. The procedure is safe and well accepted.
CRIS-Team Scopus Importer:2020-03-27
Keywords: Adolescent females; Cancer; Fertility preservation; Ovarian tissue cryopreservation; Ovarian tissue transplantation; Prepubertal females

The SNP rs6500843 in 16p13.3 is associated with survival specifically among chemotherapy-treated breast cancer patients - Fagerholm, Rainer; Schmidt, Marjanka K.; Khan, Sofia; Rafiq, Sajjad; Tapper, William; Aittomaki, Kristiina; Greco, Dario; Heikkinen, Tuomas; Muranen, Taru A.; Fasching, Peter; Janni, Wolfgang; Weinshilboum, Richard; et al. (Oncotarget, 2015)
We have utilized a two-stage study design to search for SNPs associated with the survival of breast cancer patients treated with adjuvant chemotherapy. Our initial GWS data set consisted of 805 Finnish breast cancer cases (360 treated with adjuvant chemotherapy). The top 39 SNPs from this stage were analyzed in three independent data sets: iCOGS (n=6720 chemotherapy-treated cases), SUCCESS-A (n=3596), and POSH (n=518). Two SNPs were successfully validated: rs6500843 (any chemotherapy; per-allele HR 1.16, 95% C.I. 1.08-1.26, p=0.0001, p(adjusted)=0.0091), and rs11155012 (anthracycline therapy; per-allele HR 1.21, 95% C.I. 1.08-1.35, p=0.0010, p(adjusted)=0.0270). The SNP rs6500843 was found to specifically interact with adjuvant chemotherapy, independently of standard prognostic markers (p(interaction)=0.0009), with the rs6500843-GG genotype corresponding to the highest hazard among chemotherapy-treated cases (HR 1.47, 95% C.I. 1.20-1.80). Upon trans-eQTL analysis of public microarray data, the rs6500843 locus was found to associate with the expression of a group of genes involved in cell cycle control, notably AURKA, the expression of which also exhibited differential prognostic value between chemotherapy-treated and untreated cases in our analysis of microarray data. Based on previously published information, we propose that the eQTL genes may be connected to the rs6500843 locus via a RBFOX1-FOXM1 -mediated regulatory pathway.
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The UGT1A6_19_GG genotype is a breast cancer risk factor - Justenhoven, Christina; Obazee, Ofure; Winter, Stefan; Rabstein, Sylvia; Lotz, Anne; Harth, Volker; Pesch, Beate; Brüning, Thomas; Baisch, Christian; Hartikainen, Jaana M.; Mannermaa, Arto; Kosma, Veli Matti; et al. (Frontiers in Genetics, 2013)
Validation of an association between the UGT1A6_19_T>G (rs6759892) polymorphism and overall breast cancer risk. A pilot study included two population-based case-control studies from Germany (MARIE-GENICA). An independent validation study comprised four independent breast cancer case-control studies from Finland (KBCP, OBCS), Germany (BBCC), and Sweden (SASBAC). The pooled analysis included 7418 cases and 8720 controls from all six studies. Participants were of European descent. Genotyping was done by MALDI-TOF MS and statistical analysis was performed by logistic regression adjusted for age and study. The increased overall breast cancer risk for women with the UGT1A6_19_GG genotype which was observed in the pilot study was confirmed in the set of four independent study collections (OR 1.13, 95% CI 1.05-1.22; p = 0.001). The pooled study showed a similar effect (OR 1.09, 95% CI 1.04-1.14; p = 0.001). The risk effect on the basis of allele frequencies was highly significant, the pooled analysis showed an OR of 1.11 (95% CI 1.06-1.16; p = 5.8 × 10-6). We confirmed the association of UGT1A6_19_GG with increased overall breast cancer risk and conclude that our result from a well powered multi-stage study adds a novel candidate to the panel of validated breast cancer susceptibility loci. © 2013 Justenhoven, Obazee, Winter, Rabstein, Lotz, Harth, Pesch, Brüning, Baisch, Hartikainen, Mannermaa, Kosma, Kataja, Winqvist, Pylkäs, Jukkola-Vuorinen, Grip, Fasching, Beckmann, Ekici, Hein, Hall, Li, Chang-Claude, Flesch-Janys, Seibold, Rudolph, Hamann, Ko and Brauch.
CRIS-Team Scopus Importer:2021-07-19
Keywords: Breast cancer risk; Metabolism; Polymorphism; UGT1A6; Validation

The Use of Assisted Reproductive Technology by European Childhood Cancer Survivors - Borgmann-Staudt, Anja; Michael, Simon; Sommerhaeuser, Greta; Fernandez-Gonzalez, Marta-Julia; Friedrich, Lucia Alacan; Klco-Brosius, Stephanie; Kepak, Tomas; Kruseova, Jarmila; Michel, Gisela; Panasiuk, Anna; Schmidt, Sandrin; Lotz, Laura; et al. (Current Oncology, 2022)
CCS often wish to have biological children yet harbour concerns about fertility impairment, pregnancy risks and the general health risks of prospective offspring. To clarify these concerns, health outcomes in survivor offspring born following ART (n = 74, 4.5%) or after spontaneous conception (n = 1585) were assessed in our European offspring study by descriptive and bivariate analysis. Outcomes were compared to a sibling offspring cohort (n = 387) in a 4:1 matched-pair analysis (n = 1681). (i) Survivors were more likely to employ ART than their siblings (4.5% vs. 3.7%, p = 0.501). Successful pregnancies were achieved after a median of one cycle with, most commonly, intracytoplasmic sperm injection (ICSI) using non-cryopreserved oocytes/sperm. (ii) Multiple-sibling births (p < 0.001, 29.7% vs. 2.5%), low birth weight (p < 0.001; OR = 3.035, 95%-CI = 1.615–5.706), and preterm birth (p < 0.001; OR = 2.499, 95%-CI = 1.401–4.459) occurred significantly more often in survivor offspring following ART utilisation than in spontaneously conceived children. ART did not increase the prevalence of childhood cancer, congenital malformations or heart defects. (iii) These outcomes had similar prevalences in the sibling population. In our explorative study, we could not detect an influence on health outcomes when known confounders, such as multiple births, were taken into account.
CRIS-Team Scopus Importer:2022-09-09
Keywords: ART; cancer; childhood and adolescence; health outcome; offspring; survivor

The use of PAMG-1 testing in patients with preterm labor, intact membranes and a short sonographic cervix reduces the rate of unnecessary antenatal glucocorticoid administration - Kehl, Sven; Weiss, Christel; Pretscher, Jutta; Baier, Friederike; Faschingbauer, Florian; Beckmann, Matthias; Stumpfe, Florian (Journal of Perinatal Medicine, 2021)
Objectives: To assess the frequency of antenatal corticosteroid (ACS) administration in cases with shortened cervical length by addition of placental alpha-microglobulin-1 (PAMG-1) testing to sonographic examination. Methods: Single centre retrospective cohort study. Rate of ACS administration was compared between cases with cervical length between 15 and 25 mm and cases with positive PAMG-1 testing and cervical length between 15 and 25 mm. We evaluated the following outcome parameters: Rate of ACS administration, gestational age at delivery, time to delivery, delivery within seven days, delivery <34 and <37 weeks' gestation, rate of admission to neonatal intensive care unit (NICU). Results: In total, 130 cases were included. "PAMG-1 group" consisted of 68 women, 62 cases built the "historical control group". ACS administration was performed less frequently in the "PAMG-1 cohort" (18 (26%) vs. 46 (74%); p<0.001). The rate of delivery within seven days did not differ (2 (3%) vs. 4 (6.5%); p=0.4239). The rates of delivery <34 weeks' gestation (7 (10%) vs. 9 (15%); p=0.4643) and <37 weeks' gestation (19 (28%) vs. 26 (42%); p=0.0939) did not differ. Time to delivery interval was longer in the PAMG-1 group (61.5 vs. 43 days, p=0.0117). NICU admission occurred more often in the "historical control group" (22 (38%) vs. 28 (60%); p=0.0272). Conclusions: Addition of biomarker testing can help to avoid unnecessary ACS administrations in women with shortened cervical length.
CRIS-Team WoS Importer:2021-12-03

The villoglandular Adenocarcinoma of the Cervix as a Tumor Model. A Literature Analysis - Dietl, Anna; Aumann, K.; Beckmann, Matthias (GEBURTSHILFE UND FRAUENHEILKUNDE, 2020)
CRIS-Team WoS Importer:2020-10-30

TILGen: A Program to Investigate Immune Targets in Breast Cancer Patients - First Results on the Influence of Tumor-Infiltrating Lymphocytes - Würfel, Franziska; Erber, Ramona; Hübner, Hanna; Hein, Alexander; Lux, Michael P.; Jud, Sebastian; Kremer, Anita; Kranich, Hannah; Mackensen, Andreas; Häberle, Lothar; Hack, Carolin; Rauh, Claudia; et al. (Breast Care, 2018)
Background: Despite advancements in the treatment of primary and metastatic breast cancer, many patients lack a durable response to these treatments. Patients with triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2(HER2)-positive breast cancer who do not have a pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) have a very poor prognosis. Tumor-infiltrating lymphocytes (TILs) have been identified as a predictive marker for pCR after NACT in TNBC and HER2-positive breast cancer. These patient populations could also be suitable for novel treatment strategies including neoepitope-based therapies. This work analyses the effect of TILs on the pCR in neoadjuvantly treated patients in the TILGen study and presents the procedures aimed at establishing neoepitope-based therapies in this study. Methods: Neoadjuvantly treated HER2-positive and TNBC patients were eligible for the presented analysis concerning the association between TILs and pCR. A total of 146 patients could be identified within the TILGen study. TILs were evaluated as percentage of stromal tumor tissue in core biopsies at primary diagnosis. The phenotype ‘lymphocyte-predominant breast cancer' (LPBC) was associated with pCR by logistic regression adjusted for estrogen receptor status, progesterone receptor status, HER2 status, age at diagnosis, and grading. Results: LPBC was seen in 24 (16.4%) patients. In this patient group, 66.7% achieved a pCR, while the pCR rate was 32.8% in patients with a low TIL count. The adjusted odds ratio was 6.60 (95% confidence interval 2.02-21.56; p < 0.01). Conclusion: TILs are a strong predictor of pCR in TNBC and HER2-positive breast cancer patients. Implications for the use of this information including the effect on prognosis might help to identify patients most likely to benefit from a neoepitope-based therapy approach.<br

TILGen: A Program to Investigate Immune Targets in Breast Cancer Patients - First Results on the Influence of Tumor-Infiltrating Lymphocytes - Würfel, Franziska; Erber, Ramona; Hübner, Hanna; Hein, Alexander; Lux, Michael P.; Jud, Sebastian; Kremer, Anita; Kranich, Hannah; Mackensen, Andreas; Häberle, Lothar; Hack, Carolin; Rauh, Claudia; et al. (Breast Care, 2018)
Background: Despite advancements in the treatment of primary and metastatic breast cancer, many patients lack a durable response to these treatments. Patients with triplenegative breast cancer (TNBC) and human epidermal growth factor receptor 2(HER2)-positive breast cancer who do not have a pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) have a very poor prognosis. Tumor-infiltrating lymphocytes (TILs) have been identified as a predictive marker for pCR after NACT in TNBC and HER2-positive breast cancer. These patient populations could also be suitable for novel treatment strategies including neoepitope-based therapies. This work analyses the effect of TILs on the pCR in neoadjuvantly treated patients in the TILGen study and presents the procedures aimed at establishing neoepitope-based therapies in this study. Methods: Neoadjuvantly treated HER2positive and TNBC patients were eligible for the presented analysis concerning the association between TILs and pCR. A total of 146 patients could be identified within the TILGen study. TILs were evaluated as percentage of stromal tumor tissue in core biopsies at primary diagnosis. The phenotype 'lymphocyte-predominant breast cancer' (LPBC) was associated with pCR by logistic regression adjusted for estrogen receptor status, progesterone receptor status, HER2 status, age at diagnosis, and grading. Results: LPBC was seen in 24 (16.4%) patients. In this patient group, 66.7% achieved a pCR, while the pCR rate was 32.8% in patients with a low TIL count. The adjusted odds ratio was 6.60 (95% confidence interval 2.02-21.56; p < 0.01). Conclusion: TILs are a strong predictor of pCR in TNBC and HER2-positive breast cancer patients. Implications for the use of this information including the effect on prognosis might help to identify patients most likely to benefit from a neoepitope-based therapy approach. (C) 2018 S. Karger GmbH, Freiburg
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TILGen study-immunological targets in patients with breast cancer : Influence of tumor-infiltrating lymphocytes - Erber, Ramona; Hartmann, Arndt; Beckmann, Matthias; Mackensen, Andreas; Kremer, Anita; Reimann, Hannah; Hübner, Hanna; Hein, Alexander; Lux, Michael P.; Jud, Sebastian; Häberle, Lothar; Gaß, Paul; et al. (Pathologe, 2018)
BACKGROUND: The interaction of our immune system with breast cancer (BC) cells prompted the investigation of tumor-infiltrating lymphocytes (TILs) and targeted, tumor antigen-specific immunotherapy. OBJECTIVES: Correlation between TILs and pathological complete response (pCR) after neoadjuvant systemic therapy (NACT). Tumor-specific antigens (TSAs) in HER2+ and triple negative BC and establishment of TSA-specific therapies within the interdisciplinary TILGen study. METHODS: Illustration of the TILGen study design. Assessment of TILs and correlation with pCR within this BC study. RESULTS: pCR was achieved in 38.4% (56/146) and associated with estrogen receptor/progesterone receptor negative (ER-/PR-) and HER2+ tumors. Lymphocytic predominant BC (LPBC) was found in 16.4% (24/146), particularly in ER-/PR- (ER-: 27.3% vs. ER+: 9.9%, PR-: 22.3% vs. PR+: 8.2%), large, and poorly differentiated BC. TILs were significantly correlated with pCR in multivariate analysis. In LPBC, pCR was achieved in 66.7%, whereas it was 32.8% in non-LPBC. CONCLUSIONS: First results confirm the influence of the human immune system on the response to NACT in HER2+ and triple negative BC. TSA-specific immunotherapy might improve the outcome in BC patients but there is an urgent need for comprehensive studies to further investigate this issue.
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Time and Resources Needed to Document Patients with Breast Cancer from Primary Diagnosis to Follow-up - Results of a Single-center Study - Lux, Michael P.; Sell, C. S.; Fasching, Peter; Seidl-Ertel, Janine; Bani, Mayada; Schrauder, M. G.; Jud, Sebastian; Löhberg, Christian; Rauh, C.; Hartmann, Arndt; Schulz-Wendtland, Rüdiger; Strnad, Vratislav; et al. (Geburtshilfe und Frauenheilkunde, 2014)
Aim: Certification of breast centers helps improve the quality of care but requires additional resources, particularly for documentation. There are currently no published data on the actual staff costs and financial resources required for such documentation. The aim of this study was to determine the time and resources required to document a patient with primary breast cancer from diagnosis to the end of follow-up, to establish a database for future strategic decisions. Material and Methods: All diagnostic and therapeutic procedures of patients with primary breast cancer were recorded at the University Breast Center of Franconia. All time points for documentation were evaluated using structured interviews. The times required to document a representative number of patients were determined and combined with the staff costs of the different professional groups, to calculate the financial resources required for documentation. Results: A total of 494 time points for documentation were identified. The study also identified 21 departments and 20 different professional groups involved in the documentation. The majority (54 %) of documentation was done by physicians. 62 % of all documentation involved outpatients. The results of different scenarios for the diagnosis, therapy and follow-up of breast cancer patients in a certified breast center showed that the time required for documentation can be as much as 105 hours, costing EUR 4135. Conclusion: This analysis shows the substantial staffing and financial costs required for documentation in certified centers. A multi-center study will be carried out to compare the costs for certified breast centers of varying sizes with the costs of non-certified care facilities.
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Timing of sequential use of double-balloon catheter and oral misoprostol for induction of labor - Kehl, Sven; Böhm, Lea; Weiss, Christel; Heimrich, Jutta; Dammer, Ulf; Baier, Friederike; Suetterlin, Marc; Beckmann, Matthias; Faschingbauer, Florian (Journal of Obstetrics and Gynaecology Research, 2016)
AIM: The best time to commence cervical ripening with a balloon catheter is unknown. The aim of this study was to evaluate whether application of a balloon catheter in the morning or in the evening is better when sequential prostaglandin application is planned. METHODS: This multicenter historical cohort study included 415 women with an unfavorable cervix undergoing labor induction at term. Labor was induced with a double-balloon catheter and the sequential use of oral misoprostol if necessary. The balloon catheter was placed in the morning group between 02:00-15:00 and in the evening group between 15:00-02:00. The primary outcome measure was the cesarean section rate. Secondary outcome measures included failed labor induction (no vaginal delivery within 72 h). RESULTS: The cesarean section rate did not differ between the groups (morning 26.9%, evening 24.3%; P = 0.5553); however, more women in the morning group did not deliver within 72 h (8.8% vs 3.1%; P = 0.0138). In nulliparous women, labor induction failed more often in the morning group (12% vs. 4%, P = 0.043). In parous women, the induction-to-delivery interval was longer in the morning group (1756 vs. 1349 min; P = 0.046), and there were fewer deliveries within 24 h (35% vs. 56%, P = 0.016). CONCLUSIONS: When sequential use of a double-balloon catheter and oral misoprostol for labor induction is planned, the preferable time for catheter placement is in the evening. This resulted in fewer failed inductions in nulliparous women and a shorter induction-to-delivery interval and more deliveries within 24 h in parous women.
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Tomosynthese - Schulz-Wendtland, Rüdiger; Beckmann, Matthias; Fasching, Peter; Uder, Michael (Chirurgische Praxis, 2016)
Full field digital mammography (FFDM) is the most important method for early diagnosis of breast cancer. The typical overlapping of normal and pathological tissue during the standard 2D projection, however, often reduces the specificity and sensitivity of the mammographic investigation. Digital breast tomosynthesis (DBT) provides on the basis of a limited number of single images with different projection angles not superimposed tomograms and may remove the unwanted masking by superimposed structures. Clinical studies show that the digital tomosynthesis has the real potential to reduce the recall rate and simultaneously increase the cancer detection rate, especially in women with dense breasts (detection and volumetry). The use of tomosynthesis seems to be superior to full field digital mammography in mammography screening. Other possibilities of the tomosynthesis are the dual energy mammography, contrast medium-enhanced mammography and intervention.
CRIS-Team Scopus Importer:2023-03-08
Keywords: Contrast medium-enhanced mammography; Dual energy mammography; Full-field digital mammography; Intervention; Mammography screening; Tomosynthesis

Total laparoscopic hysterectomy: how does training for surgeons in a standardized operation affect hospitals and patients? - Hildebrandt, Thomas; Emir, Seher; Boosz, Alexander; Beckmann, Matthias; Mueller, Andreas (Archives of Gynecology and Obstetrics, 2018)
PURPOSE: Surgical training usually means inexperienced physicians initially doing operations supervised by an experienced physician, to gain the experience and skills needed to conduct surgery independently. Various issues arise here for both hospitals and patients. Are training procedures associated with higher complication rates, blood losses, and transfusion rates? What does training in the operating room ultimately cost in terms of valuable surgical time? Do longer hospitalization periods potentially mean financial losses for the hospital under the diagnosis-related groups (DRG) system? METHODS: A retrospective analysis was carried out of data for 571 patients who underwent total laparoscopic hysterectomy (TLH) in the Department of Gynecology at the University of Erlangen from 2009 to 2012, with/without adnexectomy, due to benign indication; and of data for 255 patients who underwent the same procedures in Karlsruhe Municipal Hospital in 2013-2014. The patients were classified into two groups: those in whom surgery was carried out by experienced specialists who had carried out at least 40 independent operations; and those in whom it was carried out by a trainee resident who had personally done fewer than 40 operations. RESULTS: In the two groups, the patients had similar mean body mass indexes, uterus weights, and blood losses. Patients in the specialist group were slightly older. There were no differences in complication rates. Over two-thirds of complications occurred in patients with previous surgery. Procedures by residents took significantly longer. Hospitalization periods in both groups were still below the mean threshold length of stay under Germany's DRG system, so that no income losses occurred even with training procedures. CONCLUSIONS: Training and teaching operations supervised by experienced surgeons are just as safe as operations by experienced surgeons themselves. Interpretation of these data is of course limited by the retrospective study design; patients treated by specialists tended to have more prior operations and were older, with a trend toward larger uteri. Surgical training, as the example of TLH in benign indication shows here, involves an additional time of approximately 10-20 min per operation. With regard to the revenue situation, the hospitalization periods in both groups were within the profit zone for the hospital concerned.
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Touch Imprint Cytology and Stereotactically-Guided Core Needle Biopsy of Suspicious Breast Lesions: 15-Year Follow-up - Schulz-Wendtland, Rüdiger; Fasching, Peter; Bani, Mayada; Lux, Michael P.; Jud, Sebastian; Rauh, C.; Bayer, C.; Wachter, David; Hartmann, Arndt; Beckmann, Matthias; Uder, Michael; Löhberg, Christian (Geburtshilfe und Frauenheilkunde, 2016)
Introduction: Stereotactically-guided core needle biopsies (CNB) of breast tumours allow histological examination of the tumour without surgery. Touch imprint cytology (TIC) of CNB promises to be useful in providing same-day diagnosis for counselling purposes and for planning future surgery. Having addressed the issue of accuracy of immediate microscopic evaluation of TIC, we wanted to re-examine the usefulness of this procedure in light of the present health care climate of cost containment by incorporating the surgical 15-year follow-up data and outcome. Patients and Methods: From January until December 1996 we performed TIC in core needle biopsies of 173 breast tumours in 169 patients, consisting of 122 malignant and 51 benign tumours. Histology of core needle biopsies was proven by surgical histology in all malignant and in 5 benign tumours. Surgical breast biopsy was not performed in 46 patients with 46 benign lesions, as the histological result from the core needle biopsy and the result of the TIC were in agreement with the suspected diagnosis from the complementary breast diagnostics. A 15-year follow-up of these patients followed in 2013 and follow-up data was collected from 40 women. Results: In the 15-year follow-up of the 40 benign lesions primarily confirmed using CNB and TIC, a diagnostic sensitivity, specificity, positive and negative predictive value and accuracy of 100 % was found. Conclusion: TIC and stereotactically guided CNB showed excellent long-term follow-up in patients with benign breast lesions. The use of TIC to complement CNB can therefore provide immediate cytological diagnosis of breast lesions.
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Towards a Computable Data Corpus of Temporal Correlations between Drug Administration and Lab Value Changes - Newe, Axel; Wimmer, Stefan; Neubert, Antje; Becker, Linda; Prokosch, Hans-Ulrich; Beckmann, Matthias; Fietkau, Rainer; Forster, Christian; Neurath, Markus; Schett, Georg; Ganslandt, Thomas (PLoS ONE, 2015)
Background The analysis of electronic health records for an automated detection of adverse drug reactions is an approach to solve the problems that arise from traditional methods like spontaneous reporting or manual chart review. Algorithms addressing this task should be modeled on the criteria for a standardized case causality assessment defined by the World Health Organization. One of these criteria is the temporal relationship between drug intake and the occurrence of a reaction or a laboratory test abnormality. Appropriate data that would allow for developing or validating related algorithms is not publicly available, though. Methods In order to provide such data, retrospective routine data of drug administrations and temporally corresponding laboratory observations from a university clinic were extracted, transformed and evaluated by experts in terms of a reasonable time relationship between drug administration and lab value alteration. Result The result is a data corpus of 400 episodes of normalized laboratory parameter values in temporal context with drug administrations. Each episode has been manually classified whether it contains data that might indicate a temporal correlation between the drug administration and the change of the lab value course, whether such a change is not observable or whether a decision between those two options is not possible due to the data. In addition, each episode has been assigned a concordance value which indicates how difficult it is to assess. This is the first open data corpus of a computable ground truth of temporal correlations between drug administration and lab value alterations. Discussion The main purpose of this data corpus is the provision of data for further research and the provision of a ground truth which allows for comparing the outcome of other assessments of this data with the outcome of assessments made by human experts. It can serve as a contribution towards systematic, computerized ADR detection in retrospective data. With this lab value curve data as a basis, algorithms for detecting temporal relationships can be developed, and with the classification made by human experts, these algorithms can immediately be validated. Due to the normalization of the lab value data, it allows for a generic approach rather than for specific or solitary drug/lab value combination

Toxic effect of light on oocyte and pre-implantation embryo: a systematic review - Khodavirdilou, Rasa; Pournaghi, Marjaneh; Oghbaei, Hajar; Rezaei, Yeganeh Rastgar; Javid, Farzin; Khodavirdilou, Lida; Shakibfar, Farah; Latifi, Zeinab; Hakimi, Parvin; Nouri, Mohammad; Fattahi, Amir; Dittrich, Ralf (Archives of Toxicology, 2021)
In the female reproductive tract, oocytes and embryos are in a dark environment, while during the in vitro fertilization (IVF) they are exposed to various visible and invisible lights such as daylight, microscope, and laminar hood fluorescent lights. Studies have shown that light could damage cellular compartments of oocytes and embryos and consequently decrease rates of fertilization, development, and blastocyst formation. However, due to the lack of consensus about the effects of light on the embryos, and subsequently the inability to make definitive decisions regarding the light exposure management to improve IVF results, in the present study, we systematically reviewed the effect of light with different wavelengths and intensities on pre-implantation embryos. The toxic impact of light depends on the wavelength, intensity, and duration of light exposure and also the stage of embryo. Therefore, reducing the observation time of embryos out of the incubator and also using light filters can alleviate the detrimental effect of light in IVF labs.
CRIS-Team WoS Importer:2021-09-10

Toxicity Assessment of a Phase III Study Evaluating FEC-Doc and FEC-Doc Combined with Gemcitabine as an Adjuvant Treatment for High-Risk Early Breast Cancer: the SUCCESS-A Trial - Schroeder, L.; Rack, B.; Sommer, H.; Koch, J. G.; Weissenbacher, T.; Janni, W.; Schneeweiss, A.; Rezai, M.; Lorenz, R.; Jaeger, B.; Schramm, A.; Häberle, Lothar; et al. (Geburtshilfe und Frauenheilkunde, 2016)
Introduction: This paper aims to evaluate the toxicity profile of additive gemcitabine to adjuvant taxane-based chemotherapy in breast cancer patients.Methods:Patients enrolled in this open-label randomized controlled Phase III study were treated with 3 cycles of epirubicin-fluorouracil-cyclophosphamide (FEC) chemotherapy followed by 3 cycles of docetaxel with those receiving 3 cycles of FEC followed by 3 cycles of gemcitabine-docetaxel (FEC-DG). 3690 patients were evaluated according to National Cancer Institute (NCI) toxicity criteria (CTCAE). The study medications were assessed by the occurrence of grade 3-4 adverse events, dose reductions, postponements of treatment cycles and granulocyte colony-stimulating factor (G-CSF) support.Results:No differences in neutropenia or febrile neutropenia were demonstrated. However, thrombocytopenia was significantly increased with FEC-DG treatment (2.0 vs. 0.5 %, p < 0.001), as was leukopenia (64.1 vs. 58.5 %, p < 0.001). With FEC-DG significantly more G-CSF support in cycles 4 to 6 (FEC-DG: 57.8 %, FEC-D: 36.3 %, p < 0.001) was provided. Transaminase elevation was significantly more common with FEC-DG (SGPT: 6.3 %, SGOT: 2 %), whereas neuropathy (1.2 %), arthralgia (1.6 %) and bone pain (2.6 %) were more common using FEC-D. Dose reductions > 20 % (4 vs. 2.4 %) and postponement of treatment cycles (0.9 vs. 0.4 %) were significantly more frequent in the FEC-DG arm. Eight deaths occurred during treatment in the FEC-DG arm and four in the FEC-D arm.Conclusion:The addition of gemcitabine increased hematological toxicity and was associated with more dose reductions and postponements of treatment cycles.
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TP53-based interaction analysis identifies cis-eQTL variants for TP53BP2, FBXO28, and FAM53A that associate with survival and treatment outcome in breast cancer - Fagerholm, Rainer; Khan, Sofia; Schmidt, Marjanka K.; Garcia-Closas, Montserrat; Heikkila, Pavi; Saarela, Jani; Beesley, Jonathan; Jamshidi, Maral; Aittomaki, Kristiina; Liu, Jianjun; Ali, H. Raza; Andrulis, Irene L.; et al. (Oncotarget, 2017)
TP53 overexpression is indicative of somatic TP53 mutations and associates with aggressive tumors and poor prognosis in breast cancer. We utilized a two-stage SNP association study to detect variants associated with breast cancer survival in a TP53-dependent manner. Initially, a genome-wide study (n = 575 cases) was conducted to discover candidate SNPs for genotyping and validation in the Breast Cancer Association Consortium (BCAC). The SNPs were then tested for interaction with tumor TP53 status (n = 4,610) and anthracycline treatment (n = 17,828). For SNPs interacting with anthracycline treatment, siRNA knockdown experiments were carried out to validate candidate genes.In the test for interaction between SNP genotype and TP53 status, we identified one locus, represented by rs10916264 (p(interaction) = 3.44 × 10-5; FDR-adjusted p = 0.0011) in estrogen receptor (ER) positive cases. The rs10916264 AA genotype associated with worse survival among cases with ER-positive, TP53-positive tumors (hazard ratio [HR] 2.36, 95% confidence interval [C.I] 1.45 - 3.82). This is a cis-eQTL locus for FBXO28 and TP53BP2; expression levels of these genes were associated with patient survival specifically in ER-positive, TP53-mutated tumors. Additionally, the SNP rs798755 was associated with survival in interaction with anthracycline treatment (p(interaction) = 9.57 × 10-5, FDR-adjusted p = 0.0130). RNAi-based depletion of a predicted regulatory target gene, FAM53A, indicated that this gene can modulate doxorubicin sensitivity in breast cancer cell lines.If confirmed in independent data sets, these results may be of clinical relevance in the development of prognostic and predictive marker panels for breast cancer.
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Transcriptome-wide association study of breast cancer risk by estrogen-receptor status - Feng, Helian; Gusev, Alexander; Pasaniuc, Bogdan; Wu, Lang; Long, Jirong; Abu-Full, Zomoroda; Aittomaki, Kristiina; Andrulis, Irene L.; Anton-Culver, Hoda; Antoniou, Antonis C.; Arason, Adalgeir; Arndt, Volker; et al. (Genetic Epidemiology, 2020)
Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER−). We further compared associations with ER+ and ER− subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER– breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER− breast cancer.
CRIS-Team Scopus Importer:2020-03-20
Keywords: breast cancer subtype; causal gene; GWAS; TWAS

Translational Highlights in Breast and Ovarian Cancer 2019 – Immunotherapy, DNA Repair, PI3K Inhibition and CDK4/6 Therapy - Hartkopf, Andreas D.; Mueller, Volkmar; Woeckel, Achim; Lux, Michael P.; Janni, Wolfgang; Ettl, Johannes; Belleville, Erik; Schuetz, Florian; Fasching, Peter; Kolberg, Hans-Christian; Welslau, Manfred; Overkamp, Friedrich; et al. (Geburtshilfe und Frauenheilkunde, 2019)
In the near future, important translational questions of clinical relevance will be adressed by studies currently in progress. On the one hand, the role of PD-L1 expression must be further understood, after it was found to be relevant in the use of atezolizumab in first-line therapy of patients with metastatic triple-negative breast cancer (TNBC). No association between efficacy and PD-L1 expression was found in a neoadjuvant study that included pembrolizumab in TNBC. The pathological complete response rate (pCR) was higher in both patient groups with and without PD-L1 expression when pembrolizumab was added to chemotherapy. Another future question is the identification of further patient groups in which efficacy of PARP inhibitors is seen, which are licensed for the pBRCA1/2 germline mutation. These include, for example, patients with mutations in other genes, which are involved in homologous recombination, or patients with tumours that show an abnormality in global tests of homologous recombination deficiencies (HRD tests). The question of whether a PARP inhibitor can be given and with which chemotherapy combination partners is currently being investigated in both breast and ovarian cancer. While the data on improved overall survival are being consolidated for the CDK4/6 inhibitors, knowledge of molecular changes during the therapy and during progression on the therapy is growing. Both the accumulation of PI3K mutations and also PTEN changes might play a part in planning subsequent therapies. This review article summarises these recent developments in breast cancer and in part also in ovarian cancer.
CRIS-Team WoS Importer:2020-01-17

Translational highlights in breast cancer research and treatment: recent developments with clinical impact - Fasching, Peter; Schneeweiss, Andreas; Kolberg, Hans-Christian; Ettl, Johannes; Fehm, Tanja N.; Overkamp, Friedrich; Lueftner, Diana (Current Opinion in Obstetrics & Gynecology, 2019)
Purpose of review Over the last decades the time which is needed to translate a preclinical finding or idea in the clinic has reduced continuously. Especially but not only for breast cancer the number of tested drugs and targeted pathways have increased immensely. In addition, the introduction of immune-oncological treatments has further advanced the possibilities for future treatments. This review focuses on recent developments in the prevention and treatment of breast cancer including results from major clinical trials and recent conferences. Recent findings Many pathways involved in the progression or treatment of breast cancer have been also identified in the cause and pathogenesis of breast cancer. Therefore, breast cancer risk can be described in much more detail, possibly leading to new prevention strategies. In breast cancer treatment the introduction of PARP inhibitors has begun. Recent trials will lead to a better understanding whether PI3K inhibitors can be developed for application in the clinic and first large randomized trials show the superiority of anti PD-1/PD-L1 treatments. Treatment strategies which were developed over the last decade are moving rapidly into the clinical use. The understanding of treatment targets and involved side effects will be important for the safe implementation of these treatments into routine practice.
CRIS-Team WoS Importer:2019-04-12

Transplantation of ovarian tissue to postpone menopause - is it really more advantageous for women's health than menopause hormone therapy? - Von Wolff, Michael; Dittrich, Ralf; Stute, Petra (Reproductive Biomedicine Online, 2015)
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Transplantation of refreezed ovarian tissue after unexpected occurrence of endometriosis - Dietl, Anna; Dittrich, Ralf; Hoffmann, Inge; Denschlag, D.; Hanjalic-Beck, A.; Mueller, A.; Beckmann, Matthias; Lotz, Laura (GEBURTSHILFE UND FRAUENHEILKUNDE, 2022)
CRIS-Team WoS Importer:2022-11-04

Trastuzumab Biosimilars in the Therapy of Breast Cancer – “Real World” Experiences from four Bavarian University Breast Centres - Hester, Anna; Gaß, Paul; Fasching, Peter; Kraemer, Anne Katrin; Ettl, Johannes; Diessner, Joachim; Woeckel, Achim; Egger, Tobias; Stock, Katja; Redlin, Jutta; Andraschko, Monika; Harbeck, Nadia; et al. (Geburtshilfe und Frauenheilkunde, 2020)
Introduction With the introduction of the first trastuzumab biosimilar in the summer of 2018, biosimilar antibodies for breast cancer have found their way into the area of gynaecological oncology. The switch of anti-human epidermal growth factor receptor 2 (HER2) therapy from the reference drug Herceptin ® to a biosimilar has presented challenges to the clinics. In addition to structural and organisational measures, training of employees as well as patient briefing and acceptance were major challenges. The study presented here records - within the context of quality assurance - how the switch to a trastuzumab biosimilar was implemented at four Bavarian university clinics in the Purchasing Association of Bavarian University Pharmacies. Materials/Methods Questionnaires on treatment figures and the switching process were sent to breast centres and pharmacies of four Bavarian university clinics between July and December 2019. The neoadjuvant, adjuvant and metastasised anti-HER2 therapy with trastuzumab with or without pertuzumab was recorded, evaluated and summarised. Results In the anti-HER2-therapy, trastuzumab was used intravenously (i. v.) and subcutaneously. Between July and December 2018, all four clinics in the Purchasing Association switched the i. v. trastuzumab therapy from the reference drug (Herceptin) to a biosimilar (for 2018: Kanjinti ®). Over 200 patients were treated with trastuzumab i. v. in each of the two half-years of 2018 (before and after the switch). The spectrum of side effects and pCR rates under therapy with the biosimilar were comparable to the experiences made with the reference drug. Three out of four clinics provided training to employees and informed patients by means of a defined information leaflet. Patient acceptance was high. Summary The anti-HER2 therapy could be switched successfully and safely to trastuzumab biosimilars at the Bavarian university hospitals. This may serve as guideline for the further implementation of biosimilars. The structures necessary for this initial switching process have been prepared with trastuzumab as an example.
CRIS-Team Scopus Importer:2020-12-18
Keywords: biosimilar; breast cancer; HER2; pCR; trastuzumab

Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer - Von Minckwitz, G.; Huang, C. -S.; Mano, M. S.; Loibl, S.; Mamounas, E. P.; Untch, M.; Wolmark, N.; Rastogi, P.; Schneeweiss, A.; Redondo, A.; Fischer, H. H.; Jacot, W.; et al. (New England Journal of Medicine, 2019)
BACKGROUND
CRIS-Team WoS Importer:2019-02-27

Trastuzumab versus observation for HER2 nonamplified early breast cancer with circulating tumor cells (EORTC 90091-10093, BIG 1-12, Treat CTC): a randomized phase II trial - Ignatiadis, M.; Litiere, S.; Rothe, F.; Riethdorf, S.; Proudhon, C.; Fehma, T.; Aalders, K.; Forstbauer, H.; Fasching, Peter; Brain, E.; Vuylsteke, P.; Guardiola, E.; et al. (Annals of Oncology, 2018)
Trastuzumab improves the outcome of women with HER2 positive breast cancer. We aimed to assess whether trastuzumab decreases the detection rate of circulating tumor cells (CTCs) in women with high risk, HER2 nonamplified, early breast cancer.The EORTC 90091-10093 BIG 1-12 Treat CTC is a phase II trial, conducted in 70 hospitals and 6 CTC laboratories across 5 European countries. Patients with centrally confirmed HER2 nonamplified breast cancer and >=1 centrally confirmed CTC per 15 ml of blood by CellSearch® following surgery and (neo)adjuvant chemotherapy were randomized (1 : 1) to 6 cycles of trastuzumab intravenously versus 18 weeks of observation. Randomization was stratified for center, locally confirmed estrogen receptor status and adjuvant versus neoadjuvant chemotherapy. The primary end point was rate of detection of >=1 CTC per 15 ml of blood at week 18. Secondary end points were invasive disease-free survival (iDFS) and cardiac safety.Between 30 April 2013 and 17 October 2016, 1317 patients were screened; 95 (7.2%) had detectable CTC(s), and 63 (4.8%) were randomized to trastuzumab (n = 31) or observation (n = 32). Fifty-eight patients were assessable for the primary end point, 29 in each arm. In 9 of the 58 patients, CTC(s) were still detected at week 18 : 5 in the trastuzumab and 4 in the observation arm (one-sided Fisher's exact test, P = 0.765). An Independent Data Monitoring Committee recommended stopping further accrual for futility for the primary end point. Median follow-up at database lock was 13 months (IQR 4-16.5). The 1-year iDFS was 93.8% (95% CI 77.3-98.4) in the observation versus 84.8% (95% CI 63.4-94.2) in the trastuzumab arm. No grade 2-4 cardiac events were observed in the trastuzumab arm.Trastuzumab does not decrease the detection rate of CTCs in HER2 nonamplified, nonmetastatic breast cancer.
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Treatment and outcomes of patients in the Brain Metastases in Breast Cancer Network Registry - Witzel, I.; Laakmann, E.; Weide, R.; Neunhoeffer, T.; Park-Simon, T. -J.; Schmidt, Marcus; Fasching, Peter; Hesse, T.; Polasik, A.; Mohrmann, S.; Wuerschmidt, F.; Schem, C.; et al. (European Journal of Cancer, 2018)
Brain metastases (BMs) have a major impact on life expectancy and quality of life for many breast cancer patients. Knowledge about treatment patterns and outcomes is limited.We analysed clinical data of 1712 patients diagnosed with BMs from breast cancer between January 2000 and December 2016 at 80 institutions.Median age at diagnosis of BMs was 56 years (22-90 years). About 47.8% (n = 732) of patients had HER2-positive, 21.4% (n = 328) had triple-negative and 30.8% (n = 471) had hormone receptor (HR)-positive, HER2-negative (luminal-like) primary tumours. The proportion of patients with HER2-positive BMs decreased comparing the years 2000-2009 with 2010-2015 (51%-44%), whereas the percentage of patients with luminal-like tumours increased (28%-34%; p = 0.0331). Patients with BMs in the posterior fossa were more often HER2 positive (n = 169/314, 53.8%) than those diagnosed with triple-negative (n = 65/314, 20.7%) or luminal-like primary breast cancer (n = 80/314, 25.5%), (p < 0.0001). Median overall survival (OS) time after development of BMs for the overall cohort was 7.4 months (95% confidence interval [CI]: 6.7-8.0 months). One-year survival rate was 37.7% (95% CI: 35.2-40.1). Patients with HER2-positive tumours had the longest median OS of 11.6 months (95% CI: 10.0-13.4) compared with 5.9 months (95% CI: 5.0-7.2) for patients with luminal-like and 4.6 months (95% CI: 3.9-5.4) for patients with triple-negative tumours. Patients with HER2-positive tumours who received anti-HER2 treatment had longer median OS than those without (17.1 months versus 7.2 months, p < 0.0001).Prognosis of patients after developing BMs varies significantly according to the subtype. The outcome in this cohort is similarly poor in triple-negative and HR-positive/HER2-negative patients. Our results underline the high medical need for improvement of treatment and prevention strategies for BMs in breast cancer patients.
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Treatment landscape and prognosis after treatment with trastuzumab emtansine - Laakmann, Elena; Emons, Julius; Taran, Florin Andrei; Janni, Wolfgang; Uhrig, Sabrina; Overkamp, Friedrich; Kolberg, Hans Christian; Hadji, Peyman; Tesch, Hans; Häberle, Lothar; Ettl, Johannes; Lüftner, Diana; et al. (Geburtshilfe und Frauenheilkunde, 2020)
Purpose Pertuzumab and T-DM1 are two efficient anti-HER2 treatments for patients with HER2-positive advanced breast cancer. While pertuzumab is usually given in first-line treatment and T-DM1 in second-line treatment, standard therapy options seem to be exhausted up to now after the treatment of patients with these two therapy options. Therefore, it is important to have data that describes the therapy situation and prognosis after T-DM1 treatment. Methods The PRAEGNANT metastatic breast cancer registry (NCT02338167) is a prospective registry for breast cancer patients with a focus on molecular biomarkers. Patients of all therapy lines with any kind of treatment are eligible. Collected data comprises therapies, adverse events, quality of life and other patient reported outcomes. Here we report on the patient characteristics and descriptive prognostic data for HER2-positive patients who have completed a treatment with T-DM1. Therapy patterns after T-DM1 and progression-free survival are reported as well as overall survival. Results A total of 85 patients were identified for the study who were prospectively observed during therapy after the termination of T-DM1. The main reason for T-DM1 termination was progress. Following T-DM1, lapatinib, trastuzumab and chemotherapy were the main therapy choices. Median progression-free survival was 4.8 months (95% CI: 3.2-6.3) and median overall survival was 18.4 months (95% CI: 15.5-21.3). Conclusions Therapy options after T-DM1 in a real-world setting seem to exhibit a relevant clinical efficacy, supporting the concept of continuous anti-HER2 treatments in the advanced therapy setting for breast cancer patients. Novel therapies are needed to improve the rather short median progression-free survival.
CRIS-Team Scopus Importer:2020-11-20
Keywords: advanced breast cancer; antihormone therapy; chemotherapy; HER2 c-erbB2; HER2/neu; lapatinib; metastatic; pertuzumab; T-DM1; trastuzumab

Treatment landscape of advanced breast cancer patients with hormone receptor positive HER2 negative tumors - Data from the German PRAEGNANT breast cancer registry - Hartkopf, Andreas D.; Huober, Jens; Volz, Bernhard; Nabieva, Naiba; Taran, Florin-Andrei; Schwitulla, Judith; Overkamp, Friedrich; Kolberg, Hans-Christian; Hadji, Peyman; Tesch, Hans; Häberle, Lothar; Ettl, Johannes; et al. (BREAST, 2018)
PURPOSE: This study describes comprehensive data from a breast cancer registry concerning the use of endocrine treatment (ET) and chemotherapy in the first, second and higher therapy lines in hormone receptor (HR) positive, HER2 negative metastatic breast cancer (MBC). METHODS: The PRAEGNANT study is a real-time registry for patients with MBC. Therapies were categorized into the following categories: chemotherapy, aromatase inhibitor (AI), tamoxifen, fulvestrant, or everolimus plus ET and reported for first, second and third line or higher therapy use. Also treatment sequences for the first, second and third therapy line were analyzed. RESULTS: This analysis includes 958 patients with HR positive, HER2 negative MBC. 42.7% were treated with a chemotherapy in the first therapy line compared to 45.9% receiving an ET. A total of 25.9% were treated with everolimus plus anti-hormone therapy in any therapy line. 34.1% were treated with fulvestrant as single agent therapy. Analyzing therapy sequences, the administration of three different chemotherapies in a row was the most frequently used pattern. CONCLUSIONS: This analysis shows that across all three first therapy lines chemotherapy is a dominant therapy for HR positive, HER2 negative MBC patients. Education about the efficacy of ET might help to increase its use and decrease the possible burden of chemotherapy related toxicities.
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Treatment of Early Breast Cancer Patients: Evidence, Controversies, Consensus: Focusing on Systemic Therapy - German Experts' Opinions for the 16th International St. Gallen Consensus Conference (Vienna 2019) - Lüftner, Diana; Bauerfeind, Ingo; Braun, Michael; Brucker, Sara Y.; Fasching, Peter; Felberbaum, Ricardo; Hagemann, Friederike; Haidinger, Renate; Harbeck, Nadia; Hönig, Arnd; Huober, Jens; Jackisch, Christian; et al. (Breast Care, 2019)
A German working group of leading breast cancer experts have discussed the votes at the International St. Gallen Consensus Conference in Vienna for the treatment of primary breast cancer with regard to the German AGO (Ar-beitsgemeinschaft Gynäkologische Onkologie) recommendations for clinical practice in Germany. Three of the German breast cancer experts were also members of this year's St. Gallen panel. Comparing the St. Gallen recommendations with the annually updated treatment recommendations of the Gynecological Oncology Working Group (AGO Mamma 2019) and the German S3 Guideline is useful, because the recommendations of the St. Gallen panel are based on expert opinions of different countries and disciplines. The focus of this article is on systemic therapy. The motto of this year's 16th St. Gallen Consensus Conference was "Estimating the magnitude of clinical benefit." The rationale behind this motto is that, for every treatment decision, a benefit-risk assessment must be taken into consideration for each patient.
CRIS-Team Scopus Importer:2019-10-01

Treatment of Patients with Early Breast Cancer: Evidence, Controversies, Consensus: German Expert Opinions on the 17th International St. Gallen Consensus Conference - Untch, Michael; Fasching, Peter; Brucker, Sara Y.; Budach, Wilfried; Denkert, Carsten; Haidinger, Renate; Huober, Jens; Jackisch, Christian; Janni, Wolfgang; Kolberg-Liedtke, Cornelia; Krug, David; Kuehn, Thorsten; et al. (Geburtshilfe und Frauenheilkunde, 2021)
This years 17th St. Gallen (SG) Consensus Conference on the Treatment of Patients with Early Breast Cancer (SG-BCC) with the title "Customizing local and systemic therapies for women with early breast cancer" focused on the challenge of targeting the treatment of early breast cancer more specifically to the individual disease situation of each patient. As in previous years, a German working group of leading breast cancer experts discussed the results of the international SG-BCC 2021 in the context of the German guideline. It is helpful to compare the SG recommendations with the recently updated treatment recommendations of the Breast Commission of the German Working Group on Gynaecological Oncology (Arbeitsgemeinschaft Gynakologische Onkologie e.V., AGO) and the S3 guideline because the SG-BCC panel comprised experts from different countries, which is why country-specific aspects can be incorporated into the SG recommendations. The German treatment recommendations of the AGO and the S3 guideline are based on current evidence. Nevertheless, any therapeutic decision must always undergo a risk-benefit analysis for the specific situation and to be discussed with the patient.
CRIS-Team WoS Importer:2021-06-18

Treatment-related amenorrhea with T-DM1 plus pertuzumab (KP) is lower than with docetaxel/carboplatin/ trastuzumab/pertuzumab (TCHP) in the phase III neoadjuvant KRISTINE trial - Hurvitz, Sara A.; Fresco, Rodrigo; Afenjar, Karen; Stroyakovskiy, Daniil; Huang, Chiun-Sheng; Wildiers, Hans; Jung, Kyung Hae; Boileau, Jean-Francois; Campone, Mario; Martin, Miguel; Valero, Vicente; Sparano, Joseph A.; et al. (CANCER RESEARCH, 2021)
CRIS-Team WoS Importer:2021-03-26

Treatment-relevant biomarkers in gynecologic oncology - Ditsch, Nina; Fasching, Peter (Die Gynäkologie, 2022)
The first biomarkers were discovered decades ago. Their prognostic and predictive value is still the subject of current research. Biomarker-based treatments represent the basis of the current and future trial landscape in gynecologic oncology, as was clearly demonstrated at this year's ASCO Annual Meeting. The all-important question is founded in the quality of diagnostics at the immunohistochemical or molecular level. In breast cancer therapy, a HER-2 (human epidermal growth factor receptor 2) finding was previously considered therapeutically relevant if there was an immunohistochemical (IHC) evaluation of 3+ or a fluorescence in situ hybridization (FISH)- or chromogenic in situ hybridization (CISH)-positive value. Use of the antibody-drug conjugate trastuzumab-deruxtecan, also in HER-2-low forms (IHC1+ or 2+, even if FISH/CISH negative), is now celebrated as practice changing, since significantly improved progression-free survival (PFS) and overall survival (OS) were also shown in this situation. With the accelerating use of newer therapeutics, attention should be paid to the side effects and the cost-benefit ratio. The following article provides an overview of the currently most important prognostic and predictive markers in breast, ovarian, endometrial, and cervical cancer.
CRIS-Team WoS Importer:2022-09-09

Treatment with ribociclib shows favourable immunomodulatory effects in patients with hormone receptor-positive breast cancer—findings from the RIBECCA trial - Peuker, Caroline A.; Yaghobramzi, Sarvenaz; Grunert, Corinna; Keilholz, Luisa; Gjerga, Enio; Hennig, Steffen; Schaper, Sigrid; Na, Il Kang; Keller, Ulrich; Brucker, Sara; Decker, Thomas; Fasching, Peter; et al. (European Journal of Cancer, 2022)
Background: Inhibitors of the cyclin-dependent kinases 4 and 6 (CDK4/6i) have significantly improved clinical outcomes in patients with advanced hormone receptor-positive (HR+) breast cancer and have demonstrated favourable antitumour immune responses in preclinical studies. Methods: Here, we investigated peripheral immune responses to ribociclib in patients with metastatic HR+ breast cancer as a preplanned exploratory subanalysis of the RIBECCA trial (NCT03096847). Peripheral blood mononuclear cells were subjected to immune cell profiling, gene expression analysis of immune-related signatures, and deep T cell receptor profiling before treatment started and after 12 weeks of treatment with ribociclib. Results: Gene expression analysis revealed an upregulation of signatures associated with an activated adaptive immune system and a decrease in immunosuppressive cytokine signalling during treatment with ribociclib. Profiling of peripheral immune cell subpopulations showed a decrease in Treg cell frequencies, which was associated with treatment response. Furthermore, induction of CD4+ naive T cells could be seen, whereas effector and memory T cell populations remained largely unchanged. Correspondingly, T cell repertoire diversity remained mostly unchanged during treatment, although an increase in clonality could be observed in single patients. Conclusions: We show that treatment with ribociclib has significant effects on the peripheral innate and adaptive immune response in patients with HR+ breast cancer. Our data suggest that these effects lead to an activation of an already existing immune response rather than a de novo induction and make a strong case for future combination strategies of CDK4/6i with immunotherapies to enhance the adaptive immune response in HR+ breast cancer.
CRIS-Team Scopus Importer:2022-02-11
Keywords: Adaptive immunity; Breast cancer; CDK4/6 inhibitors; Immunomodulation; Ribociclib

Triple-Negative Breast Cancer Risk Genes Identified by Multigene Hereditary Cancer Panel Testing - Shimelis, Hermela; Laduca, Holly; Hu, Chunling; Hart, Steven N.; Na, Jie; Thomas, Abigail; Akinhanmi, Margaret; Moore, Raymond M.; Brauch, Hiltrud; Cox, Angela; Eccles, Diana M.; Ewart-Toland, Amanda; et al. (Journal of the National Cancer Institute, 2018)
BACKGROUND: Germline genetic testing with hereditary cancer gene panels can identify women at increased risk of breast cancer. However, those at increased risk of triple-negative (estrogen receptor-negative, progesterone receptor-negative, human epidermal growth factor receptor-negative) breast cancer (TNBC) cannot be identified because predisposition genes for TNBC, other than BRCA1, have not been established. The aim of this study was to define the cancer panel genes associated with increased risk of TNBC. METHODS: Multigene panel testing for 21 genes in 8753 TNBC patients was performed by a clinical testing laboratory, and testing for 17 genes in 2148 patients was conducted by a Triple Negative Breast Cancer Consortium (TNBCC) of research studies. Associations between deleterious mutations in cancer predisposition genes and TNBC were evaluated using results from TNBC patients and reference controls. RESULTS: Germline pathogenic variants in BARD1, BRCA1, BRCA2, PALB2, and RAD51D were associated with high risk (odds ratio > 5.0) of TNBC and greater than 20% lifetime risk for overall breast cancer among Caucasians. Pathogenic variants in BRIP1, RAD51C, and TP53 were associated with moderate risk (odds ratio > 2) of TNBC. Similar trends were observed for the African American population. Pathogenic variants in these TNBC genes were detected in 12.0% (3.7% non-BRCA1/2) of all participants. CONCLUSIONS: Multigene hereditary cancer panel testing can identify women with elevated risk of TNBC due to mutations in BARD1, BRCA1, BRCA2, PALB2, and RAD51D. These women can potentially benefit from improved screening, risk management, and cancer prevention strategies. Patients with mutations may also benefit from specific targeted therapeutic strategies.
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Trophoblast expression dynamics of the tumor suppressor gene gastrokine 2 - Fahlbusch, Fabian B.; Ruebner, Matthias; Hübner, Hanna; Volkert, Gudrun; Bartunik, Hannah; Winterfeld, Ilona; Hartner, Andrea; Menendez-Castro, Carlos; Nögel, Stephanie; Marek, Ines; Wachter, David; Schneider-Stock, Regine; et al. (Histochemistry and Cell Biology, 2015)
Gastrokines (GKNs) were originally described as stomach-specific tumor suppressor genes. Recently, we identified GKN1 in extravillous trophoblasts (EVT) of human placenta. GKN1 treatment reduced the migration of the trophoblast cell line JEG-3. GKN2 is known to inhibit the proliferation, migration and invasion of gastric cancer cells and may interact with GKN1. Recently, GKN2 was detected in the placental yolk sac of mice. We therefore aimed to further characterize placental GKN2 expression. By immunohistochemistry, healthy first-trimester placenta showed ubiquitous staining for GKN2 at its early gestational stage. At later gestational stages, a more differentiated expression pattern in EVT and villous cytotrophoblasts became evident. In healthy third-trimester placenta, only EVT retained strong GKN2 immunoreactivity. In contrast, HELLP placentas showed a tendency of increased levels of GKN2 expression with a more prominent GKN2 staining in their syncytiotrophoblast. Choriocarcinoma cell lines did not express GKN2. Besides its trophoblastic expression, we found human GKN2 in fibrotic villi, in amniotic membrane and umbilical cord. GKN2 co-localized with smooth muscle actin in villous myofibroblasts and with HLA-G and GKN1 in EVT. In the rodent placenta, GKN2 was specifically located in the spongiotrophoblast layer. Thus, the gestational age-dependent and compartment-specific expression pattern of GKN2 points to a role for placental development. The syncytial expression of GKN2 in HELLP placentas might represent a reduced state of functional differentiation of the syncytiotrophoblast. Moreover, the specific GKN2 expression in the rodent spongiotrophoblast layer (equivalent to human EVT) might suggest an important role in EVT physiology.
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Tumor handling of early-stage cervical cancer: A literature analysis of villoglandular adenocarcinoma of the cervix - Dietl, Anna; Aumann, Konrad; Beckmann, Matthias (Anticancer Research, 2020)
Background/Aim: Recent studies have demonstrated the inferior overall survival outcomes of patients with early-stage cervical cancer who undergo minimally invasive surgery (MIS). One possible explanation for these unexpected results is intraoperative tumor manipulation. Materials and Methods: Considering this hypothesis, we have reviewed the literature on the oncological outcomes of patients with villoglandular adenocarcinoma (VGA) of the cervix, an uncommon variant of cervical cancer that has an excellent prognosis. Results: VGA generally presents as an exophytic mass arising from the endocervix. In a systematic review, we identified 221 patients treated surgically for VGA (FIGO stage Ia-Ib1). Of these, 11 developed recurrence, and four died. The recurrence sites in 8 cases were the pelvis (n=3), vaginal cuff (n=3), episiotomy scar (n=1), and cervix (n=1). Furthermore, 23 VGA-patients were treated by MIS, four experienced recurrence, and one died. Three intraabdominal metastases after MIS were reported. Conclusion: Excessive tumor-handling during MIS or manipulations, e.g. cervix-dilation (during delivery), can worsen the otherwise excellent prognosis.
CRIS-Team Scopus Importer:2020-06-19
Keywords: Early-stage cervical cancer; Minimal handling; Minimal invasive surgery; Review; Villoglandular adenocarcinoma of the uterine cervix

Tumor-infiltrating CD8-positive T-lymphocytes in tubo-ovarian high-grade serous cancer are associated with multiple germline variants in 22q12.1 in a genome-wide association analysis - Natanzon, Yanina; Kobel, Martin; Winham, Stacey J.; Armasu, Sebastian M.; Mccauley, Bryan M.; Vierkant, Robert A.; Cunningham, Julie M.; Bowtell, David; Campbell, Ian G.; Chang-Claude, Jenny; Defazio, Anna; Fasching, Peter; et al. (CANCER RESEARCH, 2018)
CRIS-Team WoS Importer:2019-06-18

Tumor-infiltrating lymphocytes and response prediction to neoadjuvant chemotherapy in HER2-positive breast cancer - Heppner, B. Ingold; Untch, M.; Denkert, C.; Pfitzner, B. M.; Lederer, B.; Schmidt, W.; Eidtmann, H.; Fasching, Peter; Tesch, H.; Solbach, C.; Rezai, M.; Zahm, D. -M.; et al. (2016)
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Tumor-Infiltrating Lymphocytes: A Predictive and Prognostic Biomarker in Neoadjuvant-Treated HER2-Positive Breast Cancer - Heppner, Barbara Ingold; Untch, Michael; Denkert, Carsten; Pfitzner, Berit M.; Lederer, Bianca; Schmitt, Wolfgang; Eidtmann, Holger; Fasching, Peter; Tesch, Hans; Solbach, Christine; Rezai, Mahdi; Zahm, Dirk M.; et al. (Clinical Cancer Research, 2016)
PURPOSE: We elucidated the value of tumor-infiltrating lymphocytes (TIL) as an independent predictor for pathologic complete response (pCR) rate and as a prognostic marker for disease-free survival (DFS) in patients with HER2-positive breast cancer in the neoadjuvant setting. EXPERIMENTAL DESIGN: We evaluated stromal TILs in 498 HER2-positive breast cancer samples of the neoadjuvant GeparQuattro (G4) and GeparQuinto (G5) trials. Levels of TILs were determined as a continuous parameter per 10% increase and as lymphocyte-predominant breast cancer (LPBC; ≥ 60% TILs), and correlated with pCR rate and DFS. RESULTS: In the complete cohort, HER2-positive LPBC cases had a significantly increased pCR rates compared with non-LPBC types. They were significant predictors for pCR in univariate (10% TILs: OR 1.12, P = 0.002; LPBC: OR 2.02, P = 0.002) and multivariate analyses (10% TILs: OR 1.1, P = 0.014; LPBC: OR 1.87, P = 0.009). This effect was also detectable in the trastuzumab-treated (10% TILs: OR 1.12, P = 0.018; LPBC: OR 2.08, P = 0.013) but not in the lapatinib-treated subgroup. We identified a low-risk (pCR/LPBC) and a high-risk group (no pCR/no LPBC) regarding DFS. In triple-positive breast cancer, TILs are of more prognostic relevance than pCR. CONCLUSIONS: We could demonstrate the predictive and prognostic impact of TILs in HER2-positive breast cancer in the neoadjuvant setting. In combination with pCR rate, TILs may help to stratify prognostic subgroups, thereby guiding future therapy decisions. Clin Cancer Res; 22(23); 5747-54. ©2016 AACR.
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Tumor mutational burden and immune infiltration as independent predictors of response to neoadjuvant immune checkpoint inhibition in early TNBC in GeparNuevo - Karn, T.; Denkert, C.; Weber, K. E.; Holtrich, U.; Hanusch, C.; Sinn, B. V.; Higgs, B. W.; Jank, P.; Sinn, H. P.; Huober, J.; Becker, C.; Blohmer, J. U.; et al. (Annals of Oncology, 2020)
Background: The predictive value of tumor mutational burden (TMB), alone or in combination with an immune gene expression profile (GEP), for response to neoadjuvant therapy in early triple negative breast cancer (TNBC) is currently not known, either for immune checkpoint blockade (ICB) or conventional chemotherapy. Patients and methods: We obtained both whole exome sequencing and RNA-Seq data from pretreatment samples of 149 TNBC of the recent neoadjuvant ICB trial, GeparNuevo. In a predefined analysis, we assessed the predictive value of TMB and a previously developed immune GEP for pathological complete remission (pCR). Results: Median TMB was 1.52 mut/Mb (range 0.02–7.65) and was significantly higher in patients with pCR (median 1.87 versus 1.39; P = 0.005). In multivariate analysis, odds ratios for pCR per mut/Mb were 2.06 [95% confidence intervals (CI) 1.33–3.20, P = 0.001] among all patients, 1.77 (95% CI 1.00–3.13, P = 0.049) in the durvalumab treatment arm, and 2.82 (95% CI 1.21–6.54, P = 0.016) in the placebo treatment arm, respectively. We also found that both continuous TMB and immune GEP (or tumor infiltrating lymphocytes) independently predicted pCR. When we stratified patients in groups based on the upper tertile of TMB and median GEP, we observed a pCR rate of 82% (95% CI 60% to 95%) in the group with both high TMB and GEP in contrast to only 28% (95% CI 16% to 43%) in the group with both low TMB and GEP. Conclusions: TMB and immune GEP add independent value for pCR prediction. Our results recommend further analysis of TMB in combination with immune parameters to individually tailor therapies in breast cancer.
CRIS-Team Scopus Importer:2020-07-10
Keywords: exome sequencing; neoadjuvant immune checkpoint inhibition; triple negative breast cancer; tumor mutational burden

Tumour-infiltrating inflammatory cells in early breast cancer: An underrated prognostic and predictive factor? - Schnellhardt, Sören; Erber, Ramona; Büttner-Herold, Maike; Rosahl, Marie Charlotte; Ott, Oliver; Strnad, Vratislav; Beckmann, Matthias; King, Lillian; Hartmann, Arndt; Fietkau, Rainer; Distel, Luitpold (International Journal of Molecular Sciences, 2020)
The role of tumour-infiltrating inflammatory cells (TIICs) in the disease progression of hormone-receptor-positive breast cancer (HR+ BC) is largely unclear since it is generally regarded as the least immunogenic BC subtype. This study investigated the prognostic significance of CD1a+ dendritic cells, CD20+ B cells, CD45RO+ memory T cells and CD4+ T-helper cells in HR+ BC. One hundred and forty-six patients were treated for early stage, distant-metastases-free HR+ BC in an accelerated partial breast irradiation (APBI) phase II trial. Immunohistochemistry was used to double-stain two adjoining sets of tissue microarrays from pre-RT (radiotherapy) tumour resection samples for CD1a/CD20 and CD45RO/CD4. Cell densities of CD1a+, CD20+, CD45RO+ and CD4+ TIICs in the stromal and intraepithelial compartment were registered semiautomatically. High densities of CD20+ and CD4+ TIICs were strongly associated with reduced disease-free survival (DFS), while high stromal CD45RO+ TIIC densities were indicators of subsequent successful treatment. An immunoscore based on CD20+ and CD45RO+ TIIC densities identified three different risk groups (p < 0.001). Thus, contrary to current assumptions, intratumoural immune cell composition might be an important prognostic indicator and a possible contributing factor in the outcome of HR+ BC and should be the subject of further research. Specifically, B-cell infiltration entailed an increased relapse rate and could play an important role in disease progression.
CRIS-Team Scopus Importer:2020-11-20
Keywords: Accelerated partial breast irradiation; Breast cancer; CD1a; CD20; CD4; CD45RO; Hormone receptor positive; Immunoscore; Prognosis; TIL

Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy - Denkert, Carsten; Von Minckwitz, Gunter; Darb-Esfahani, Silvia; Lederer, Bianca; Heppner, Barbara I.; Weber, Karsten E.; Budczies, Jan; Huober, Jens; Klauschen, Frederick; Furlanetto, Jenny; Schmitt, Wolfgang D.; Blohmer, Jens-Uwe; et al. (Lancet Oncology, 2018)
BACKGROUND: Tumour-infiltrating lymphocytes (TILs) are predictive for response to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) and HER2-positive breast cancer, but their role in luminal breast cancer and the effect of TILs on prognosis in all subtypes is less clear. Here, we assessed the relevance of TILs for chemotherapy response and prognosis in patients with TNBC, HER2-positive breast cancer, and luminal-HER2-negative breast cancer. METHODS: Patients with primary breast cancer who were treated with neoadjuvant combination chemotherapy were included from six randomised trials done by the German Breast Cancer Group. Pretherapeutic core biopsies from 3771 patients included in these studies were assessed for the number of stromal TILs by standardised methods according to the guidelines of the International TIL working group. TILs were analysed both as a continuous parameter and in three predefined groups of low (0-10% immune cells in stromal tissue within the tumour), intermediate (11-59%), and high TILs (≥60%). We used these data in univariable and multivariable statistical models to assess the association between TIL concentration and pathological complete response in all patients, and between the amount of TILs and disease-free survival and overall survival in 2560 patients from five of the six clinical trial cohorts. FINDINGS: In the luminal-HER2-negative breast cancer subtype, a pathological complete response (pCR) was achieved in 45 (6%) of 759 patients with low TILs, 48 (11%) of 435 with intermediate TILs, and 49 (28%) of 172 with high TILs. In the HER2-positive subtype, pCR was observed in 194 (32%) of 605 patients with low TILs, 198 (39%) of 512 with intermediate TILs, and 127 (48%) of 262 with high TILs. Finally, in the TNBC subtype, pCR was achieved in 80 (31%) of 260 patients with low TILs, 117 (31%) of 373 with intermediate TILs, and 136 (50%) of 273 with high TILs (p<0·0001 for each subtype, χ2 test for trend). In the univariable analysis, a 10% increase in TILs was associated with longer disease-free survival in TNBC (hazard ratio [HR] 0·93 [95% CI 0·87-0·98], p=0·011) and HER2-positive breast cancer (0·94 [0·89-0·99], p=0·017), but not in luminal-HER2-negative tumours (1·02 [0·96-1·09], p=0·46). The increase in TILs was also associated with longer overall survival in TNBC (0·92 [0·86-0·99], p=0·032), but had no association in HER2-positive breast cancer (0·94 [0·86-1·02], p=0·11), and was associated with shorter overall survival in luminal-HER2-negative tumours (1·10 [1·02-1·19], p=0·011). INTERPRETATION: Increased TIL concentration predicted response to neoadjuvant chemotherapy in all molecular subtypes assessed, and was also associated with a survival benefit in HER2-positive breast cancer and TNBC. By contrast, increased TILs were an adverse prognostic factor for survival in luminal-HER2-negative breast cancer, suggesting a different biology of the immunological infiltrate in this subtype. Our data support the hypothesis that breast cancer is immunogenic and might be targetable by immune-modulating therapies. In light of the results in luminal breast cancer, further research investigating the interaction of the immune system with different types of endocrine therapy is warranted. FUNDING: Deutsche Krebshilfe and European Commission.
EVALuna2:34264

Tumour stage distribution and survival of malignant melanoma in Germany 2002-2011 - Schoffer, Olaf; Schuelein, Stefanie; Arand, Gerlinde; Arnholdt, Hans; Baaske, Dieter; Bargou, Ralf C.; Becker, Nikolaus; Beckmann, Matthias; Bodack, Yves; Boehme, Beatrix; Bozkurt, Tayfun; Breitsprecher, Regine; et al. (BMC Cancer, 2016)
Over the past two decades, there has been a rising trend in malignant melanoma incidence worldwide. In 2008, Germany introduced a nationwide skin cancer screening program starting at age 35. The aims of this study were to analyse the distribution of malignant melanoma tumour stages over time, as well as demographic and regional differences in stage distribution and survival of melanoma patients.Pooled data from 61 895 malignant melanoma patients diagnosed between 2002 and 2011 and documented in 28 German population-based and hospital-based clinical cancer registries were analysed using descriptive methods, joinpoint regression, logistic regression and relative survival.The number of annually documented cases increased by 53.2% between 2002 (N = 4 779) and 2011 (N = 7 320). There was a statistically significant continuous positive trend in the proportion of stage UICC I cases diagnosed between 2002 and 2011, compared to a negative trend for stage UICC II. No trends were found for stages UICC III and IV respectively. Age (OR 0.97, 95% CI 0.97-0.97), sex (OR 1.18, 95% CI 1.11-1.25), date of diagnosis (OR 1.05, 95% CI 1.04-1.06), 'diagnosis during screening' (OR 3.24, 95% CI 2.50-4.19) and place of residence (OR 1.23, 95% CI 1.16-1.30) had a statistically significant influence on the tumour stage at diagnosis. The overall 5-year relative survival for invasive cases was 83.4% (95% CI 82.8-83.9%).No distinct changes in the distribution of malignant melanoma tumour stages among those aged 35 and older were seen that could be directly attributed to the introduction of skin cancer screening in 2008.
EVALuna2:19618

Twenty-five-year-old Woman with Bilateral Borderline Ovarian Tumour Desiring to Preserve Fertility - Case Report and Literature Review on the Current State of Fertility Preservation in Women with Borderline Ovarian Tumours - Findeklee, S.; Lotz, Laura; Heusinger, K.; Hoffmann, Inge; Dittrich, Ralf; Beckmann, Matthias (Geburtshilfe und Frauenheilkunde, 2016)
Borderline ovarian tumours are semimalignant tumours occurring unilaterally or bilaterally with a peak incidence among women of reproductive age. Since the affected women often wish to preserve fertility, particular precautions must be taken when counselling the patient and obtaining consent prior to planning an individual treatment. Options for preserving fertility include an organ-sparing surgical procedure and cryopreservation of oocytes and/or ovarian tissue. In this article, we report on a 25-year-old patient with a bilateral seromucinous borderline tumour who desired all fertility-preserving options. In order to perform the procedure without delay, we opted to perform luteal phase stimulation prior to oocyte retrieval. We conclude by discussing the current literature on the state of fertility preservation in the treatment of borderline ovarian tumours.
EVALuna2:32942

Two truncating variants in FANCC and breast cancer risk - Dork, Thilo; Peterlongo, Paolo; Mannermaa, Arto; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Ahearn, Thomas; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Aronson, Kristan J.; Augustinsson, Annelie; et al. (Scientific Reports, 2019)
Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44–1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
CRIS-Team Scopus Importer:2019-09-17

Ultrasound Elastography of Pulmonary Lesions - A Feasibility Study - Adamietz, B. R.; Fasching, Peter; Jud, Sebastian; Schulz-Wendtland, Rüdiger; Anders, Katharina; Uder, Michael; Wüst, Wolfgang; Rauh, C.; Meier-Meitinger, M. (Ultraschall in der Medizin, 2014)
Introduction: The potential of sonography in the examination of lung tissue is extremely limited by the air-filled alveoles of the lung. Only in special circumstances like pleural adhesion lesions, atelectasis or pneumonia can lung tissue be visualized by B-mode sonography. Real-time elastography was primarily applied to detect and visualize pulmonary lesions. Methods and Patients: 8 patients with a total of 18 histologically proven metastases of the lung were included. All pulmonary lesions were detected by computed tomography. Sonographic examination was performed with a 7.5 MHz linear transducer (Acuson Antares premium edition, Siemens, Erlangen, Germany), including B-mode and real-time elastography (RTE). The mean distance between pleura and the lesions ranged from 0 to 2.5 cm. Two lesions were located in the upper right lobe, eleven lesions in the lower right and five in the lower left lobe. Results: RTE was able to detect and visualize all 18 pulmonary lesions in contrast to B-mode. The size and distance of the lesions from the pleura correlated with the CT findings. Conclusion: In contrast to B-mode sonography, RTE is able to detect and visualize peripheral, non-pleural adherent pulmonary lesions.
EVALuna2:14352

Ultrasound Fetal Weight Estimation in Diabetic Pregnancies - Pretscher, Jutta; Kehl, Sven; Stumpfe, Florian M.; Mayr, Andreas; Schmid, Matthias; Schild, Ralf L.; Beckmann, Matthias; Faschingbauer, Florian (Journal of Ultrasound in Medicine, 2019)
Objectives To evaluate different formulas for estimating fetal weight in diabetic pregnancies. Methods This retrospective study evaluated the precision of ultrasound fetal weight estimation in 756 pregnancies complicated by gestational diabetes between 2002 and 2016. The estimated fetal weights (EFWs) were obtained within 7 days of delivery from 10 weight estimation formulas and were compared with pair-wise matched controls from 15,701 patients. The precision of the evaluated formulas for EFW was analyzed by median absolute percentage errors (MAPEs), mean percentage errors (MPEs), and proportions of estimates within 10% of actual birth weight. Results Among the tested formulas, the lowest MAPE was detected with formula I of Hadlock et al (Am J Obstet Gynecol 1985; 151:333-337), and the formula of Schild et al (Ultrasound Obstet Gynecol 2004; 23:30-35) had the highest proportion of estimates within the 10% range. The EFW in diabetic patients showed a slight trend toward overestimation in comparison with the matched controls (MPE estimates showed a trend toward more positive values). In most of the EFW formulas that were evaluated, no significant differences were detected in MAPEs and estimates within the 10% range. The MPE estimates with most formulas in both groups were close to zero. Overall, the differences between most of the evaluated formulas were small. Conclusions Little evidence was found for differences in the accuracy of the EFW in diabetic pregnancies and controls. The Hadlock I formula showed the lowest MAPE, and the Schild formula had the highest proportion of estimates within the 10% range.
CRIS-Team WoS Importer:2019-09-13

Ultrasound Fetal Weight Estimation in Diabetic Pregnancies - Pretscher, Jutta; Kehl, Sven; Stumpfe, Florian M.; Mayr, Andreas; Schmid, Matthias; Schild, Ralf L.; Beckmann, Matthias; Faschingbauer, Florian (Journal of Ultrasound in Medicine, 2020)
OBJECTIVES: To evaluate different formulas for estimating fetal weight in diabetic pregnancies. METHODS: This retrospective study evaluated the precision of ultrasound fetal weight estimation in 756 pregnancies complicated by gestational diabetes between 2002 and 2016. The estimated fetal weights (EFWs) were obtained within 7 days of delivery from 10 weight estimation formulas and were compared with pair-wise matched controls from 15,701 patients. The precision of the evaluated formulas for EFW was analyzed by median absolute percentage errors (MAPEs), mean percentage errors (MPEs), and proportions of estimates within 10% of actual birth weight. RESULTS: Among the tested formulas, the lowest MAPE was detected with formula I of Hadlock et al (Am J Obstet Gynecol 1985; 151:333-337), and the formula of Schild et al (Ultrasound Obstet Gynecol 2004; 23:30-35) had the highest proportion of estimates within the 10% range. The EFW in diabetic patients showed a slight trend toward overestimation in comparison with the matched controls (MPE estimates showed a trend toward more positive values). In most of the EFW formulas that were evaluated, no significant differences were detected in MAPEs and estimates within the 10% range. The MPE estimates with most formulas in both groups were close to zero. Overall, the differences between most of the evaluated formulas were small. CONCLUSIONS: Little evidence was found for differences in the accuracy of the EFW in diabetic pregnancies and controls. The Hadlock I formula showed the lowest MAPE, and the Schild formula had the highest proportion of estimates within the 10% range.
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Unbiased high-dimensional flow cytometry identified NK and DC immune cell signature in Luminal A-type and triple negative breast cancer - Heger, Lukas; Heidkamp, Gordon Frederik; Amon, Lukas; Nimmerjahn, Falk; Bäuerle, Tobias; Maier, Andreas; Erber, Ramona; Hartmann, Arndt; Hack, Carolin; Rübner, Matthias; Hübner, Hanna; Fasching, Peter; et al. (OncoImmunology, 2024)
Breast cancer is the most common malignancy in women worldwide and a highly heterogeneous disease. Four different subtypes are described that differ in the expression of hormone receptors as well as the growth factor receptor HER2. Treatment modalities and survival rate depend on the subtype of breast cancer. However, it is still not clear which patients benefit from immunotherapeutic approaches such as checkpoint blockade. Thus, we aimed to decipher the immune cell signature of the different breast cancer subtypes based on high-dimensional flow cytometry followed by unbiased approaches. Here, we show that the frequency of NK cells is reduced in Luminal A and B as well as triple negative breast cancer and that the phenotype of residual NK cells is changed toward regulatory CD11b−CD16− NK cells. Further, we found higher frequencies of PD-1+ CD4+ and CD8+ T cells in triple negative breast cancer. Moreover, while Luminal A-type breast cancer was enriched for CD14+ cDC2 (named type 3 DC (DC3)), CD14− cDC2 (named DC2) were more frequent in triple negative breast cancer. In contrast, HER2-enriched breast cancer did not show major alterations in the composition of the immune cell compartment in the tumor microenvironment. These findings suggest that patients with Luminal A- and B-type as well as triple negative breast cancer might benefit from immunotherapeutic approaches targeting NK cells.
CRIS-Team Scopus Importer:2024-01-12
Keywords: Breast cancer; immune cell signature; NK cells; PD-1; tumor microenvironment

Unexpected diagnose of endometriosis in women undergoing ovarian tissue transplantation - Lotz, Laura; Dietl, Anna; Hoffmann, Inge; Mueller, A.; Burghaus, Stefanie; Beckmann, Matthias; Dittrich, Ralf (GEBURTSHILFE UND FRAUENHEILKUNDE, 2022)
CRIS-Team WoS Importer:2022-11-04

Update Breast Cancer 2017 - Implementation of Novel Therapies - Lux, Michael P.; Janni, Wolfgang; Hartkopf, Andreas D.; Nabieva, Naiba; Taran, Florin-Andrei; Overkamp, Friedrich; Kolberg, Hans-Christian; Hadji, Peyman; Tesch, Hans; Ettl, Johannes; Huober, Jens B.; Lueftner, Diana; et al. (Geburtshilfe und Frauenheilkunde, 2017)
In recent years, numerous new therapy options for patients with breast cancer have been developed in clinical studies, with some options already approved for routine treatment. As the speed at which innovations are introduced increases, the importance of conferences also increases, as conferences are where the data underpinning new therapies are usually presented for the first time. This review looks at publications of the ASCO (American Society of Clinical Oncology) and ESMO (European Society of Medical Oncology) conferences in 2017, summarizes them and evaluates them in the context of existing data. The focus is on new insights for neoadjuvant therapy and new treatment options in the metastatic setting, such as the use of CDK4/6 inhibitors or PARP inhibitors. The first results of treatments with checkpoint inhibitors are presented. With the patent expiry of trastuzumab, a number of study results for trastuzumab biosimilars have also been published. The digitization of patient care provides the first results on quality of life and prognosis of patients with advanced cancer. Digital communications between patients and physicians are being evaluated in several studies in Germany. As the discussion about patient-relevant endpoints for patients in the metastatic setting continues, overall survival rates from studies of big endocrine-based therapies are urgently needed. Preliminary analyses of small study cohorts offer initial insights. In the context of improving patient care, in the coming years, questions will center on which patients particularly benefit from certain therapies and which patients need particular protection from specific side effects. Questions about these predictors are raised in many scientific projects as attention increasingly focuses on this topic.
EVALuna2:36116

Update Breast Cancer 2018 (Part 1) - Primary Breast Cancer and Biomarkers - Taran, Florin-Andrei; Schneeweiss, Andreas; Lux, Michael P.; Janni, Wolfgang; Hartkopf, Andreas D.; Nabieva, Naiba; Overkamp, Friedrich; Kolberg, Hans-Christian; Hadji, Peyman; Tesch, Hans; Woeckel, Achim; Ettl, Johannes; et al. (Geburtshilfe und Frauenheilkunde, 2018)
This summary provides an overview of how new therapies or new aspects of established therapies relate to the latest findings. Neoadjuvant therapy, local therapy, new aspects of systemic therapy, and prognostic and predictive factors are presented. In the neoadjuvant setting, the association between pathological complete response (pCR) and prognosis is still of interest as is the identification of new molecular predictors for new therapies such as CDK4/6 inhibitors. As regards surgical treatment, the target is still to reduce the aggressiveness of surgery. To achieve this, a better understanding particularly of ductal carcinoma in situ is required. With regard to systemic therapy, more data on the best combinations and therapy sequences for existing therapies is available. Finally, the use of prognostic and predictive factors may help to avoid overtreatment and ensure that patients only receive therapies which have been shown to be effective for their specific condition and have fewer side effects.
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Update Breast Cancer 2018 (Part 2) - Advanced Breast Cancer, Quality of Life and Prevention - Schneeweiss, Andreas; Lux, Michael P.; Janni, Wolfgang; Hartkopf, Andreas D.; Nabieva, Naiba; Taran, Florin-Andrei; Overkamp, Friedrich; Kolberg, Hans-Christian; Hadji, Peyman; Tesch, Hans; Woeckel, Achim; Ettl, Johannes; et al. (Geburtshilfe und Frauenheilkunde, 2018)
The treatment of metastatic breast cancer has become more complicated due to increasing numbers of new therapies which need to be tested. Therapies are now being developed to treat special clinical or molecular subgroups. Even though intrinsic molecular subtypes play a major role, more and more new therapies for subgroups and histological subtypes are being developed, such as the use of PARP inhibitors to treat patients with BRCA mutations (breast and ovarian cancer). Supportive therapies are also evolving, allowing problems such as alopecia or nausea and vomiting to be treated more effectively. Treatment-related side effects have a direct impact on the prognosis of patients with metastatic breast cancer, and supportive therapy can improve compliance. Digital tools could be useful to establish better patient management systems. This overview provides an insight into recent trials and how the findings could affect routine treatment. Current aspects of breast cancer prevention are also presented.
EVALuna2:51284

Update Breast Cancer 2018 (Part 3) - Genomics, Individualized Medicine and Immune Therapies - in the Middle of a New Era: Prevention and Treatment Strategies for Early Breast Cancer - Woeckel, Achim; Lux, Michael P.; Janni, Wolfgang; Hartkopf, Andreas D.; Nabieva, Naiba; Taran, Florin-Andrei; Overkamp, Friedrich; Hadji, Peyman; Tesch, Hans; Ettl, Johannes; Lueftner, Diana; Mueller, Volkmar; et al. (Geburtshilfe und Frauenheilkunde, 2018)
In primary early breast cancer, the aim of treatment planning is to obtain an increasingly better understanding of the disease. The identification of patients with an excellent prognosis could help this group avoid unnecessary treatments. Furthermore, the planning of treatment is becoming increasingly patient-focussed. There is a growing understanding of those patients who benefit particularly from chemotherapy, as well as of those who could benefit from immunotherapy. Studies conducted on immunotherapies will be published shortly. Smaller individual studies offer an initial insight into the efficacy of checkpoint inhibitors (anti-PD1/PDL1 therapies). Not least, one of the largest breast cancer studies of all times has recently come to an end. The use of a multigene test has shown that it is sufficient to identify patients with such a good prognosis that chemotherapy is unnecessary. This review article is intended to summarise the current studies and give an outlook on current developments.
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Update Breast Cancer 2018 (Part 4) - Genomics, Individualized Medicine and Immune Therapies - in the Middle of a New Era: Treatment Strategies for Advanced Breast Cancer - Mueller, Volkmar; Woeckel, Achim; Lux, Michael P.; Janni, Wolfgang; Hartkopf, Andreas D.; Nabieva, Naiba; Taran, Florin-Andrei; Hadji, Peyman; Tesch, Hans; Ettl, Johannes; Lueftner, Diana; Welslau, Manfred; et al. (Geburtshilfe und Frauenheilkunde, 2018)
New therapeutic developments aimed at treating women with advanced breast cancer currently focus both on identifying patients eligible for targeted therapeutic concepts and on the continuing development of immune therapies. The data on CDK4/6 inhibitors are now complete and consistent in this class of substances (palbociclib, ribociclib and abemaciclib). Further pathways under investigation are PI3K and AKT signalling pathways along with diverse approaches to their inhibition. Initial study results were also presented recently on both mechanisms of action. Insights into the PARP inhibitors, moreover, are increasing; studies in this respect are also examining in which population they can be used most effectively. This review offers a summary of the recent studies and an outline of the latest developments.
EVALuna2:51296

Update Breast Cancer 2019 Part 1-Implementation of Study Results of Novel Study Designs in Clinical Practice in Patients with Early Breast Cancer - Hartkopf, Andreas D.; Mueller, Volkmar; Woeckel, Achim; Lux, Michael P.; Janni, Wolfgang; Nabieva, Naiba; Taran, Florin-Andrei; Ettl, Johannes; Lueftner, Diana; Belleville, Erik; Schuetz, Florian; Fasching, Peter; et al. (Geburtshilfe und Frauenheilkunde, 2019)
For many years, small but significant advancements have been made time and again in the prevention and treatment of early breast cancer. The so-called panel gene analyses are becoming more and more important in prevention, since the risk due to the tested genes is better understood and as a result, concepts for integration in health care can be developed. In the adjuvant situation, the first study in the so-called post-neoadjuvant situation was able to demonstrate a clear improvement in the prognosis with an absent pathological complete remission following trastuzumab or pertuzumab + trastuzumab. Additional studies with this post-neoadjuvant therapeutic concept are still being conducted at present. The CDK4/6 inhibitors which had shown a significant improvement in progression-free survival in a metastatic situation are currently being tested in the adjuvant situation in large therapeutic studies. These and other new data for the treatment or prevention of primary breast cancer are presented in this review against the backdrop of current studies.
CRIS-Team WoS Importer:2019-04-02

Update Breast Cancer 2019 Part 2-Implementation of Novel Diagnostics and Therapeutics in Advanced Breast Cancer Patients in Clinical Practice - Janni, Wolfgang; Schneeweiss, Andreas; Mueller, Volkmar; Woeckel, Achim; Lux, Michael P.; Hartkopf, Andreas D.; Nabieva, Naiba; Taran, Florin-Andrei; Tesch, Hans; Overkamp, Friedrich; Lueftner, Diana; Belleville, Erik; et al. (Geburtshilfe und Frauenheilkunde, 2019)
The treatment of patients with advanced breast cancer has developed further in recent years. In addition to therapeutic progress in the established subgroups (hormone receptor and HER2 status), there are now therapies which are geared to individual molecular characteristics, such as PARP inhibitor therapy in BRCA-mutated patients. In addition to this, tests are being developed which are intended to establish addition-al markers within subgroups in order to predict the efficacy of a therapy. PI3K mutation testing in HER2-negative, hormonereceptor- positive tumours and PD-L1 testing of immune cells in triple-negative tumours are expected to become established in clinical practice in order to select patients for the respective therapies. With new therapeutic approaches, new adverse effects also appear. The management of these adverse effects, just as those of classical therapy (supportive therapy), is essential with the introduction of new treatments in order to preserve patients ' quality of life. Knowledge regarding measures to preserve and improve quality of life has significantly increased in recent years. Lifestyle factors should be taken into account, as should modern therapeutic methods. This review summarises the latest studies and publications and evaluates them in regard to the relevance for clinical practice.
CRIS-Team WoS Importer:2019-04-02

Update Breast Cancer 2019 Part 2 - Implementation of Novel Diagnostics and Therapeutics in Advanced Breast Cancer Patients in Clinical Practice Update Mammakarzinom 2019 Teil 2 - Implementierung neuer Diagnostika und Therapien bei Patientinnen mit fortgeschrittenem Brustkrebs in der klinischen Praxis - Janni, Wolfgang; Schneeweiss, Andreas; Müller, Volkmar; Wöckel, Achim; Lux, Michael P.; Hartkopf, Andreas D.; Nabieva, Naiba; Taran, Florin Andrei; Tesch, Hans; Overkamp, Friedrich; Lüftner, Diana; Belleville, Erik; et al. (TumorDiagnostik & Therapie, 2019)
The treatment of patients with advanced breast cancer has developed further in recent years. In addition to therapeutic progress in the established subgroups (hormone receptor and HER2 status), there are now therapies which are geared to individual molecular characteristics, such as PARP inhibitor therapy in BRCA-mutated patients. In addition to this, tests are being developed which are intended to establish additional markers within subgroups in order to predict the efficacy of a therapy. PI3K mutation testing in HER2-negative, hormonereceptor-positive tumours and PDâ€ L1 testing of immune cells in triple-negative tumours are expected to become established in clinical practice in order to select patients for the respective therapies. With new therapeutic approaches, new adverse effects also appear. The management of these adverse effects, just as those of classical therapy (supportive therapy), is essential with the introduction of new treatments in order to preserve patientsÊ¼ quality of life. Knowledge regarding measures to preserve and improve quality of life has significantly increased in recent years. Lifestyle factors should be taken into account, as should modern therapeutic methods. This review summarises the latest studies and publications and evaluates them in regard to the relevance for clinical practice.
CRIS-Team Scopus Importer:2019-09-17
Keywords: advanced; alpelisib; atezolizumab; breast cancer; metastatic; PARP; PD-L1; PI3K; supportive therapy

Update Breast Cancer 2019 Part 3 - Current Developments in Early Breast Cancer: Review and Critical Assessment by an International Expert Panel - Kolberg, Hans Christian; Schneeweiss, Andreas; Fehm, Tanja N.; Wöckel, Achim; Huober, Jens; Pontones, Constanza; Titzmann, Adriana; Belleville, Erik; Lux, Michael P.; Janni, Wolfgang; Hartkopf, Andreas D.; Taran, Florin Andrei; et al. (Geburtshilfe und Frauenheilkunde, 2019)
The treatment of breast cancer patients in a curative situation is special in many ways. The local therapy with surgery and radiation therapy is a central aspect of the treatment. The complete elimination of tumour cells at the site of the primary disease must be ensured while simultaneously striving to keep the long-term effects as minor as possible. There is still focus on the continued reduction of the invasiveness of local therapy. With regard to systemic therapy, chemotherapies with taxanes, anthracyclines and, in some cases, platinum-based chemotherapies have become established in the past couple of decades. The context for use is being continually further defined. Likewise, there are questions in the case of antihormonal therapy which also still need to be further defined following the introduction of aromatase inhibitors, such as the length of therapy or ovarian suppression in premenopausal patients. Finally, personalisation of the treatment of early breast cancer patients is also being increasingly used. Prognostic tests could potentially support therapeutic decisions. It must also be considered how the possible use of new therapies, such as checkpoint inhibitors and CDK4/6 inhibitors could look in practice once study results in this regard are available. This overview addresses the backgrounds on the current votes taken by the international St. Gallen panel of experts in Vienna in 2019 for current questions in the treatment of breast cancer patients in a curative situation.
CRIS-Team Scopus Importer:2019-06-04
Keywords: adjuvant therapy; early breast cancer; neoadjuvant therapy; St. Gallen panel of experts

Update Breast Cancer 2019 Part 3 - Current Developments in Early Breast Cancer: Review and Critical Assessment by an International Expert Panel Update Mammakarzinom 2019 Teil 3 - aktuelle Entwicklungen bei der kurativen Behandlung von Mammakarzinom-Patientinnen: Eine Übersicht und Bewertung durch ein internationales Expertenpanel - Kolberg, Hans Christian; Schneeweiss, Andreas; Fehm, Tanja N.; Wöckel, Achim; Huober, Jens; Pontones, Constanza; Titzmann, Adriana; Belleville, Erik; Lux, Michael P.; Janni, Wolfgang; Hartkopf, Andreas D.; Taran, Florin Andrei; et al. (TumorDiagnostik & Therapie, 2019)
The treatment of breast cancer patients in a curative situation is special in many ways. The local therapy with surgery and radiation therapy is a central aspect of the treatment. The complete elimination of tumour cells at the site of the primary disease must be ensured while simultaneously striving to keep the long-term effects as minor as possible. There is still focus on the continued reduction of the invasiveness of local therapy. With regard to systemic therapy, chemotherapies with taxanes, anthracyclines and, in some cases, platinum-based chemotherapies have become established in the past couple of decades. The context for use is being continually further defined. Likewise, there are questions in the case of antihormonal therapy which also still need to be further defined following the introduction of aromatase inhibitors, such as the length of therapy or ovarian suppression in premenopausal patients. Finally, personalisation of the treatment of early breast cancer patients is also being increasingly used. Prognostic tests could potentially support therapeutic decisions. It must also be considered how the possible use of new therapies, such as checkpoint inhibitors and CDK4/6 inhibitors could look in practice once study results in this regard are available. This overview addresses the backgrounds on the current votes taken by the international St. Gallen panel of experts in Vienna in 2019 for current questions in the treatment of breast cancer patients in a curative situation.
CRIS-Team Scopus Importer:2019-09-17
Keywords: adjuvant therapy; early breast cancer; neoadjuvant therapy; St. Gallen panel of experts

Update Breast Cancer 2019 Part 4 – Diagnostic and Therapeutic Challenges of New, Personalised Therapies for Patients with Early Breast Cancer - Schütz, Florian; Fasching, Peter; Welslau, Manfred; Hartkopf, Andreas D.; Wöckel, Achim; Lux, Michael P.; Janni, Wolfgang; Ettl, Johannes; Lüftner, Diana; Belleville, Erik; Kolberg, Hans Christian; Overkamp, Friedrich; et al. (Geburtshilfe und Frauenheilkunde, 2019)
The further development of therapies for women with early breast cancer is progressing far more slowly than in the case of patients with advanced breast cancer and is additionally delayed compared to developments in metastatic breast cancer. Nonetheless, significant advancements have been able to be recorded recently. This review summarises the latest developments in view of the most recent publications and professional conferences. For hormone-receptor-positive patients, new aspects for the duration of antihormone therapy and with regard to the benefits of multigene tests have been published. In the case of HER2-positive patients, the value of post-neoadjuvant therapy and de-escalation of the therapy is discussed. In patients with triple-negative breast cancer, there is a question of whether the knowledge of the biological background of a homologous recombination deficiency (HRD) helps develop new therapies for this subtype. In particular the use of a BRCA1/2 mutation or the biological characteristic HRD as a potential motive for therapy plays a role here in specifying the significance of platinum therapy and therapy with PARP inhibitors.
CRIS-Team Scopus Importer:2019-11-05
Keywords: adjuvant; antihormone therapy; breast cancer; chemotherapy; multigene tests; neoadjuvant

Update Breast Cancer 2019 Part 5 - Diagnostic and Therapeutic Challenges of New, Personalised Therapies in Patients with Advanced Breast Cancer. - Welslau, Manfred; Hartkopf, Andreas D.; Mueller, Volkmar; Woeckel, Achim; Lux, Michael P.; Janni, Wolfgang; Ettl, Johannes; Lueftner, Diana; Belleville, Erik; Schuetz, Florian; Fasching, Peter; Kolberg, Hans-Christian; et al. (Geburtshilfe und Frauenheilkunde, 2019)
Significant advancements have been made in recent years in advanced breast cancer and nearly all of them have been in the field of targeted therapy. Pertuzumab and trastuzumab-emtansine (T-DM1) have been able to be introduced in HER2-positive breast cancer. Now other anti-HER2 therapies are being developed (e.g. margetuximab, DS-8201a, pyrotinib) which can overcome other resistance mechanisms in the HER2 signalling pathway. In the field of hormone-receptor-positive breast cancer, an mTOR inhibitor and CDK4/6 inhibitors were introduced in the past. Now the introduction of the first PI3K inhibitor is forthcoming and this inhibitor will involve genetic testing of the tumour for a mutation in the PIK3CA gene. There are also significant advancements in triple-negative breast cancer: By combining chemotherapy and immunotherapy, an advantage for overall survival was able to be demonstrated in a subgroup (immune cells PD-L1-positive). The PARP inhibitor therapy for HER2-negative patients with a germ line mutation in BRCA1 or BRCA2 was also associated with an improved overall survival in a subgroup. These promising new study results are summarised in this review.
EVALuna2:206462

Update Breast Cancer 2020 Part 1 – Early Breast Cancer: Consolidation of Knowledge About Known Therapies - Schneeweiss, Andreas; Hartkopf, Andreas D.; Mueller, Volkmar; Woeckel, Achim; Lux, Michael P.; Janni, Wolfgang; Ettl, Johannes; Belleville, Erik; Huober, Jens; Thill, Marc; Fasching, Peter; Kolberg, Hans-Christian; et al. (Geburtshilfe und Frauenheilkunde, 2020)
This review is intended to present the latest developments in the prevention and treatment of early breast cancer. The risk of breast cancer can be increasingly better characterised with large epidemiological studies on genetic and non-genetic risk factors. Through new analyses, the evidence for high-penetrance genes as well as for low-penetrance genes was able to be improved. New data on denosumab and atezolizumab are available in the neoadjuvant situation as is a pooled appraisal of numerous studies on capecitabine in the curative situation. There is also an update to the overall survival data of pertuzumab in the adjuvant situation with a longer follow-up observation period. Finally, digital medicine is steadily finding its way into science. A recently conducted study on automated breast cancer detection using artificial intelligence establishes the basis for a future review in clinical studies.
CRIS-Team Scopus Importer:2020-03-27
Keywords: digital medicine; early breast cancer; immune therapy; prevention; prognosis; therapy

Update Breast Cancer 2020 Part 2 - Advanced Breast Cancer: New Treatments and Implementation of Therapies with Companion Diagnostics - Lüftner, Diana; Schneeweiss, Andreas; Hartkopf, Andreas D.; Müller, Volkmar; Wöckel, Achim; Janni, Wolfgang; Ettl, Johannes; Belleville, Erik; Schütz, Florian; Thill, Marc; Huober, Jens; Fasching, Peter; et al. (Geburtshilfe und Frauenheilkunde, 2020)
For patients with locally advanced or metastatic breast cancer, new and effective therapies such as CDK4/6 inhibitors, PARP inhibitors and a PD-L1 inhibitor have been introduced in recent years. This review presents an update on the available studies with their data. In addition, two innovative anti-HER2 therapies are presented (trastuzumab-deruxtecan and tucatinib) for which the results from new studies have been reported. Molecular tests offer the possibility of defining patient populations or also monitoring courses of therapy. This can help identify patients with specific characteristics in order to provide them with individually targeted therapy within the framework of studies. In a large study, the benefit of such a biomarker study was able to be described for the first time.
CRIS-Team Scopus Importer:2020-05-15
Keywords: advanced breast cancer; BRCA1/2; CDK4/6; immune therapy; metastases; mutational testing; PARP; PD-L1; therapy

Update Breast Cancer 2020 Part 3 - Early Breast Cancer - Huober, Jens; Schneeweiss, Andreas; Hartkopf, Andreas D.; Müller, Volkmar; Lux, Michael P.; Janni, Wolfgang; Ettl, Johannes; Belleville, Erik; Thill, Marc; Fasching, Peter; Kolberg, Hans Christian; Schulmeyer, Carla; et al. (Geburtshilfe und Frauenheilkunde, 2020)
The treatment of patients with early breast cancer has always been characterised by escalation by new therapies and de-escalation through identification of better treatment regimens or introduction of better tools to estimate prognosis. Efforts in some of these areas in the last few years have led to solid data. The results of the large studies of de-escalation through use of multi-gene tests are available, as are the results of some studies that investigated the new anti-HER2 substances T-DM1 and pertuzumab in the early treatment situation. Several large-scale studies examining the role of CDK4/6 inhibitors will soon be concluded so innovations can be anticipated in this area also. This review article will summarise and classify the results of the latest publications.
CRIS-Team Scopus Importer:2020-11-27
Keywords: digital medicine; early breast cancer; immunotherapy; prevention; prognosis; treatment

Update Breast Cancer 2020 Part 4 – Advanced Breast Cancer - Tesch, Hans; Müller, Volkmar; Wöckel, Achim; Ettl, Johannes; Belleville, Erik; Schütz, Florian; Hartkopf, Andreas; Thill, Marc; Huober, Jens; Fasching, Peter; Kolberg, Hans Christian; Schulmeyer, Carla E.; et al. (Geburtshilfe und Frauenheilkunde, 2020)
Substances with good effectiveness that intervene in specific signalling pathways have been used increasingly in recent years in the treatment of patients with advanced breast cancer, and new therapies and approaches have now been added, which actually relate to quite specific changes, such as the treatment of patients with HR+/HER2 tumours with a PIK3CA mutation. The treatment of patients with a BRCA1 or BRCA2 mutation has also been improved by the introduction of PARP inhibitors. Attempts are now being made increasingly to extend treatment indications based on molecular patterns, to identify other patients who could benefit from a treatment and to integrate the newly established treatment methods in existing therapy sequences. This review articles summarises the latest information in this connection.
CRIS-Team Scopus Importer:2020-11-20
Keywords: Advanced breast cancer; BRCA1/2; CDK4/6; immunotherapy; metastases; mutation testing; PARP; PD-L1; treatment

Update Breast Cancer 2020 Part 5 - Moving Therapies from Advanced to Early Breast Cancer Patients - Lux, Michael P.; Schneeweiss, Andreas; Hartkopf, Andreas D.; Müller, Volkmar; Janni, Wolfgang; Belleville, Erik; Stickeler, Elmar; Thill, Marc; Fasching, Peter; Kolberg, Hans Christian; Untch, Michael; Harbeck, Nadia; et al. (Geburtshilfe und Frauenheilkunde, 2021)
In recent years, significant progress has been made in new therapeutic approaches to breast cancer, particularly in patients with HER2-positive and HER2-negative/hormone receptor-positive (HR+) breast cancer. In the case of HER2-positive tumours, these approaches have included, in particular, treatment with pertuzumab, T-DM1, neratinib and, soon, also tucatinib and trastuzumab deruxtecan (neither of which has yet been authorised in Europe). In patients with HER2-/HR+ breast cancer, CDK4/6 inhibitors and the PIK3CA inhibitor alpelisib are of particular importance. Further novel therapies, such as Akt kinase inhibitors and oral SERDs (selective estrogen receptor down regulators), are already being investigated in ongoing clinical trials. These therapeutic agents are not only being introduced into curative, (neo-)adjuvant therapeutic settings for HER2-positive tumours; a first favourable study on abemaciclib as an adjuvant therapy has now also been published. In patients with triple-negative breast cancer, after many years of negative study results with the Trop-2 antibody drug conjugate (ADC) sacituzumab govitecan, a randomised study has been published that may represent a significant therapeutic advance. This review describes the latest developments in breast cancer subsequent to the ESMO Congress 2020.
CRIS-Team Scopus Importer:2021-05-21
Keywords: digital medicine; early breast cancer; immune therapy; prognosis; therapy

Update Breast Cancer 2021 Part 1-Prevention and Early Stages - Stickeler, Elmar; Aktas, Bahriye; Behrens, Annika; Belleville, Erik; Ditsch, Nina; Fasching, Peter; Fehm, Tanja N.; Hartkopf, Andreas D.; Jackisch, Christian; Janni, Wolfgang; Kolberg-Liedtke, Cornelia; Kolberg, Hans-Christian; et al. (Geburtshilfe und Frauenheilkunde, 2021)
This review summarises not only the latest evidence on prevention, but also the current research on the treatment of early-stage breast cancer patients. Recent years have seen a growing body of evidence on the risk of high- and moderate-penetrance breast cancer susceptibility genes. A large international consortium has now been able to further refine the answer to the question of the significance of the so-called panel genes. Moreover, the data on treatment selection regarding endocrine efficacy and the decision for or against chemotherapy have also been advanced markedly. There is also new data on adjuvant CDK4/6 (cyclin-dependent kinase 4/6) inhibitors, which are standard in first-line treatment in patients with metastatic HER2-negative, hormone receptor-positive (HR+) breast cancer. For other therapies such as immune checkpoint inhibitors, which have successfully improved the rate of pathologic complete response (pCR) in neoadjuvant treatment settings for patients with triple-negative breast cancer (TNBC), there is a growing understanding of the quality of life and side effects. This is especially important in situations where patients could possibly be cured without such a regimen.
CRIS-Team WoS Importer:2021-05-21

Update Breast Cancer 2021 Part 2-Advanced Stages, Long-Term Consequences and Biomarkers - Ditsch, Nina; Stickeler, Elmar; Behrens, Annika; Belleville, Erik; Fasching, Peter; Fehm, Tanja N.; Hartkopf, Andreas D.; Jackisch, Christian; Janni, Wolfgang; Kolberg-Liedtke, Cornelia; Kolberg, Hans-Christian; Lueftner, Diana; et al. (Geburtshilfe und Frauenheilkunde, 2021)
This review summarises and discusses significant aspects of recently published studies on patient treatment in advanced breast cancer and on biomarkers in breast cancer. In recent years, a large number of drugs for all molecular subtypes have been developed up to phase III trials. With regard to immune checkpoint inhibitors in metastasised breast cancer, the recent discussion has centred on the best candidate for combined chemotherapy. The oral taxanes could become a new type of oral chemotherapies. There is a growing body of data on biomarkers for the use of CDK4/6 inhibitors, which could also signify further development for other molecular subtypes. New substances have been developed for metastatic HER2+ breast cancer that still result in good remission even after massive prior treatment and/or cerebral metastasis. Similarly, knowledge is growing about targeted therapies with antibody-drug conjugates (ADC) against Trop-2, which could bolster our therapeutic armoury in triple-negative breast cancer (TNBC). In addition, the clinical focus is on understanding how to maintain fertility after breast cancer treatment. Here, pooled analyses provide new insights.
CRIS-Team WoS Importer:2021-05-21

Update Breast Cancer 2021 Part 3 – Current Developments in the Treatment of Early Breast Cancer: Review and Assessment of Specialised Treatment Scenarios by an International Expert Panel - Fehm, Tanja N.; Stickeler, Elmar; Fasching, Peter; Janni, Wolfgang; Kolberg-Liedtke, Cornelia; Kolberg, Hans Christian; Lüftner, Diana; Müller, Volkmar; Schütz, Florian; Thomssen, Christoph; Belleville, Erik; Behrens, Annika; et al. (Geburtshilfe und Frauenheilkunde, 2021)
The continuous availability of findings from new studies repeatedly results in updated treatment recommendations and guidelines. In the case of breast carcinoma in particular, several studies have been published in the last few years that have transformed how early and advanced breast carcinoma is being treated. However, this by no means means implies that there is agreement among all experts on specific issues. It is precisely the diversity of interpretation of guidelines and study findings that reflects the constantly changing available data and its complexity, as well as the availability of new drugs. In recent years, new substances such as pertuzumab, T-DM1, neratinib and capecitabine have become available to treat patients with early stages of breast carcinoma. Furthermore, the first results on the use of CDK4/6 inhibitors for adjuvant treatment have now been published. Last but not least, the use of multigene tests to avoid the necessity of chemotherapy in certain patients is still under discussion. This review summarises the state of the data and publishes the results of the survey completed by experts at the 2021 St. Gallen Breast Cancer Conference on early-stage breast cancer.
CRIS-Team Scopus Importer:2021-07-02
Keywords: early breast cancer; expert panel; therapy decisions

Update Breast Cancer 2021 Part 4 - Prevention and Early Stages. - Thomssen, Christoph; Fehm, Tanja N.; Stickeler, Elmar; Fasching, Peter; Janni, Wolfgang; Kolberg-Liedtke, Cornelia; Kolberg, Hans-Christian; Lueftner, Diana; Mueller, Volkmar; Schuetz, Florian; Belleville, Erik; Bader, Simon; et al. (Geburtshilfe und Frauenheilkunde, 2022)
This past year has seen new and effective options for further improving treatment outcome in many patients with early-stage breast cancer. Patients with hormone receptor-positive disease benefited significantly from the addition of the CDK4/6 inhibitor abemaciclib to endocrine adjuvant therapy. In triple-negative disease, data were presented for two treatment regimens. Patients with advanced disease (stage 2 and 3) benefit from neoadjuvant treatment with the immune checkpoint inhibitor pembrolizumab in combination with standard chemotherapy, regardless of PD-L1 expression. When neoadjuvant therapy has failed to achieve the desired remission in BRCA1 and BRCA2 mutations, the administration of the PARP inhibitor olaparib has demonstrated an impressive response. Other data address translational issues in HER2-positive breast cancer and neoadjuvant therapy approaches with the oral SERD giredestrant and the PARP inhibitor talazoparib. This review presents and analyses the findings of this year' s most important study outcomes.
EVALuna2:506656
Keywords: BRCA (breast cancer associated gene); breast; genetics; Her-2/neu (human epidermal growth factor receptor); hormonal receptor; breast cancer

Update Breast Cancer 2021 Part 5 - Advanced Breast Cancer. - Lueftner, Diana; Schuetz, Florian; Stickeler, Elmar; Fasching, Peter; Janni, Wolfgang; Kolberg-Liedtke, Cornelia; Kolberg, Hans-Christian; Thomssen, Christoph; Mueller, Volkmar; Fehm, Tanja N.; Belleville, Erik; Bader, Simon; et al. (Geburtshilfe und Frauenheilkunde, 2022)
Despite the COVID 19 pandemic and mostly virtual congresses, innovation in the treatment of breast cancer patients continues at an unabated pace. This review summarises the current developments. Initial overall survival data for CDK4/6 inhibitor treatment in combination with an aromatase inhibitor as the first advanced line of therapy in treatment-naive postmenopausal patients have been published. Similarly, a trial comparing trastuzumab-deruxtecan versus trastuzumab-emtansine revealed a clear benefit regarding progression-free survival. Understanding of biomarkers making checkpoint inhibitor therapy particularly effective is increasing, and new compounds such as oral selective estrogen receptor destabilisers (SERDs) are entering clinical development and completing the first phase III trials.
EVALuna2:506657

Update Breast Cancer 2022 Part 1 - Early Stage Breast Cancer. - Welslau, Manfred; Mueller, Volkmar; Lueftner, Diana; Schuetz, Florian; Stickeler, Elmar; Fasching, Peter; Janni, Wolfgang; Thomssen, Christoph; Witzel, Isabell; Fehm, Tanja N.; Belleville, Erik; Bader, Simon; et al. (Geburtshilfe und Frauenheilkunde, 2022)
Evidence relating to the treatment of breast cancer patients with early-stage disease has increased significantly in the past year. Abemaciclib, olaparib, and pembrolizumab are new drugs with good efficacy in the relevant patient groups. However, some questions remain unanswered. In particular, it remains unclear which premenopausal patients with hormone receptor-positive breast cancer should be spared unnecessary treatment. The question of the degree to which chemotherapy exerts a direct cytotoxic effect on the tumor or reduces ovarian function through chemotherapy could be of key importance. This group of patients could potentially be spared chemotherapy. New, previously experimental biomarker analysis methods, such as spatial analysis of gene expression (spatial transcriptomics) are gradually finding their way into large randomized phase III trials, such as the NeoTRIP trial. This in turn leads to a better understanding of the predictive factors of new therapies, for example immunotherapy. This review summarizes the scientific innovations from recent congresses such as the San Antonio Breast Cancer Symposium 2021 but also from recent publications.
EVALuna2:511215

Update Breast Cancer 2022 Part 2 - Advanced Stage Breast Cancer - Müller, Volkmar; Welslau, Manfred; Lüftner, Diana; Schütz, Florian; Stickeler, Elmar; Fasching, Peter; Janni, Wolfgang; Thomssen, Christoph; Witzel, Isabell; Fehm, Tanja N.; Belleville, Erik; Bader, Simon; et al. (Geburtshilfe und Frauenheilkunde, 2022)
For patients with advanced breast cancer, several novel therapies have emerged in recent years, including CDK4/6 inhibitors, immune checkpoint inhibitors, PARP inhibitors, alpelisib, tucatinib and trastuzumab-deruxtecan, and sacituzumab-govitecan, which have transformed and expanded the therapeutic landscape for patients with advanced breast cancer. Some of these substances have now been approved for use in the early stages of the disease, or are expected to be approved in the near future, so the therapeutic landscape will change once again. Therefore, current scientific efforts are focused on the introduction of new substances and understanding their mechanisms of progression and efficacy. This review summarizes recent developments with reference to recent publications and conferences. Findings on the treatment of patients with HER2-positive breast cancer and brain metastases are presented, as are a number of studies looking at biomarkers in patients with HER2-negative, hormone receptor-positive breast cancer. In particular, the introduction of oral selective estrogen receptor degraders provides new opportunities to establish biomarker-based therapy. Molecular diagnostics is establishing itself as a diagnostic marker and parameter of progression.
CRIS-Team Scopus Importer:2022-08-05
Keywords: ADC; biomarker; breast cancer; metastatic; PD-L1

Update Breast Cancer 2022 Part 3 - Early-Stage Breast Cancer. - Fehm, Tanja N.; Welslau, Manfred; Mueller, Volkmar; Lueftner, Diana; Schuetz, Florian; Fasching, Peter; Janni, Wolfgang; Thomssen, Christoph; Witzel, Isabell; Belleville, Erik; Untch, Michael; Thill, Marc; et al. (Geburtshilfe und Frauenheilkunde, 2022)
This review summarizes recent developments in the prevention and treatment of patients with early-stage breast cancer. The individual disease risk for different molecular subtypes was investigated in a large epidemiological study. With regard to treatment, new data are available from long-term follow-up of the Aphinity study, as well as new data on neoadjuvant therapy with atezolizumab in HER2-positive patients. Biomarkers, such as residual cancer burden, were investigated in the context of pembrolizumab therapy. A Genomic Grade Index study in elderly patients is one of a group of studies investigating the use of modern multigene tests to identify patients with an excellent prognosis in whom chemotherapy may be avoided. These and other aspects of the latest developments in the diagnosis and treatment of breast cancer are described in this review.
EVALuna2:511790

Update Breast Cancer 2022 Part 4 - Advanced-Stage Breast Cancer. - Aktas, Bahriye; Fehm, Tanja N.; Welslau, Manfred; Mueller, Volkmar; Lueftner, Diana; Schuetz, Florian; Fasching, Peter; Janni, Wolfgang; Thomssen, Christoph; Witzel, Isabell; Belleville, Erik; Untch, Michael; et al. (Geburtshilfe und Frauenheilkunde, 2022)
For the treatment of patients with advanced HER2-negative hormone receptor-positive breast cancer, several substances have been introduced into practice in recent years. In addition, other drugs are under development. A number of studies have been published over the past year which have shown either an advantage for progression-free survival or for overall survival. This review summarizes the latest results, which have been published at current congresses or in specialist journals, and classifies them in the clinical treatment context. In particular, the importance of therapy with CDK4/6 inhibitors - trastuzumab deruxtecan, sacituzumab govitecan and capivasertib - is discussed. For trastuzumab deruxtecan, an overall survival benefit in HER2-negative breast cancer with low HER2 expression (HER2-low expression) was reported in the Destiny-Breast-04 study. Similarly, there was an overall survival benefit in the FAKTION study with capivasertib. The lack of overall survival benefit for palbociclib in the first line of therapy raises the question of clinical classification.
EVALuna2:511788

Update Breast Cancer 2022 Part 5 – Early Stage Breast Cancer - Fehm, Tanja N.; Welslau, Manfred; Müller, Volkmar; Lüftner, Diana; Schütz, Florian; Fasching, Peter; Janni, Wolfgang; Thomssen, Christoph; Witzel, Isabell; Beierlein, Milena; Belleville, Erik; Untch, Michael; et al. (Geburtshilfe und Frauenheilkunde, 2023)
The treatment of patients with early stage breast cancer has changed in recent years due to the introduction of pembrolizumab, olaparib, and abemaciclib. These and other drugs with the same class of active ingredient are currently in trial for various indications. This review article summarizes the latest results that have either been presented at major conferences such as the ESMO 2022 or published recently in international journals. This includes reports on newly discovered breast cancer genes, atezolizumab in neoadjuvant therapy in HER2-positive patients, long-term data from the APHINITY study, and on how preoperative peritumoral application of local anesthetics can influence the prognosis. We also present solid data on dynamic Ki-67 from the ADAPT studies.
CRIS-Team Scopus Importer:2023-03-31
Keywords: breast cancer; chemotherapy; surgery; therapy standard

Update Breast Cancer 2022 Part 6 – Advanced-Stage Breast Cancer - Lüftner, Diana; Lux, Michael P.; Fehm, Tanja N.; Welslau, Manfred; Müller, Volkmar; Schütz, Florian; Fasching, Peter; Janni, Wolfgang; Thomssen, Christoph; Witzel, Isabell; Beierlein, Milena; Belleville, Erik; et al. (Geburtshilfe und Frauenheilkunde, 2023)
Large-scale study programs on CDK4/6 inhibitors, targeted therapies, and antibody-drug conjugates launched in recent years have yielded results from current studies which are now being published in journals and presented at international conferences. In this context, new results are available from the major CDK4/6 inhibitor studies. Also, an increasing amount of data is being published from large-scale genomic studies on efficacy and resistance mechanisms in patients treated with CDK4/6 inhibitors. These results now form the basis for further research plans to investigate combination therapies and treatment sequencing. Based on the latest published results, sacituzumab govitecan is now available as a second antibody-drug conjugate; this brings an advantage in terms of overall survival for patients with hormone receptor-positive (HRpos)/HER2-negative (HER2neg) breast cancer. In this review article, we summarize the latest developments and place them in context according to the current status of research.
CRIS-Team Scopus Importer:2023-03-31
Keywords: advanced breast cancer; chemotherapy; therapy standard

Updated overall survival from the MONALEESA-3 trial in postmenopausal women with HR+/HER2− advanced breast cancer receiving first-line ribociclib plus fulvestrant - Neven, P.; Fasching, Peter; Chia, S.; Jerusalem, G.; De Laurentiis, M.; Im, S. A.; Petrakova, K.; Bianchi, G. V.; Martín, M.; Nusch, A.; Sonke, G. S.; De la Cruz-Merino, L.; et al. (Breast Cancer Research, 2023)
Background: The phase III MONALEESA-3 trial included first- (1L) and second-line (2L) patients and demonstrated a significant overall survival (OS) benefit for ribociclib + fulvestrant in patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative (HR+/HER2−) advanced breast cancer (ABC) in the final protocol-specified and exploratory (longer follow-up) OS analyses. At the time of these analyses, the full OS benefit of 1L ribociclib was not completely characterized because the median OS (mOS) was not reached. As CDK4/6 inhibitor (CDK4/6i) + endocrine therapy (ET) is now a preferred option for 1L HR+/HER2− ABC, we report an exploratory analysis (median follow-up, 70.8 months; 14.5 months longer than the prior analysis) to fully elucidate the OS benefit in the MONALEESA-3 1L population. Methods: Postmenopausal patients with HR+/HER2− ABC were randomized 2:1 to 1L/2L fulvestrant + ribociclib or placebo. OS in 1L patients (de novo disease or relapse > 12 months from completion of [neo]adjuvant ET) was assessed by Cox proportional hazards model and Kaplan–Meier methods. Progression-free survival 2 (PFS2) and chemotherapy-free survival (CFS) were analyzed. MONALEESA-3 is registered with ClinicalTrials.gov (NCT02422615). Results: At data cutoff (January 12, 2022; median follow-up time, 70.8 months), mOS was 67.6 versus 51.8 months with 1L ribociclib versus placebo (hazard ratio (HR) 0.67; 95% CI 0.50–0.90); 16.5% and 8.6% of ribociclib and placebo patients, respectively, were still receiving treatment. PFS2 (HR 0.64) and CFS (HR 0.62) favored ribociclib versus placebo. Among those who discontinued treatment, 16.7% and 35.0% on ribociclib or placebo, respectively, received a subsequent CDK4/6i. No new safety signals were observed. Conclusions: This analysis of MONALEESA-3 reports the longest mOS thus far (67.6 months) for 1L patients in a phase III ABC trial. These results in a 1L population show that the OS benefit of ribociclib was maintained through extended follow-up, further supporting its use in HR+/HER2− ABC.
CRIS-Team Scopus Importer:2023-09-08
Keywords: Advanced breast cancer; CDK4/6 inhibitor; First line; Overall survival; Ribociclib

Updated overall survival (OS) results from the first-line (1L) population in the phase III MONALEESA-3 trial of postmenopausal patients (PTS) with HR+/HER2-advanced breast cancer (ABC) treated with ribociclib (RIB) plus fulvestrant (FUL) - Neven, P.; Fasching, Peter; Chia, S.; Jerusalem, G.; De Laurentiis, M.; Im, S. -A.; Petrakova, K.; Bianchi, G. V.; Martin Jimenez, M.; Nusch, A.; Sonke, G. S.; De La Cruz Merino, L.; et al. (ANNALS OF ONCOLOGY, 2022)
CRIS-Team WoS Importer:2022-06-03

Update in the certification of endometriosis centers Neues in der Zertifizierung von Endometriosezentren - Schaefer, Sebastian D.; Sillem, Martin; Schweppe, Karl-Werner; Burghaus, Stefanie; Beckmann, Matthias (Gynäkologe, 2021)
Endometriosis is among the most frequent diseases of women during reproductive age. The disease itself but also its treatment significantly impairs quality of life. Top-level specialized centers have been established to ensure diagnosis and treatment. The certification process defined by Stiftung Endometriose-Forschung (SEF), European Endometriosis League (EEL) and patient self-help organisations is intended to guarantee comparable quality. Diagnosis and treatment need to be based on current guidelines. The redefinition of the term center by the German Gemeinsame Bundesausschuss (G-BA) has made it necessary to adapt the established staging concept. In the future specialized “endometriosis practices”, “endometriosis units” and “endometriosis centers” will be certified according to predefined criteria.
CRIS-Team Scopus Importer:2021-05-21
Keywords: Guidelines; Integrative medicine; Quality of life; Reproduction; Shared decision making

Update Mammakarzinom 2019 Teil 1 – Implementierung der Ergebnisse neuer Studienkonzepte beim frühen Mammakarzinom in die klinische Praxis - Hartkopf, Andreas D.; Müller, Volkmar; Wöckel, Achim; Lux, Michael P.; Janni, Wolfgang; Nabieva, Naiba; Taran, Florin Andrei; Ettl, Johannes; Lüftner, Diana; Belleville, Erik; Schütz, Florian; Fasching, Peter; et al. (TumorDiagnostik & Therapie, 2019)
For many years, small but significant advancements have been made time and again in the prevention and treatment of early breast cancer. The so-called panel gene analyses are becoming more and more important in prevention, since the risk due to the tested genes is better understood and as a result, concepts for integration in health care can be developed. In the adjuvant situation, the first study in the so-called postneoadjuvant situation was able to demonstrate a clear improvement in the prognosis with an absent pathological complete remission following trastuzumab or pertuzumab + trastuzumab. Additional studies with this post-neoadjuvant therapeutic concept are still being conducted at present. The CDK4/6 inhibitors which had shown a significant improvement in progression-free survival in a metastatic situation are currently being tested in the adjuvant situation in large therapeutic studies. These and other new data for the treatment or prevention of primary breast cancer are presented in this review against the backdrop of current studies.
CRIS-Team Scopus Importer:2019-09-17
Keywords: adjuvant therapy; early breast cancer; Katherine; neoadjuvant therapy; prevention; TDM1

Update S3-Leitlinie Zervixkarzinom: Diagnostik, Therapie und Nachsorge - Stübs, Frederik; Beckmann, Matthias; Fehm, Tanja (Best Practice Onkologie, 2022)
There is constant progress in the treatment of women with cervical cancer. Therefore, the German S3 guideline requires regular revision. The new statements and recommendations are based on a systematic literature review. The revision process involved around 50 specialist societies under the expert guidance of the Association of the Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF). The new standard of care in surgical therapy for cervical cancer up to FIGO stage IB1 is open radical hysterectomy. The evidence base for the role of intensity-modulated radiotherapy and individualized brachytherapy was strengthened. Patients with metastatic cervical cancer benefit from addition of bevacizumab to standard chemotherapy in first-line treatment. From the second line onward, the use of pembrolizumab is recommended for women with PD-L1-positive cervical cancer.
CRIS-Team Scopus Importer:2022-07-08
Keywords: Bevacizumab; Brachytherapy; Open radical hysterectomy; Pembrolizumab; PET-CT

Updates on the role of receptor activator of nuclear factor κB/receptor activator of nuclear factor κB ligand/osteoprotegerin pathway in breast cancer risk and treatment - Bayer, Christian M.; Beckmann, Matthias; Fasching, Peter (Current Opinion in Obstetrics & Gynecology, 2017)
PURPOSE OF REVIEW: Treatment with bisphosphonates and denosumab is the standard of care in bone metastatic disease. In addition, the adjuvant therapy of denosumab or bisphosphonates is very effective to prevent loss of bone mineral density, for example in osteoporosis. However, it is still unclear if this therapy has an influence on preventing cancer. RECENT FINDINGS: Since the identification of novel genes in the 1980s, it took about 30 years until denosumab, as a fully human mAb against receptor activator of nuclear factor (NF)-κB ligand (RANKL), could be introduced to clinical practice. The discovery of the receptor activator of NF-κB/RANKL/osteoprotegerin pathway in the 1990s is an example of how modern databases of genes were utilized to discover new pathways relevant to a variety of diseases. The essential role of this pathway for the function, differentiation and survival of osteoclasts, and the influence on the bone microenvironment helped to understand the vicious circle of bone resorption and destruction in many skeletal diseases. SUMMARY: In the following review, we discuss the important role of rational targeting concerning receptor activator of NF-κB/RANKL/osteoprotegerin and the bisphosphonate therapy and provide an update for the related treatment of patients suffering from breast cancer and further implications for clinical practice and research using denosumab as a potential chemoprevention in BRCA1-related breast cancer.
EVALuna2:36158

Use of a molecular Registry (PRAEGNANT) for Patient-Selection and Biomarker-Analysis for the SHERBOC Study - Hübner, Hanna; Kurbacher, C.; Kuesters, G.; Hartkopf, A. D.; Lux, M. P.; Huober, J.; Volz, B.; Taran, F. A.; Overkamp, F.; Tesch, H.; Häberle, Lothar; Lueftner, D.; et al. (GEBURTSHILFE UND FRAUENHEILKUNDE, 2020)
CRIS-Team WoS Importer:2020-10-30

Use of complementary and integrative medicine among German breast cancer patients: predictors and implications for patient care within the PRAEGNANT study network - Fremd, Carlo; Hack, Carolin; Schneeweiss, Andreas; Rauch, Geraldine; Wallwiener, Diethelm; Brucker, Sara Yvonne; Taran, Florin-Andrei; Hartkopf, Andreas; Overkamp, Friedrich; Tesch, Hans; Fehm, Tanja; Hadji, Peyman; et al. (Archives of Gynecology and Obstetrics, 2017)
PURPOSE: The present study aims to analyze a cohort of advanced breast cancer patients in Germany to assess their interest in complementary and alternative medicine (CAM) and patient's use of most frequent CAM methods. PATIENTS AND METHODS: Based on the PREGNANT real-time breast cancer registry which is a multicenter study in Germany, questionnaires of 580 patients with advanced breast cancer were evaluated. The implemented questionnaire for CAM asked for general interest in CAM and for patient's use of different CAM methods at present and in the past. The interest and application of CAM were analyzed for association with patients' characteristics such as tumor, patient, and therapy characteristics. RESULTS: In total, 436 out of 580 (75%) patients claimed to be interested in CAM. Further, interest in CAM is significantly correlated with younger age and absence of metastasis at the time of diagnosis. Multivariate analysis confirmed the patient's age and distant disease status at the time of diagnosis as related to interest in CAM. A total of 56.4% of patients applied any CAM method in the past. Moreover, with increasing lines of therapies, the more frequent use of CAM was observed. Hereby, praying, vitamin supplements, and other food supplements were most frequently applied. CONCLUSION: Our data demonstrate high overall interest and frequent use of CAM in advanced breast cancer patients supporting a strong demand of breast cancer patients for complementary counseling and treatments additional to the established cancer therapies. It is indispensable to implement counseling and evidence-based complementary treatments into clinical routine of cancer centers and to adapt postgraduate medical education, respectively.
EVALuna2:36145

Use of Granulocyte-colony Stimulating Factor During Chemotherapy and Its Association With CA27.29 and Circulating Tumor Cells-Results From the SUCCESS A Trial - Hepp, Philip; Fasching, Peter; Beckmann, Matthias; Fehm, Tanja; Salmen, Jessica; Hagenbeck, Carsten; Jaeger, Bernadette; Widschwendter, Peter; De Gregorio, Nikolaus; Schochter, Fabienne; Mahner, Sven; Harbeck, Nadia; et al. (Clinical Breast Cancer, 2018)
Little is known about the effect of granulocyte colony-stimulating factor (G-CSF) treatment during adjuvant chemotherapy on prognostic markers. The present study explored the association between G-CSF and changes in cancer antigen (CA)27.29 and circulating tumor cell (CTC) levels during therapy.A total of 3754 node-positive or high-risk node-negative early-stage breast cancer patients were treated within the SUCCESS-A trial (simultaneous study of gemcitabine-docetaxel combination adjuvant treatment, as well as extended bisphosphonate and surveillance-trial). CA27.29 and CTCs were determined before the start and within 6 weeks after the end of chemotherapy.Overall, 1324 of the 2646 patients (50.0%) available for analysis had >= 1 G-CSF applications during chemotherapy. G-CSF application was significantly associated with CA27.29 status before and after chemotherapy (? = 30.6, df = 3; P < .001), because 238 patients (18.0%) with G-CSF treatment but only 146 (11.0%) without G-CSF treatment switched from a negative CA27.29 status before to a positive CA27.29 status after chemotherapy. In addition, patients with G-CSF application showed a significantly greater increase in CA27.29 levels after chemotherapy compared with patients without any G-CSF application during chemotherapy (Mann-Whitney U test; Z = -7.81, P < .001). No significant association was found between G-CSF application and CTC status before or after chemotherapy (? = 1.2, df = 3; P = .75).Cautious interpretation is needed regarding elevated levels of MUC-1-derived tumor markers such as CA27.29 shortly after adjuvant chemotherapy when G-CSF has been given, because G-CSF treatment was associated with increased CA27.29 levels after chemotherapy.
EVALuna2:56150

Using automated texture features to determine the probability for masking of a tumor on mammography, but not ultrasound - Haeberle, Lothar; Hack, Carolin; Heusinger, Katharina; Wagner, Florian; Jud, Sebastian; Uder, Michael; Beckmann, Matthias; Schulz-Wendtland, Rüdiger; Wittenberg, Thomas; Fasching, Peter (European Journal of Medical Research, 2017)
BACKGROUND: Tumors in radiologically dense breast were overlooked on mammograms more often than tumors in low-density breasts. A fast reproducible and automated method of assessing percentage mammographic density (PMD) would be desirable to support decisions whether ultrasonography should be provided for women in addition to mammography in diagnostic mammography units. PMD assessment has still not been included in clinical routine work, as there are issues of interobserver variability and the procedure is quite time consuming. This study investigated whether fully automatically generated texture features of mammograms can replace time-consuming semi-automatic PMD assessment to predict a patient's risk of having an invasive breast tumor that is visible on ultrasound but masked on mammography (mammography failure). METHODS: This observational study included 1334 women with invasive breast cancer treated at a hospital-based diagnostic mammography unit. Ultrasound was available for the entire cohort as part of routine diagnosis. Computer-based threshold PMD assessments ("observed PMD") were carried out and 363 texture features were obtained from each mammogram. Several variable selection and regression techniques (univariate selection, lasso, boosting, random forest) were applied to predict PMD from the texture features. The predicted PMD values were each used as new predictor for masking in logistic regression models together with clinical predictors. These four logistic regression models with predicted PMD were compared among themselves and with a logistic regression model with observed PMD. The most accurate masking prediction was determined by cross-validation. RESULTS: About 120 of the 363 texture features were selected for predicting PMD. Density predictions with boosting were the best substitute for observed PMD to predict masking. Overall, the corresponding logistic regression model performed better (cross-validated AUC, 0.747) than one without mammographic density (0.734), but less well than the one with the observed PMD (0.753). However, in patients with an assigned mammography failure risk >10%, covering about half of all masked tumors, the boosting-based model performed at least as accurately as the original PMD model. CONCLUSION: Automatically generated texture features can replace semi-automatically determined PMD in a prediction model for mammography failure, such that more than 50% of masked tumors could be discovered.
UnivIS-Import:2017-12-18:Pub.2017.tech.IMMD.IMMD9.usinga
Keywords: Mammographic density; Mammography screening; Masking; Risk prediction; Sensitivity; Texture analysis; Variable selection

Using Probability for Pathological Complete Response (pCR) as a Decision Support Marker for Neoadjuvant Chemotherapy in HER2 Negative Breast Cancer Patients - a Survey Among Physicians - Gaß, Paul; Untch, Michael; Mueller, Volkmar; Moebus, Volker; Thomssen, Christoph; Häberle, Lothar; Erber, Ramona; Hein, Alexander; Jud, Sebastian; Lux, Michael P.; Hack, Carolin; Hartmann, Arndt; et al. (Geburtshilfe und Frauenheilkunde, 2018)
Background: In women with early breast cancer, a pathological complete response (pCR) after neoadjuvant chemotherapy is reported to be associated with an improvement of the survival. The aim of this survey among physicians was to investigate whether the probability of achieving pCR in patients with a hormone receptor-positive, HER2-negative disease encourages physicians to recommend neoadjuvant chemotherapy. Methods: The study was conducted via an online survey that was sent to 493 physicians, who were either known as members of national guideline committees, heads of breast cancer centers, being high recruiters in clinical trials or leading a private practice. Participants were asked about a specific case that should resemble patients for whom it is unclear, whether they should be treated with chemotherapy. Results: 113 (24.5%) physicians participated at the survey, out of which 96.5% had a work experience of more than 10 years and 94.7% were board certified in their specialty. A total of 84.1% would consider pCR for a decision concerning neoadjuvant chemotherapy. With regard to the pCR probability, 2.7 and 10.6% of the participants demanded at least a pCR rate of 5 and 10%, respectively, while 25.7% were satisfied with 20% probability, and another 25.7% with a pCR rate of 30%. Conclusions: The vast majority of the long-term experienced physicians would embrace the implementation of a further method such as the prediction of pCR probability in clinical routine to support decision making regarding the necessity of neoadjuvant chemotherapy. The cut-off of around 30% pCR probability seems to be a realizable rate to distinguish patient groups.
EVALuna2:34856

Uterine contractility changes in a perfused swine uterus model induced by local anesthetics procaine, lidocaine, and ropivacaine - Weinschenk, Fabian; Dittrich, Ralf; Mueller, Andreas; Lotz, Laura; Beckmann, Matthias; Weinschenk, Stefan W. (PLoS ONE, 2018)
BACKGROUND: Local anesthetics (LAs) are increasingly used as therapeutics due to their multiple molecular effects. They may be potential agents also in gynecology and reproductive medicine. The objective of this study was to investigate the contractility response of the perfused swine uterus to different concentrations of the LAs procaine, lidocaine, and ropivacaine. METHODS AND FINDINGS: In an extracorporeal perfusion model with fresh swine uteri, effects of administered boli of these three LAs in concentrations of 0.1 mg/mL, 0.5 mg/mL and 1.0 mg/mL on uterine contractility and peristalsis were assessed using an intrauterine double-chip micro-catheter. A dose-dependent increase in intrauterine pressure (IUP) in the isthmus and corpus uteri was observed after the administration of the ester-LA procaine 0.1, 0.5, and 1.0%, which was not seen with lower concentrations, or buffer solution. An increase-decrease curve was found after increasing concentrations of the amide-LA lidocaine and ropivacaine, with an IUP plateau with 0.1 and 0.5%, and a decrease with 1% (p<0.01). All reactions were seen in both the isthmus and corpus uteri. The difference of the contractility pattern between ester- and amide-LA at 1% concentration was significant. CONCLUSION: LAs dose-dependently modulate contractility in non-pregnant swine uteri. The amid-LAs lidocaine and ropivacaine reduce contractility in higher concentrations and may be used as therapeutics in disorders with increased uterine contractility, as dysmenorrhoea, endometriosis, and infertility. The multiple molecular effects of LAs may explain these effects. This in-vitro pilot study in vitro provides initial data for designing further studies to transfer the results onto humans.
EVALuna2:209956

Utility of the CPS + EG scoring system in triple-negative breast cancer treated with neoadjuvant chemotherapy - Marmé, Frederik; Solbach, Christine; Michel, Laura; Schneeweiss, Andreas; Blohmer, Jens Uwe; Huober, Jens; Fasching, Peter; Jackisch, Christian; Nekljudova, Valentina; Link, Theresa; Rhiem, Kerstin; Rey, Julia; et al. (European Journal of Cancer, 2021)
Background: Pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) is associated with superior survival. This association is strongest in triple-negative breast cancer (TNBC). The CPS + EG system, based on pre-treatment clinical (CS) and post-treatment pathological stage (PS), oestrogen-receptor status (E) and grade (G), leads to a refined estimate of prognosis after NACT in all-comers and hormone receptor–positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Here, we investigate if CPS + EG scoring provides a superior estimate of prognosis in TNBC to select patients for postneoadjuvant therapy. Methods: We calculated the CPS + EG score for 1795 patients with TNBC from 8 prospective German trials. Five-year disease-free survival (DFS) and overall survival estimates were calculated using the Kaplan-Meier method. Results: In TNBC, patients with pCR (ypT0/is ypN0, n = 822, 45.8%) had a 5-year DFS of 86%, whereas patients with residual American Joint Committee on Cancer stage I disease (n = 383; 21.3%) had a 5-year DFS of 77.5%.CPS + EG led to superior prognostic information compared with that provided by the clinical stage, but it was inferior to the prognostic information provided by the pathological stage (c-index statistics, p < 0.001). CPS + EG did not discriminate prognosis within the two best prognostic groups (score 1 and 2; n = 362; 37.2%). In contrast, pCR status added prognostic information beyond CPS + EG. Patients with a CPS + EG score of 3 had a 5-year DFS rate of 64% overall, but those with pCR had a 5-year DFS rate of 84%, and those without pCR had a 5-year DFS rate of only 49.7%. Conclusions: In TNBC, CPS + EG scoring provided inferior prognostic information compared with the pathological stage and was unable to identify patients without pCR and with a sufficiently good prognosis, who could avoid postneoadjuvant therapy. pCR remains the strongest and most clinically useful prognostic factor after NACT. Other biologic factors beyond pCR are needed in TNBC.
CRIS-Team Scopus Importer:2021-07-23
Keywords: CPS + EG; Neoadjuvant therapy; Prognosis; Triple-negative breast cancer

Utility of the CPS plus EG scoring system in triple-negative breast cancer treated with neoadjuvant chemotherapy - Marme, F.; Solbach, C.; Michel, L.; Fasching, Peter; Schneeweiss, A.; Blohmer, J. -U.; Rezai, M.; Huober, J.; Jackisch, C.; Nekljudova, V.; Link, T.; Rhiem, K.; et al. (ANNALS OF ONCOLOGY, 2019)
CRIS-Team WoS Importer:2019-11-08

Validation of the MammaTyper (R) pathological complete response (pCR)-score as a predictor for response after neoadjuvant chemotherapy (NACT) in patients with early breast cancer (BC) - Fasching, Peter; Laible, M.; Weber, K. E.; Wirtz, R. M.; Denkert, C.; Schlombs, K.; Schmatloch, S.; Camara, O.; Lueck, H. J.; Huober, J.; Karn, T.; Van Mackelenbergh, M. T.; et al. (ANNALS OF ONCOLOGY, 2018)
CRIS-Team WoS Importer:2019-03-08

Variable expression of the disialoganglioside gd2 in breast cancer molecular subtypes - Erber, Ramona; Kailayangiri, Sareetha; Hübner, Hanna; Rübner, Matthias; Hartmann, Arndt; Häberle, Lothar; Meyer, Julia; Völkl, Simon; Mackensen, Andreas; Landgraf, Laura; Geppert, Carol-Immanuel; Schulz-Wendtland, Rüdiger; et al. (Cancers, 2021)
The disialoganglioside GD2 is a tumor-associated antigen that may allow for the application of targeted immunotherapies (anti-GD2 antibodies, GD2 CAR T cells) in patients with neuroblastoma and other solid tumors. We retrospectively investigated GD2 expression in a breast cancer cohort, using immunohistochemistry (IHC) and immunofluorescence (IF) on tissue microarrays (TMAs), and its impact on survival. GD2 expression on IHC (n = 568) and IF (n = 503) was investigated in relation to subtypes and patient outcome. Overall, 50.2% of the 568 IHC-assessed samples and 69.8% of the 503 IF-assessed samples were GD2-positive. The highest proportion of GD2-positive tumors was observed in luminal tumors. Significantly fewer GD2-positive cases were detected in triple-negative breast cancer (TNBC) compared with other subtypes. The proportion of GD2-expressing tumors were significantly lower in HER2-positive breast cancer in comparison with luminal tumors on IF staining (but not IHC). GD2 expression of IHC or IF was not significantly associated with disease-free or overall survival, in either the overall cohort or in individual subtypes. However, GD2 expression can be seen in more than 50% of breast cancer cases, with the highest frequency in hormone receptorpositive tumors. With this high expression frequency, patients with GD2-positive advanced breast cancer of all subtypes may benefit from GD2-targeting immunotherapies, which are currently subject to clinical testing.
CRIS-Team Scopus Importer:2021-11-12
Keywords: Breast cancer; Disialoganglioside; GD2; Immunofluorescence; Immunohistochemistry; Prognosis

Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility - Earp, Madalene; Tyrer, Jonathan P.; Winham, Stacey J.; Lin, Hui-Yi; Chornokur, Ganna; Dennis, Joe; Aben, Katja K. H.; Anton-Culver, Hoda; Antonenkova, Natalia; Bandera, Elisa V.; Bean, Yukie T.; Beckmann, Matthias; et al. (PLoS ONE, 2018)
Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations.
EVALuna2:34624

Variation in NF-?B signaling pathways and survival in invasive epithelial ovarian cancer - Block, Matthew S.; Charbonneau, Bridget; Vierkant, Robert A.; Fogarty, Zachary; Bamlet, William R.; Pharoah, Paul D. P.; Chenevix-Trench, Georgia; Rossing, Mary Anne; Cramer, Daniel; Pearce, Celeste Leigh; Schildkraut, Joellen; Menon, Usha; et al. (Cancer Epidemiology Biomarkers & Prevention, 2014)
Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that affect prognosis are not known. The nuclear factor-?B (NF-?B) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-?B family in 10,084 patients with invasive EOC (5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance, P < 2.5 × 10(-5)). Results were statistically significant when assessed for patients of a single histology. Key associations were with caspase recruitment domain family, member 11 (CARD11) rs41324349 in patients with mucinous EOC [HR, 1.82; 95% confidence interval (CI), 1.41-2.35; P = 4.13 × 10(-6)] and tumor necrosis factor receptor superfamily, member 13B (TNFRSF13B) rs7501462 in patients with endometrioid EOC (HR, 0.68; 95% CI, 0.56-0.82; P = 2.33 × 10(-5)). Other associations of note included TNF receptor-associated factor 2 (TRAF2) rs17250239 in patients with high-grade serous EOC (HR, 0.84; 95% CI, 0.77-0.92; P = 6.49 × 10(-5)) and phospholipase C, gamma 1 (PLCG1) rs11696662 in patients with clear cell EOC (HR, 0.43; 95% CI, 0.26-0.73; P = 4.56 × 10(-4)). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies.
EVALuna2:9241

Venöse Luftembolie bei vaginalen Verletzungen durch Geschlechtsverkehr - Zack, F.; Zinka, B.; Beckmann, Matthias; Banaschak, Sibylle; Fischer, H.; Gabriel, P.; Gerber, B.; Costa, S. D.; Ledwon, P.; Schwenzer, T.; Buettner, A. (Rechtsmedizin, 2019)
Background: In a criminal trial in Germany in 2013, a medical expert nominated by the defence stated in the appeal trial the controversially discussed opinion that a woman had died from an air embolism due to vaginal intercourse with exclusively penile penetration and injury to the vaginal wall. This diagnosis had been established by the expert based on histological examination of the lungs and vaginal injuries years after the woman‘s death. Objective: The frequency of the diagnosis “air embolism as a result of vaginal injuries due to intravaginal intercourse” and the modality of the diagnosis were reviewed. Material and methods: A selective literature review was performed. Furthermore, questionnaires were sent to all forensic medical institutes and to directors and chief physicians of gynecological clinics of large cities in Germany. Results: In the literature two case reports could be found, which by critical analysis showed significant errors in the diagnosis according to the state of science at the time of publication. In over 300,000 autopsies performed between 1990 and 2016, the 26 forensic medical institutes in Germany, which had answered the questionnaire, had never diagnosed “air embolism as a result of vaginal injuries due to intravaginal intercourse”. All 32 professionally experienced gynecologists who responded to the questionnaire had never in their career treated survived or fatal cases of air embolism after vaginal injuries through sexual intercourse or had knowledge of them. Conclusion: According to the survey and critical analysis of the very few published case reports, there is no evidence for a diagnosis of the cause of death as air embolism after vaginal injuries. When diagnosing a fatal venous air embolism, scientific standards should be strictly followed. A diagnosis made solely by histological examination was and is not possible according to the state of the art in forensic medicine and thus violates the principles of expert medical opinions.
CRIS-Team Scopus Importer:2020-02-21
Keywords: Cause of death; Expert opinion; Pregnancy; Questionnaire; Sexual behavior

Ventral rectopexy with biological mesh for recurrent disorders of the posterior pelvic organ compartment - Brunner, Michaela; Roth, H.; Günther, K.; Grützmann, Robert; Matzel, Klaus E. (International Journal of Colorectal Disease, 2019)
PURPOSE: Recurrent prolapse of the posterior pelvic organ compartment presents a management challenge, with the best surgical procedure remaining unclear. We present functional outcome and patient satisfaction after laparoscopic and robotic ventral mesh rectopexy (VMR) with biological mesh in patients with recurrence. METHODS: We analyzed data from 30 patients with recurrent posterior pelvic organ prolapse who underwent VMR with biological mesh from August 2012 to January 2018. Data included patient demographics and intra- and postoperative findings; functional outcome as assessed by Cleveland Clinic Constipation Score (CCCS), Obstructed Defecation Score Longo (ODS), and Cleveland Clinic Incontinence Score (CCIS); and patient satisfaction. RESULTS: CCCS, CCIS, and ODS were significantly improved at 6-12 months postoperatively and at last follow-up. Patient satisfaction (visual analog scale [VAS] 6.7 [0 to 10]), subjective symptoms (+ 3.4 [scale - 5 to + 5]), and quality of life improvement (+ 3.0 [scale from - 5 to + 5]) were high at last follow-up. The rates of morbidity and major complications were 13% and 3%, respectively. There were no mesh-related complications or deaths. Difference in type of previous surgery (abdominal or transanal/perineal) had no significant effect on results. CONCLUSIONS: VMR with biological mesh is a safe and effective option for patients with recurrent posterior pelvic organ prolapse. It reduces functional symptoms, has a low complication rate, and promotes patient satisfaction.
CRIS-Team Scopus Importer:2019-10-01
Keywords: Biological mesh; Functional outcome; Laparoscopic ventral rectopexy; Recurrent posterior compartment prolapse; Recurrent rectal prolapse

Ventral rectopexy with biological mesh: short-term functional results - Brunner, Michaela; Roth, H.; Guenther, K.; Grützmann, Robert; Matzel, K. E. (International Journal of Colorectal Disease, 2018)
PURPOSE: Ventral mesh rectopexy (VMR) is an established, minimally invasive, nerve-sparing procedure for the treatment of various symptomatic morphological changes in the posterior pelvic compartment. We present the short-term functional outcome and patient satisfaction after laparoscopic and robotic VMR with biological mesh. METHODS: We analyzed data from 123 patients who underwent laparoscopic ventral mesh rectopexy (LVMR) or robotic ventral mesh rectopexy (RVMR) from August 2012 to January 2017. Included in these data were patient demographics, intra- and postoperative findings, Cleveland Clinic Constipation Score (CCCS), Obstructed Defecation Score Longo (ODS), Cleveland Clinic Incontinence Score (CCIS), and patient satisfaction as measured by visual analog scale (0-10). RESULTS: Improvements in CCCS, CCIS, and ODS were statistically significant at 6 and 12 months (p < 0.001). Patient satisfaction was excellent at 6 and 12 months (8.2/10 and 8.3/10, respectively). The overall complication rate was 14%, with a major complication rate of 2%. No mesh-related complications were observed. The need for surgical re-intervention because of relapse, symptom persistence or recurrence, or new symptoms was 3%. Outcome appears to be similar between LVMR and RVMR. CONCLUSIONS: Both LVMR and RVMR with biological mesh are safe and effective in reducing symptoms, as measured by CCCS, CCIS, and ODS, and patient satisfaction is high.
EVALuna2:212626

Veranstaltungsbericht: 10. Wissenschaftliches Symposium der AGO-TraFo - Banys-Paluchowski, Malgorzata; Antoniadis, Sophia; Hein, Alexander; Fehm, Tanja N.; Arnold, Norbert; Fasching, Peter (Geburtshilfe und Frauenheilkunde, 2018)
CRIS-Team Scopus Importer:2021-07-19

Veranstaltungsbericht – 11. Wissenschaftliches Symposium der AGO-TraFo - Banys-Paluchowski, Malgorzata; Wunderle, Marius; Fehm, Tanja N.; Arnold, Norbert; Fasching, Peter (Geburtshilfe und Frauenheilkunde, 2019)
CRIS-Team Scopus Importer:2020-02-21

Villoglandular adenocarcinoma of the uterine cervix: a systematic review and meta-analysis - Dietl, Anna; Beckmann, Matthias; Aumann, Konrad (Archives of Gynecology and Obstetrics, 2021)
Purpose: Villoglandular adenocarcinoma (VGA) of the uterine cervix has been classified as a rare subtype of cervical adenocarcinoma with good prognosis. A conservative surgical approach is considered feasible. The main risk factor is the presence of other histologic types of cancer. In this largest systematic review to date, we assess oncological outcomes associated with conservative therapy compared to those associated with invasive management in the treatment of stage Ia and Ib1 VGA. Methods: Case series and case reports identified by searching the PubMed database were eligible for inclusion in this review (stage Ia–Ib1). Results: A total of 271 patients were included in our literature review. 54 (20%) patients were treated by “conservative management” (conization, simple hysterectomy, and trachelectomy) and 217 (80%) by “invasive management” (radical hysterectomy ± radiation, hysterectomy, and radiation). Recurrences of disease (RODs) were found in the conservative group in two (4%) cases and in the invasive group in nine (4%) cases. There was no significant difference in disease-free survival (DFS) according to conservative or invasive treatment (p = 0.75). The histology of VGA may be complex with underlying usual adenocarcinoma (UAC) combined with VGA. Conclusion: The excellent prognosis of pure VGA and the young age of the patients may justify the management of this tumor using a less radical procedure. The histological diagnosis of VGA is a challenge, and pretreatment should not be based solely on a simple punch biopsy but rather a conization with wide tumor-free margins.
CRIS-Team Scopus Importer:2021-06-04
Keywords: Cervix; Conservative therapy; Invasive therapy; Review; Villoglandular adenocarcinoma

Virilizing Hilus Cell Tumor of the Ovary Associated With Efferent Ductules-like Metaplasia Within Paratubal Mesonephric Remnants - Wachter, David; Burghaus, Stefanie; Beckmann, Matthias; Agaimy, Abbas (International Journal of Gynecological Pathology, 2016)
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Volume Quantification of the Thyroid Gland Using 3-D Ultrasound Imaging - Kollorz, Eva Nicole Karin; Hahn, Dieter; Grunewald, Markus; Goecke, Tamme W.; Hornegger, Joachim; Kuwert, Torsten (Nuklearmedizin Kongressausgabe 02/07, 2007)

What do patients want to know about contraception and which method would they prefer? - Oppelt, Patricia; Baier, Friederike; Fahlbusch, Christine; Heusinger, Katharina; Hildebrandt, Thomas; Breuel, Christiane; Dittrich, Ralf (Archives of Gynecology and Obstetrics, 2017)
PURPOSE: The aim of this study was to determine the extent to which women's choice of contraceptive method depends on the advice received from their gynecologist and whether more intensive counseling might lead to more frequent use of long-acting reversible contraception (LARC). METHODS: A total of 1089 physicians and 18,521 women responded to 32 or 37 questions, respectively, using an online questionnaire. The women were asked about their current use of contraceptive methods, the extent of their satisfaction with them, their satisfaction with the counseling they had received, and whether they wanted to have more information about contraception. The physicians were similarly asked which contraceptive methods were being used, how satisfied with them they were, how they would assess their patients' satisfaction with them, and whether the women wanted to have more information. RESULT: The results showed that 61% of the women were using oral contraceptives, and a total of only 9% were using behavior-independent long-term contraceptive methods. However, 60% of the women stated that long-term contraception would be an option for them if they had more information about it. Gynecologists underestimated this figure, at only 18%. Whereas 66% of the gynecologists believed that their patients never forgot to take the pill, nearly, half of the women stated that they had forgotten it at least once during the previous 3 months. CONCLUSION: The small number of women who use long-term contraception is in clear contrast to the fact that many women want to have a very safe but also behavior-independent method.
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Whole blood microRNAs as potential biomarkers in post-operative early breast cancer patients - Alunni-Fabbroni, Marianna; Majunke, Leonie; Trapp, Elisabeth K.; Tzschaschel, Marie; Mahner, Sven; Fasching, Peter; Fehm, Tanja; Schneeweiss, Andreas; Beck, Thomas; Lorenz, Ralf; Friedl, Thomas W. P.; Janni, Wolfgang; et al. (BMC Cancer, 2018)
microRNAs (miRNAs) are considered promising cancer biomarkers, showing high reliability, sensitivity and stability. Our study aimed to identify associations between whole blood miRNA profiles, presence of circulating tumor cells (CTCs) and clinical outcome in post-operative early breast cancer patients (EBC) to assess the utility of miRNAs as prognostic markers in this setting.A total of 48 post-operative patients, recruited in frame of the SUCCESS A trial, were included in this retrospective study and tested with a panel of 8 miRNAs (miR-10b, -19a, - 21, - 22, -20a, - 127, - 155, -200b). Additional 17 female healthy donors with no previous history of cancer were included in the study as negative controls. Blood samples were collected at different time points (pre-adjuvant therapy, post-adjuvant therapy, 2 years follow up), total RNA was extracted and the relative concentration of each miRNA was measured by quantitative PCR and compared in patients stratified on blood collection time or CTC detection. Furthermore, we compared miRNA profiles of patients, for each time point separately, and healthy donors. CTCs were visualized and quantified with immunocytochemistry analysis. Data were analyzed using non-parametric statistical tests.In our experimental system, miR-19a, miR-22 and miR-127 showed the most promising results, differentiating patients at different time points and from healthy controls, while miR-20a, miR-21 and miR-200b did not show any difference among the different groups. miR-10b and miR-155 were never detectable in our experimental system. With respect to patients' clinical characteristics, we found a significant correlation between miR-200b and lymph node status and between miR-20a and tumor type. Furthermore, miR-127 correlated with the presence of CTCs. Finally, we found a borderline significance between Progression Free Survival and miR-19a levels.This pilot study suggests that profiling whole blood miRNAs could help to better stratify post-operative EBC patients without any sign of metastasis to prevent later relapse or metastatic events.
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Whole-Body Electromyostimulation combined with personalized Nutritional Support improves the Body Composition of Patients with advanced Cancer - Schink, Kristin; Herrmann, Hans Joachim; Schwappacher, Raphaela; Orlemann, Till; Meyer, Julia; Waldmann, Elisabeth; Wullich, Bernd; Kahlmeyer, Andreas; Fietkau, Rainer; Lubgan, Dorota; Beckmann, Matthias; Hack, Carolin; et al. (2018)
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Willingness of Patients with Breast Cancer in the Adjuvant and Metastatic Setting to Use Electronic Surveys (ePRO) Depends on Sociodemographic Factors, Health-related Quality of Life, Disease Status and Computer Skills - Graf, Joachim; Simoes, E.; Wisslicen, K.; Rava, L.; Walter, C. B.; Hartkopf, A.; Keilmann, L.; Taran, A.; Wallwiener, S.; Fasching, Peter; Brucker, S. Y.; Wallwiener, M. (Geburtshilfe und Frauenheilkunde, 2016)
Introduction: Because of the often unfavorable prognosis, particularly for patients with metastases, health-related quality of life is extremely important for breast cancer patients. In recent years, data on patient-relevant endpoints is being increasingly collected electronically; however, knowledge on the acceptance and practicability of, and barriers to, this form of data collection remains limited.Material and Methods:A questionnaire was completed by 96 patients to determine to what extent existing computer skills, disease status, health-related quality of life and sociodemographic factors affect patients' potential willingness to use electronics methods of data collection (ePRO).Results:52 of 96 (55 %) patients reported a priori that they could envisage using ePRO. Patients who a priori preferred a paper-based survey (pPRO) tended to be older (ePRO 53 years vs. pPRO 62 years; p = 0.0014) and typically had lower levels of education (p = 0.0002), were in poorer health (p = 0.0327) and had fewer computer skills (p = 0.0003).Conclusion:Barriers to the prospective use of ePRO were identified in older patients and patients with a lower quality of life. Given the appropriate conditions with regard to age, education and current health status, opportunities to participate should be provided to encourage patients' willingness to take part and ensure the validity of survey results. Focusing on ease of use of ePRO applications and making applications more patient-oriented and straightforward appears to be the way forward.
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Xenotransplantation of cryopreserved human ovarian tissue - a systematic review of MII oocyte maturation and discussion of it as a realistic option for restoring fertility after cancer treatment - Dittrich, Ralf; Lotz, Laura; Fehm, Tanja; Kruessel, Jan; Von Wolff, Michael; Toth, Bettina; Van Der Ven, Hans; Schuering, Andreas N.; Wuerfel, Wolfgang; Hoffmann, Inge; Beckmann, Matthias (Fertility and Sterility, 2015)
To systematically review the reporting of MII (MII) oocyte development after xenotransplantation of human ovarian tissue.Systematic review in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA).Not applicable.Not applicable.Formation of MII oocytes after xenotransplantation of human ovarian tissue.Any outcome reported in Pubmed.Six publications were identified that report on formation of MII oocytes after xenotransplantation of human ovarian tissue.Xenografting of human ovarian tissue has proved to be a useful model for examining ovarian function and follicle development in vivo. With human follicles that have matured through xenografting, the possibility of cancer transmission and relapse can also be eliminated, because cancer cells are not able to penetrate the zona pellucida. The reported studies have demonstrated that xenografted ovarian tissue from a range of species, including humans, can produce antral follicles that contain mature (MII) oocytes, and it has been shown that mice oocytes have the potential to give rise to live young. Although some ethical questions remain unresolved, xenotransplantation may be a promising method for restoring fertility. This review furthermore describes the value of xenotransplantation as a tool in reproductive biology and discusses the ethical and potential safety issues regarding ovarian tissue xenotransplantation as a means of recovering fertility.
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Zoledronate for patients with invasive residual disease after anthracyclines-taxane-based chemotherapy for early breast cancer - The Phase III NeoAdjuvant Trial Add-oN (NaTaN) study (GBG 36/ABCSG 29) - Von Minckwitz, G.; Rezai, M.; Tesch, H.; Huober, J.; Gerber, B.; Zahm, D. M.; Hilfrich, J.; Costa, S. D.; Dubsky, P.; Blohmer, J. U.; Denkert, Carsten; Hanusch, C.; et al. (European Journal of Cancer, 2016)
BACKGROUND: Patients with invasive residual disease after neoadjuvant chemotherapy (NACT) are considered to have chemo-resistant breast cancer. Bisphosphonates are an established treatment for bone metastases and are of potential benefit as adjuvant treatment in early breast cancer. PATIENTS AND METHODS: Patients who had invasive tumour residuals (ypT1-4 and/or ypN+) after a minimum of four cycles of anthracycline-taxane-containing NACT were eligible for the NeoAdjuvant Trial Add-oN study. Patients were randomised within 3 years after surgery to receive zoledronate 4 mg i.v. for 5 years versus observation. Zoledronate was given every 4 weeks for the first 6 months, every 3 months for the following 2 years, and every 6 months for the last 2.5 years. Primary objective was disease-free survival. RESULTS: After a median time of 54.7 months no difference in disease-free survival was observed between the zoledronate and observation groups (hazard ratio [HR] 0.960, 95% confidence interval [CI] 0.709-1.30, log rank P=0.789). Various subgroups were examined without identifying a treatment effect of zoledronate. Patients over 55 years of age showed a HR of 0.832 in favour of zoledronate, but the result was not significant (P=0.480). A similar result was obtained for overall survival with a HR of 1.19 (95% CI 0.79-1.79; log rank P=0.408). Zoledronate was well tolerated and no new toxicity signal was identified. CONCLUSION: Postneoadjuvant treatment with zoledronate does not improve outcome in patients without pathological complete response after neoadjuvant anthracycline-taxane-based chemotherapy for early breast cancer.
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Zukunft mammographie-basierter Bildgebung [Future of mammography-based imaging] - Schulz-Wendtland, Rüdiger; Wittenberg, Thomas; Michel, Thilo; Hartmann, Arndt; Beckmann, Matthias; Rauh, Claudia; Judt, Sebastian; Brehm, Barbara; Meier-Meitinger, Martina; Anton, Gisela; Uder, Michael; Fasching, Peter (Radiologe, 2014)
Mammography is the central diagnostic method for clinical diagnostics of breast cancer and the breast cancer screening program. In the clinical routine complementary methods, such as ultrasound, tomosynthesis and optional magnetic resonance imaging (MRI) are already combined for the diagnostic procedure. Future developments will utilize investigative procedures either as a hybrid (combination of several different imaging modalities in one instrument) or as a fusion method (the technical fusion of two or more of these methods) to implement fusion imaging into diagnostic algorithms. For screening there are reasonable hypotheses to aim for studies that individualize the diagnostic process within the screening procedure. Individual breast cancer risk prediction and individualized knowledge about sensitivity and specificity for certain diagnostic methods could be tested. The clinical implementation of these algorithms is not yet in sight. (orig.) [German] Die Mammographie ist die zentrale diagnostische Methode der klinischen symptombezogenen Abklaerung von Brusterkrankungen und des Brustkrebsscreenings. In der klinischen Diagnostik wird sie heute schon oft durch zusaetzliche Untersuchungsmethoden wie dem Ultraschall, der Tomosynthese und ggf. auch der MRT-Bildgebung unterstuetzt. Zukuenftige Entwicklungen gehen in die Richtung, dass diese Kombination aus 2 oder mehr Untersuchungsverfahren entweder in Hybrid- (Aufnahme mehrerer unterschiedlicher Bildmodalitaeten in einem einzigen Geraet) oder in Fusionsmethoden (Zusammenfuehrung und Registrierung von Bilddaten aus verschiedenen Modalitaeten) technisch professionalisiert werden. Des Weiteren koennten an subgruppenbezogene Erkrankungsrisiken und individuelle Sensitivitaeten und Spezifitaeten angepasste Diagnostikkombinationen fuer eine Screeningdiagnostik Gegenstand kuenftiger Studien sein. Wir stellen die aktuellen Entwicklungen auf diesen Gebieten und deren momentane Relevanz fuer die klinische Praxis und Entwicklungspotenzial fuer die Zukunft dar. (orig
UnivIS-Import:2015-04-14:Pub.2014.tech.IMMD.IMMD9.zukunf
Keywords: MAMMOgraphy

Complementary medicine in radiation oncology : German health care professionals' current qualifications and therapeutic methods - Kessel, Kerstin A.; Klein, Evelyn; Hack, Carolin; Combs, Stephanie E. (Strahlentherapie und Onkologie, 2018)
Recently, complementary and alternative medicine (CAM) has moved more into the focus, and cancer societies such as the German Cancer Society (Deutsche Krebsgesellschaft, DKG) have established working groups to develop a guideline for CAM. The present work aims to evaluate the acceptance of CAM in the whole radiation oncology community.We conducted an online survey on CAM and sent the modified questionnaire that was successfully distributed to all members of the Research Group on Gynecological Oncology (Arbeitsgemeinschaft Gynakologische Onkologie, AGO) of the DKG in 2014 to the members of the German Society of Radiation Oncology (Deutsche Gesellschaft für Radioonkologie und Strahlentherapie, DEGRO). The survey consisted of 17 questions regarding personal information and current CAM guidelines within the workplace/clinic.A total of 143 members participated. Of these, 12% had some CAM qualification. For hematological cancer in 35% and in up to 76% for breast cancer, CAM treatment is offered in German radiation oncology facilities, mainly due to fatigue symptoms. CAM is part of routine treatment in 32.2%, 22.0% are planning to incorporate it. Most physicians advise patients to partake in sports activities and recommend dietary supplements and nutritional counseling. The cost of CAM treatment is fully covered in 9.8% of all participating facilities.Today, CAM is integrated into cancer care; however, skepticism regarding its effect still exists. Evidence-based results must be generated to convince physicians of the effectiveness of CAM methods. CAM qualifications must be included in physicians' training to improve their understanding and counseling regarding CAM options in cancer care.
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Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden - Stone, Meredith L.; Chiappinelli, Katherine B.; Li, Huili; Murphy, Lauren M.; Travers, Meghan E.; Topper, Michael J.; Mathios, Dimitrios; Lim, Michael; Shih, Ie-Ming; Wang, Tian-Li; Hung, Chien-Fu; Bhargava, Vipul; et al. (Proceedings of the National Academy of Sciences of the United States of America, 2017)
Ovarian cancer is the most lethal of all gynecological cancers, and there is an urgent unmet need to develop new therapies. Epithelial ovarian cancer (EOC) is characterized by an immune suppressive microenvironment, and response of ovarian cancers to immune therapies has thus far been disappointing. We now find, in a mouse model of EOC, that clinically relevant doses of DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi, respectively) reduce the immune suppressive microenvironment through type I IFN signaling and improve response to immune checkpoint therapy. These data indicate that the type I IFN response is required for effective in vivo antitumorigenic actions of the DNMTi 5-azacytidine (AZA). Through type I IFN signaling, AZA increases the numbers of CD45+ immune cells and the percentage of active CD8+ T and natural killer (NK) cells in the tumor microenvironment, while reducing tumor burden and extending survival. AZA also increases viral defense gene expression in both tumor and immune cells, and reduces the percentage of macrophages and myeloid-derived suppressor cells in the tumor microenvironment. The addition of an HDACi to AZA enhances the modulation of the immune microenvironment, specifically increasing T and NK cell activation and reducing macrophages over AZA treatment alone, while further increasing the survival of the mice. Finally, a triple combination of DNMTi/HDACi plus the immune checkpoint inhibitor α-PD-1 provides the best antitumor effect and longest overall survival, and may be an attractive candidate for future clinical trials in ovarian cancer.
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Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating Lung Cancer - Topper, Michael J.; Vaz, Michelle; Chiappinelli, Katherine B.; Shields, Christina E. Destefano; Niknafs, Noushin; Yen, Ray-Whay Chiu; Wenzel, Alyssa; Hicks, Jessica; Ballew, Matthew; Stone, Meredith; Tran, Phuoc T.; Zahnow, Cynthia A.; et al. (Cell, 2017)
Combining DNA-demethylating agents (DNA methyltransferase inhibitors [DNMTis]) with histone deacetylase inhibitors (HDACis) holds promise for enhancing cancer immune therapy. Herein, pharmacologic and isoform specificity of HDACis are investigated to guide their addition to a DNMTi, thus devising a new, low-dose, sequential regimen that imparts a robust anti-tumor effect for non-small-cell lung cancer (NSCLC). Using in-vitro-treated NSCLC cell lines, we elucidate an interferon α/β-based transcriptional program with accompanying upregulation of antigen presentation machinery, mediated in part through double-stranded RNA (dsRNA) induction. This is accompanied by suppression of MYC signaling and an increase in the T cell chemoattractant CCL5. Use of this combination treatment schema in mouse models of NSCLC reverses tumor immune evasion and modulates T cell exhaustion state towards memory and effector T cell phenotypes. Key correlative science metrics emerge for an upcoming clinical trial, testing enhancement of immune checkpoint therapy for NSCLC.
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MicroRNA-mediated drug resistance in ovarian cancer - Mihanfar, Aynaz; Fattahi, Amir; Nejabati, Hamid Reza (Journal of Cellular Physiology, 2019)
The development of intrinsic or acquired resistance to chemotherapeutic agents used in the treatment of various human cancers is a major obstacle for the successful abolishment of cancer. The accumulated efforts in the understanding the exact mechanisms of development of multidrug resistance (MDR) have led to the introduction of several unique and common mechanisms. Recent studies demonstrate the regulatory role of small noncoding RNA or miRNA in the several parts of cancer biology. Practically all aspects of cell physiology under normal and disease conditions are reported to be controlled by miRNAs. In this review, we discuss how the miRNA profile is changed upon MDR development and the pivotal regulatory role played by miRNAs in overcoming resistance to chemotherapeutic agents. It is hoped that further studies will support the use of these differentially expressed miRNAs as prognostic and predictive markers, as well as novel therapeutic targets to overcome resistance in ovarian cancer.
CRIS-Team WoS Importer:2019-02-22

Reply to Haffner et al.: DNA hypomethylation renders tumors more immunogenic - Stone, Meredith L.; Chiappinelli, Katherine B.; Li, Huili; Murphy, Lauren M.; Travers, Meghan E.; Topper, Michael J.; Mathios, Dimitrios; Lim, Michael; Shih, Le-Ming; Wang, Tian-Li; Hung, Chien-Fu; Bhargava, Vipul; et al. (Proceedings of the National Academy of Sciences of the United States of America, 2018)
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Role of tumour-free margin distance for loco-regional control in vulvar cancer-a subset analysis of the Arbeitsgemeinschaft Gynäkologische Onkologie CaRE-1 multicenter study - Woelber, Linn; Griebel, Lis-Femke; Eulenburg, Christine; Sehouli, Jalid; Jueckstock, Julia; Hilpert, Felix; De Gregorio, Nikolaus; Hasenburg, Annette; Ignatov, Atanas; Hillemanns, Peter; Fuerst, Sophie; Strauss, Hans-Georg; et al. (European Journal of Cancer, 2016)
AIM OF THE STUDY: A tumour-free pathological resection margin of ≥8 mm is considered state-of-the-art. Available evidence is based on heterogeneous cohorts. This study was designed to clarify the relevance of the resection margin for loco-regional control in vulvar cancer. METHODS: AGO-CaRE-1 is a large retrospective study. Patients (n = 1618) with vulvar cancer ≥ FIGO stage IB treated at 29 German gynecologic-cancer-centres 1998-2008 were included. This subgroup analysis focuses on solely surgically treated node-negative patients with complete tumour resection (n = 289). RESULTS: Of the 289 analysed patients, 141 (48.8%) had pT1b, 140 (48.4%) pT2 and 8 (2.8%) pT3 tumours. One hundred twenty-five (43.3%) underwent complete vulvectomy, 127 (43.9%) partial vulvectomy and 37 (12.8%) radical local excision. The median minimal resection margin was 5 mm (1 mm-33 mm); all patients received groin staging, in 86.5% with full dissection. Median follow-up was 35.1 months. 46 (15.9%) patients developed recurrence, thereof 34 (11.8%) at the vulva, after a median of 18.3 months. Vulvar recurrence rates were 12.6% in patients with a margin <8 mm and 10.2% in patients with a margin ≥8 mm. When analysed as a continuous variable, the margin distance had no statistically significant impact on local recurrence (HR per mm increase: 0.930, 95% CI: 0.849-1.020; p = 0.125). Multivariate analyses did also not reveal a significant association between the margin and local recurrence neither when analysed as continuous variable nor categorically based on the 8 mm cutoff. Results were consistent when looking at disease-free-survival and time-to-recurrence at any site (HR per mm increase: 0.949, 95% CI: 0.864-1.041; p = 0.267). CONCLUSIONS: The need for a minimal margin of 8 mm could not be confirmed in the large and homogeneous node-negative cohort of the AGO-CaRE database.
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Unraveling the molecular pathways of DNA-methylation inhibitors: human endogenous retroviruses induce the innate immune response in tumors - Strick, Reiner; Strissel, Pamela; Baylin, Stephen B.; Chiappinelli, Katherine B. (OncoImmunology, 2016)
Loss of DNA methylation can activate endogenous retroviral expression and dsRNA in cancer cells. This leads to induction of toll-like receptor signaling stimulating an antiviral interferon response. Recent findings provide a therapeutic rationale for combining DNA methylation inhibitors with blockage of immune checkpoint proteins to fight cancer.
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