14th St. Gallen International Breast Cancer Conference 2015: Evidence, Controversies, Consensus - Primary Therapy of Early Breast Cancer: Opinions Expressed by German Experts - Jackisch, Christian; Harbeck, Nadia; Huober, Jens; Von Minckwitz, Gunter; Gerber, Bernd; Kreipe, Hans-Heinrich; Liedtke, Cornelia; Marschner, Norbert; Moebus, Volker; Scheithauer, Heike; Schneeweiss, Andreas; Thomssen, Christoph; et al. (Breast Care, 2015)
The key topics of this year's 14th St. Gallen Consensus Conference on the diagnosis and therapy of primary breast cancer were again questions about breast surgery and axillary surgery, radio-oncology and systemic therapy options in consideration of tumor biology, and the clinical application of multigene assays. This year, the consensus conference took place in Vienna. From a German perspective, it makes sense to substantiate the results of the vote of the international panel representing 19 countries in light of the updated national therapy recommendations of the AGO (Arbeitsgemeinschaft Gynäkologische Onkologie). Therefore, 14 German breast cancer experts, 3 of whom are members of the International St. Gallen Panel, have commented on the voting results of the St. Gallen Consensus Conference 2015 in relation to clinical routine in Germany.
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243rd Statement by the German Society of Gynecology and Obstetrics (DGGG) in Response to the Call for Data on the Safety of PIP Silicone Breast Implants and the Possible Association between Breast Implants and ALCL by the Scientific Committee on Health, Environmental and Emerging Risks (SCHEER) of the European Commission - Blohmer, Jens-Uwe; Sinn, H. Peter; Seelbach-Goebel, Birgit; Beckmann, Matthias (Geburtshilfe und Frauenheilkunde, 2017)
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2D:4D biomarker reliability and validity in a within-subject pregnancy-childhood-adolescence cohort - Eichler, Anna; Kaufmann, Franziska; Titzmann, Adriana; Fasching, Peter; Beckmann, Matthias; Gerlach, Jennifer; Kratz, Oliver; Moll, Gunther; Buchholz, Verena Nadine; Kornhuber, Johannes; Lenz, Bernd (Early Human Development, 2023)
Background: A lot of studies use the second-to-fourth digit length ratio (2D:4D) as a biomarker for intrauterine androgen load to predict behavioral and mental health problems. Thus, knowledge of 2D:4D's metric properties, namely reliability and validity, is essential. Method: 2D:4D handscans were available from 149 adolescents (M = 13.32 years, SD = 0.35) and their mothers. For 88 adolescents, there were also primary-school age handscans (M = 7.87 years, SD = 0.68). Prenatal risks for the 1st to 3rd trimesters were recorded during the 3rd trimester of pregnancy (alcohol exposition: meconium biomarker and maternal self-report; nicotine exposition: maternal self-report; maternal depressive symptoms and subjective stress: questionnaires). Results: The 2D:4D ratio was highly stable from childhood to early adolescence. However, both developmental and sex effects were present: The 2D:4D ratio increased with age and was higher in adolescent girls vs. boys. Significant 2D:4D mother-child associations were found for girls. Significant main effects could be found for the prenatal risk factors alcohol (self-report) and nicotine consumption. Conclusion: In line with earlier studies, the 2D:4D biomarker proved to be an inter-individually stable measure with an intra-individual increase from childhood to early adolescence. Sex differences in adolescence and associations with maternal prenatal health behaviour underline the validity of the biomarker. Findings on heritability emphasize the importance of interpreting 2D:4D results in a sex-specific manner.
CRIS-Team Scopus Importer:2023-04-28
Keywords: 2D:4D ratio; Alcohol; Androgen load; Biomarker; Construct validity; Heritability; Nicotine; Pregnancy risk; Prenatal; Retest reliability; Stability; Testosterone exposure

2q36.3 is associated with prognosis for oestrogen receptor-negative breast cancer patients treated with chemotherapy - Li, Jingmei; Lindstroem, Linda S.; Foo, Jia N.; Rafiq, Sajjad; Schmidt, Marjanka K.; Pharoah, Paul D. P.; Michailidou, Kyriaki; Dennis, Joe; Bolla, Manjeet K.; Wang, Qin; Van'T Veer, Laura J.; Cornelissen, Sten; et al. (Nature Communications, 2014)
Large population-based registry studies have shown that breast cancer prognosis is inherited. Here we analyse single-nucleotide polymorphisms (SNPs) of genes implicated in human immunology and inflammation as candidates for prognostic markers of breast cancer survival involving 1,804 oestrogen receptor (ER)-negative patients treated with chemotherapy (279 events) from 14 European studies in a prior large-scale genotyping experiment, which is part of the Collaborative Oncological Gene-environment Study (COGS) initiative. We carry out replication using Asian COGS samples (n=522, 53 events) and the Prospective Study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) study (n=315, 108 events). Rs4458204_A near CCL20 (2q36.3) is found to be associated with breast cancer-specific death at a genome-wide significant level (n=2,641, 440 events, combined allelic hazard ratio (HR)=1.81 (1.49-2.19); P for trend=1.90 × 10(-9)). Such survival-associated variants can represent ideal targets for tailored therapeutics, and may also enhance our current prognostic prediction capabilities.
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43-jährige Patientin mit rezidivierend auffälligen PAP-Abstrichen - Dietl, Anna; Beckmann, Matthias; Gaß, Paul (Gynäkologe, 2020)
CRIS-Team Scopus Importer:2020-10-09
Keywords: Cervical cancer; Colposcopy; Human papillomavirus; Hysterectomy; Pembrolizumab

ABC5 International Consensus Conference on Advanced Breast Cancer, Lisbon, 16 November 2019 - Untch, Michael; Würstlein, Rachel; Lüftner, Diana; Haidinger, Renate; Fasching, Peter; Augustin, Doris; Briest, Susanne; Ettl, Johannes; Förster, Frank; Kurbacher, Christian M.; Lück, Hans Joachim; Marschner, Norbert; et al. (Geburtshilfe und Frauenheilkunde, 2020)
The Advanced Breast Cancer Fifth International Consensus Conference (ABC5) which focuses on the diagnosis and treatment of advanced breast cancer was held in Lisbon on November 14 - 16, 2019. The aim of the conference is to standardize the treatment of advanced breast cancer worldwide using evidence-based data and to ensure that patients with advanced breast disease anywhere in the world are treated appropriately and have access to the latest therapies. This year, the emphasis was on new developments and study results from patients with advanced breast cancer as well as precision medicine. The collaboration with patient advocates from all over the globe is also an important goal of the ABC Conference, which is why the international ABC panel also included a number of patient advocates. We present a commentary on the voting results of the ABC5 panelists in Lisbon by a working group of German breast cancer specialists together with the implications for routine clinical care in Germany. The commentary is based on the recommendations of the Breast Commission of the German Gynecological Oncology Working Group (AGO). This commentary is useful, it includes country-specific features for the ABC consensus.
CRIS-Team Scopus Importer:2020-07-24
Keywords: 2019 study data; ABC5 consensus; advanced breast cancer; precision medicine

ABC6 Consensus: Assessment by a Group of German Experts - Lueftner, Diana; Fasching, Peter; Haidinger, Renate; Harbeck, Nadia; Jackisch, Christian; Mueller, Volkmar; Schumacher-Wulf, Eva; Thomssen, Christoph; Untch, Michael; Wuerstlein, Rachel (Breast Care, 2022)
Background: The first International Consensus Conference for Advanced Breast Cancer (ABC1) took place 10 years ago in November 2011. The rationale was - and still is - to standardize treatment of advanced breast cancer (ABC) based on the available evidence and to ensure that worldwide all breast cancer patients receive adequate treatment and access to new therapies. Rationale for the Manuscript: The 6th International Consensus Conference for ABC (ABC6) took place from November 4 to 6, 2021 and was the first in a purely online format, due to the COVID-19 pandemic. In the present manuscript, a working group of German breast cancer experts comments on the voting results of the ABC6 panelists regarding their applicability for routine clinical practice in Germany. Method: The ABC6 votes mainly include modified or new statements. With regard to all statements not modified for the ABC6 consensus, the German experts refer to the published paper of the ABC5 consensus. The German experts base their comments on the current recommendations of the Breast Committee of the Gynecological Oncology Working Group (Arbeitsgemeinschaft Gynakologische Onkologie, AGO Mamma). Topics: ABC6 focused on new treatment options and their implications for clinical practice. Optimal therapy sequencing for example was one of the issues. To solve the challenge of a more individualized treatment, precision medicine is fundamental. Oligometastatic disease, brain metastases and adequate supportive and palliative care were also addressed. Of special interest was the treatment of inoperable locally advanced breast cancer, which was discussed as a separate topic. As in previous years, patient advocates from around the world were an integral part of the ABC6 conference and had a major input into the consensus.& nbsp;(c) 2022 S. Karger AG, Basel
CRIS-Team WoS Importer:2022-03-11

ABCA transporter gene expression and poor outcome in epithelial ovarian cancer - Hedditch, Ellen L.; Gao, Bo; Russell, Amanda J.; Lu, Yi; Emmanuel, Catherine; Beesley, Jonathan; Johnatty, Sharon E.; Chen, Xiaoqing; Harnett, Paul; George, Joshy; Williams, Rebekka T.; Flemming, Claudia; et al. (Journal of the National Cancer Institute, 2014)
ATP-binding cassette (ABC) transporters play various roles in cancer biology and drug resistance, but their association with outcomes in serous epithelial ovarian cancer (EOC) is unknown.The relationship between clinical outcomes and ABC transporter gene expression in two independent cohorts of high-grade serous EOC tumors was assessed with real-time quantitative polymerase chain reaction, analysis of expression microarray data, and immunohistochemistry. Associations between clinical outcomes and ABCA transporter gene single nucleotide polymorphisms were tested in a genome-wide association study. Impact of short interfering RNA-mediated gene suppression was determined by colony forming and migration assays. Association with survival was assessed with Kaplan-Meier analysis and log-rank tests. All statistical tests were two-sided.Associations with outcome were observed with ABC transporters of the "A" subfamily, but not with multidrug transporters. High-level expression of ABCA1, ABCA6, ABCA8, and ABCA9 in primary tumors was statistically significantly associated with reduced survival in serous ovarian cancer patients. Low levels of ABCA5 and the C-allele of rs536009 were associated with shorter overall survival (hazard ratio for death = 1.50; 95% confidence interval [CI] =1.26 to 1.79; P = 6.5e-6). The combined expression pattern of ABCA1, ABCA5, and either ABCA8 or ABCA9 was associated with particularly poor outcome (mean overall survival in group with adverse ABCA1, ABCA5 and ABCA9 gene expression = 33.2 months, 95% CI = 26.4 to 40.1; vs 55.3 months in the group with favorable ABCA gene expression, 95% CI = 49.8 to 60.8; P = .001), independently of tumor stage or surgical debulking status. Suppression of cholesterol transporter ABCA1 inhibited ovarian cancer cell growth and migration in vitro, and statin treatment reduced ovarian cancer cell migration.Expression of ABCA transporters was associated with poor outcome in serous ovarian cancer, implicating lipid trafficking as a potentially important process in EOC.
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ABEMACARE: Abemaciclib in combination with endocrine therapy as first line therapy in metastatic breast cancer patients with symptomatic visceral metastases or high tumor burden - Kotzur, Franziska; Bidner, Helen; Bronger, Holger; Egert, Silvia; Fasching, Peter; Fischer, Dorothea; Kehl, Victoria; Luck, Hans-Joachim; Muller, Lothar; Reuning, Ute; Rief, Lukas; Rosch, Romina; et al. (CANCER RESEARCH, 2021)
CRIS-Team WoS Importer:2021-03-26

Abklärungs- und Versorgungsalgorithmen für das Zervixkarzinom - Beckmann, Matthias (Onkologe, 2020)
CRIS-Team Scopus Importer:2020-06-26

A careful reassessment of anthracycline use in curable breast cancer - Hurvitz, Sara Alsterlind; Mcandrew, Nicholas P.; Bardia, Aditya; Press, Michael F.; Pegram, Mark; Crown, John P.; Fasching, Peter; Ejlertsen, Bent; Yang, Eric H.; Glaspy, John A.; Slamon, Dennis J. (npj Breast Cancer, 2021)
It has been over three decades since anthracyclines took their place as the standard chemotherapy backbone for breast cancer in the curative setting. Though the efficacy of anthracycline chemotherapy is not debatable, potentially life-threatening and long-term risks accompany this class of agents, leading some to question their widespread use, especially when newer agents with improved therapeutic indices have become available. Critically assessing when to incorporate an anthracycline is made more relevant in an era where molecular classification is enabling not only the development of biologically targeted therapeutics but also is improving the ability to better select those who would benefit from cytotoxic agents. This comprehensive analysis will present the problem of overtreatment in early-stage breast cancer, review evidence supporting the use of anthracyclines in the pre-taxane era, analyze comparative trials evaluating taxanes with or without anthracyclines in biologically unselected and selected patient populations, and explore published work aimed at defining anthracycline-sensitive tumor types.
CRIS-Team Scopus Importer:2021-10-22

Accelerated Partial Breast Irradiation: Identification of High Risk Tumors in Early Hormone Receptor-positive Breast Cancer by Macrophage Shift Classification - Schnellhardt, S.; Erber, Ramona; Büttner-Herold, Maike; Rosahl, M. -C; Ott, Oliver; Strnad, Vratislav; Beckmann, Matthias; King, L.; Hartmann, Arndt; Fietkau, Rainer; Distel, Luitpold (STRAHLENTHERAPIE UND ONKOLOGIE, 2020)
CRIS-Team WoS Importer:2020-10-02

Accelerated partial breast irradiation: Macrophage polarisation shift classification identifies high-risk tumours in early hormone receptor-positive breast cancer - Schnellhardt, Sören; Erber, Ramona; Büttner-Herold, Maike; Rosahl, Marie Charlotte; Ott, Oliver; Strnad, Vratislav; Beckmann, Matthias; King, Lillian; Hartmann, Arndt; Fietkau, Rainer; Distel, Luitpold (Cancers, 2020)
Studies have demonstrated correlations between accumulations of tumour-associated macrophages (TAMs), especially of M2-like phenotype, and increased mortality in advanced breast cancer. We investigated the prognostic potential of both main macrophage phenotypes in early hormone receptor-positive (HR+) breast cancer. The studied cohort of 136 patients participated in an institutional APBI phase II trial. Patient selection was characterized by HR+, small tumour size and no metastasis. Tissue microarrays from pre-RT resection samples were double stained for CD68/CD163 using immunohistochemistry. CD68+/CD163− cells were considered M1-like macrophages and CD68+/CD163+ was representative of M2-like macrophages. M1 and M2 macrophage densities were analysed semi-automatically in the stromal and intraepithelial tumour compartment. Low M1 and high M2 densities were strongly associated with decreased disease-free survival (DFS). Combined TAM phenotype densities were studied after defining a macrophage shift classification: M1-shifted (M1 high, M2 low) and non-shifted (M1 low, M2 low; M1 high, M2 high) tumours entailed a favourable outcome. In contrast, M2-shifted (M1 low, M2 high) TAM populations were associated with extremely reduced DFS. Thus, the full predictive potential of TAMs was revealed in a combined analysis of both phenotypes. The M2-shifted subgroup of tumours is classified as high-risk and probably not suitable for partial breast irradiation.
CRIS-Team Scopus Importer:2020-02-25
Keywords: Accelerated partial breast irradiation; CD163; CD68; Early breast cancer; Hormone receptor-positive; Prognosis; Tumour associated macrophages

Accelerated partial breast irradiation with external beam radiotherapy : First results of the German phase 2 trial - Ott, Oliver J.; Strnad, Vratislav; Stillkrieg, Wilhelm; Uter, Wolfgang; Beckmann, Matthias; Fietkau, Rainer (Strahlentherapie und Onkologie, 2017)
BACKGROUND AND PURPOSE: To evaluate the feasibility and efficacy of external beam three-dimensional (3D) conformal accelerated partial breast irradiation (APBI) for selected patients with early breast cancer. PATIENTS AND METHODS: Between 2011 and 2016, 72 patients were recruited for this prospective phase 2 trial. Patients were eligible for APBI if they had histologically confirmed breast cancer or pure ductal carcinoma in situ (DCIS), a tumor diameter ≤3 cm, clear resection margins ≥2 mm, no axillary lymph node involvement, no distant metastases, tumor bed clips, and were aged ≥50 years. Patients were excluded if mammography showed a multicentric invasive growth pattern, or if they had residual diffuse microcalcifications postoperatively, an extensive intraductal component, or vessel invasion. Patients received 3D conformal external beam APBI with a total dose of 38 Gy in 10 fractions in 1-2 weeks. The trial had been registered at the German Clinical Trials Register, DRKS-ID: DRKS00004417. RESULTS: Median follow-up was 25.5 months (range 1-61 months). Local control was maintained in 71 of 72 patients. The 3‑year local recurrence rate was 2.1% (95% confidence interval, CI: 0-6.1%). Early toxicity (grade 1 radiodermatitis) was seen in 34.7% (25/72). Late side effects ≥ grade 3 did not occur. Cosmetic results were rated as excellent/good in 96.7% (59/61). CONCLUSION: APBI with external beam radiotherapy techniques is feasible with low toxicity and, according to the results of the present and other studies, on the way to becoming a standard treatment option for a selected subgroup of patients.
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Accelerated partial breast irradiation with external beam radiotherapy: results of the German phase 2-trial - Ott, O. J.; Strnad, Vratislav; Sillkrieg, W.; Uter, Wolfgang; Beckmann, Matthias; Fietkau, Rainer (STRAHLENTHERAPIE UND ONKOLOGIE, 2019)
CRIS-Team WoS Importer:2019-06-07

Accuracy of colposcopic findings in detecting vaginal intraepithelial neoplasia: a retrospective study - Stuebs, F. A.; Adler, W.; Beckmann, Matthias; Gaß, Paul; Hartmann, Arndt; Mehlhorn, G.; Renner, S. K.; Schulmeyer, Carla; Strehl, J.; Koch, Matthias (GEBURTSHILFE UND FRAUENHEILKUNDE, 2020)
CRIS-Team WoS Importer:2020-10-30

Accuracy of colposcopic findings in detecting vaginal intraepithelial neoplasia: a retrospective study - Stuebs, Frederik A.; Koch, Martin; Mehlhorn, Grit; Gaß, Paul; Schulmeyer, Carla; Hartmann, Arndt; Strehl, Johanna; Adler, Werner; Beckmann, Matthias; Renner, Stefan (Archives of Gynecology and Obstetrics, 2020)
Purpose: Malignancies of the vagina are rare, but colposcopy-directed biopsies play a major role in detecting vaginal intraepithelial lesions. Data of accuracy in detecting neoplasia of the vagina are very rare compared to accuracy in detecting cervical neoplasia. The aim of this study was to evaluate the accuracy of colposcopy-directed biopsy in comparison with clinical findings of the examiner. Methods: The accuracy of colposcopy-directed biopsy was compared with the clinical finding in relation to the patient’s age and the examiner’s level of training. This was done in combination with PAP-smear, HPV-test results, and the history of other malignancies of the lower genital tract. The data were collected between January 2014 and February 2018 at the certified Dysplasia Unit of the University Hospital Erlangen. Results: In total, 253 biopsies from 253 women from the vagina were obtained. The overall accuracy of biopsy in comparison with clinical finding was 52.17% for all entities—benign lesions, low-grade squamous intraepithelial lesions (LSILs), high-grade squamous intraepithelial lesions (HSILs), and vaginal carcinoma. The accuracy for detecting HSIL was 82.46% (47/57), with an underdiagnosis rate of 15.79% and an overdiagnosis rate of 1.79%. Conclusion: With a sensitivity of over 80%, colposcopy-directed biopsy plays an important role in detecting vaginal–HSIL. A highly experienced practitioner is increasing the sensitivity in detecting vaginal–HSIL. Careful examination is required in women with a history of HSIL of the lower genital tract or with simultaneous neoplasia because they are of greater risk of developing vaginal malignancies. The combination of careful clinical work up, PAP-smear, HPV-testing, and colposcopy-guided biopsy is crucial in detecting vaginal–HSIL.
CRIS-Team Scopus Importer:2020-02-04
Keywords: Colposcopy-directed biopsy; High-grade squamous intraepithelial lesion (HSIL); Vaginal cancer; Vaginal intraepithelial neoplasia (VaIN)

Accuracy of colposcopy-directed biopsy in detecting early cervical neoplasia: a retrospective study - Stuebs, Frederik A.; Schulmeyer, Carla E.; Mehlhorn, Grit; Gaß, Paul; Kehl, Sven; Renner, Simone K.; Renner, Stefan; Geppert, Carol-Immanuel; Adler, Werner; Hartmann, Arndt; Beckmann, Matthias; Koch, Martin (Archives of Gynecology and Obstetrics, 2019)
PurposeColposcopy-directed biopsy is a cornerstone method for diagnosing cervical intraepithelial neoplasia. The aim of this study was to evaluate the accuracy of colposcopy-directed biopsy in comparison with definitive surgery.MethodsThe accuracy of colposcopy-directed biopsy was compared with the final histology in relation to different types of transformation zone (TZ), the patient's age, and the examiner's level of training.ResultsThe overall accuracy of biopsy in comparison with definitive surgery was 71.9% for all entitiesbenign lesions, low-grade squamous intraepithelial lesions, high-grade squamous intraepithelial lesions (HSILs), and cervical carcinomawith an underdiagnosis rate of 11.8% and an overdiagnosis rate of 16.5%. The accuracy for detecting HSIL was 88% (401/455), with an underdiagnosis rate of 10.5% and overdiagnosis rate of 1.3%. The accuracy rates for detecting HSIL in women with TZ1, TZ2, or TZ3 were 92.2, 90.5, and 76.5%, respectively. The accuracy rates for detecting HSIL in the different age groups were 93.1% (age 0-34), 83.6% (age 34-55), and 80% (age 55 or older).ConclusionsA combination of the colposcopic findings, cytology, human papillomavirus testing, and colposcopy-directed biopsy is necessary for the correct diagnosis of HSIL. The accuracy rate depends on the TZ and the patient's age. The examiner's level of training does not have any substantial influence on the accuracy.
CRIS-Team WoS Importer:2019-03-08

Accuracy of radiological tumour size assessment and the risk for re-excision in a cohort of primary breast cancer patients - Meier-Meitinger, Martina; Rauh, Claudia; Adamietz, B.; Fasching, Peter; Schwab, Siegfried; Häberle, Lothar; Hein, Alexander; Bayer, Christian M.; Bani, Mayada; Lux, Michael P.; Hartmann, Arndt; Wachter, David Lukas; et al. (Ejso, 2012)
Background: Re-operations after breast conserving surgery (BCS) are necessary, when specimen margins are not free of breast cancer cells. This study explored the accuracy of preoperative tumour size assessment and its influence on the rate of re-excisions and mastectomies. Methods: The study included 1591 patients with invasive breast cancer, who were planned for BCS. Patient, staging and tumor characteristics were evaluated concerning their influence on re-excision and mastectomy rates. Patient and tumor characteristics comprised histopathological tumour size, HER2 status, multifocality, in situ component, grading (G), nodal status and hormone receptor (HR) status. Staging characteristics included deviation from pathological tumour size as measured by clinical examination, sonography and mammography. Results: In 1316 patients (83%) sufficient treatment was possible with one operation. 275 patients (17%) had to undergo at least one further surgery as a result of positive specimen margins. In 138 patients (9%) mastectomy was ultimately necessary. In patients with a positive HER2 status, a larger tumour size, underestimation by ultrasound, an in situ component and multifocality, the risk for a re-operation was about doubled. Tumour size deviation in the mammogram or the clinical tumour size assessment did not have significant influence to the re-excision rates. Conclusion: Tumour size and accurate presurgical assessment of the tumour size itself are independent predictors for the need of a second surgery or even a mastectomy in patients for whom a primary BCS was planned. © 2011 Elsevier Ltd. All rights reserved.
CRIS-Team Scopus Importer:2021-07-19
Keywords: Breast cancer; Mastectomy; Re-excision; Tumour size; Ultrasound

Accuracy of sonographic fetal weight estimation: influence of the scan-to-delivery interval in combination with the applied weight estimation formula - Faschingbauer, Florian; Raabe, E.; Heimrich, J.; Faschingbauer, Cornelia; Schmid, M.; Mayr, Andreas; Schild, R. L.; Beckmann, Matthias; Kehl, Sven (Archives of Gynecology and Obstetrics, 2016)
To evaluate the influence of the time interval between examination and delivery on the accuracy of sonographic fetal weight estimation (WE).8723 singleton pregnancies were included in this retrospective cohort study. Fetuses were divided into eight groups with regard to the time interval between estimation and delivery (group 1: 0 days; group 2: 1-3 days; group 3: 4-7 days; group 4: 8-14 days; group 5: 15-21 days; group 6: 22-28 days; group 7: 29-35 days; group 8: 36-42 days). The accuracy of WE was compared between the different time interval groups and five commonly used formulas using means of percentage errors (MPE), medians of absolute percentage errors, and proportions of estimates within 10 % of actual birth weight.In group one, the Hadlock I and Warsof formula showed a systematic underestimation of fetal weight (negative MPEs). No systematic error was found with the Hadlock II formula and the equations of Merz and Shepard showed a systematic overestimation (positive MPEs). MPE values of the Hadlock I, II and Warsof formulas were closest to zero in WEs of group two. From group three to six, MPE values decreased continuously. With the Merz and Shepard equations MPEs were closest to zero in group four.The best accuracy of sonographic WE with most of the commonly used equations is achieved within a scan-to-delivery interval of 1 week.
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Accuracy of vulvoscopic findings in detecting early vulvar neoplasia - Stuebs, F. A.; Mehlhorn, G.; Gaß, Paul; Schulmeyer, Carla; Adler, Werner; Strehl, J.; Hartmann, Arndt; Beckmann, Matthias; Renner, S. K.; Koch, Matthias (GEBURTSHILFE UND FRAUENHEILKUNDE, 2020)
CRIS-Team WoS Importer:2020-10-30

A comprehensive evaluation of interaction between genetic variants and use of menopausal hormone therapy on mammographic density - Rudolph, Anja; Fasching, Peter; Behrens, Sabine; Eilber, Ursula; Bolla, Manjeet K.; Wang, Qin; Thompson, Deborah; Czene, Kamila; Brand, Judith S.; Li, Jingmei; Scott, Christopher; Pankratz, V. Shane; et al. (Breast Cancer Research, 2015)
Mammographic density is an established breast cancer risk factor with a strong genetic component and can be increased in women using menopausal hormone therapy (MHT). Here, we aimed to identify genetic variants that may modify the association between MHT use and mammographic density.The study comprised 6,298 postmenopausal women from the Mayo Mammography Health Study and nine studies included in the Breast Cancer Association Consortium. We selected for evaluation 1327 single nucleotide polymorphisms (SNPs) showing the lowest P-values for interaction (P int) in a meta-analysis of genome-wide gene-environment interaction studies with MHT use on risk of breast cancer, 2541 SNPs in candidate genes (AKR1C4, CYP1A1-CYP1A2, CYP1B1, ESR2, PPARG, PRL, SULT1A1-SULT1A2 and TNF) and ten SNPs (AREG-rs10034692, PRDM6-rs186749, ESR1-rs12665607, ZNF365-rs10995190, 8p11.23-rs7816345, LSP1-rs3817198, IGF1-rs703556, 12q24-rs1265507, TMEM184B-rs7289126, and SGSM3-rs17001868) associated with mammographic density in genome-wide studies. We used multiple linear regression models adjusted for potential confounders to evaluate interactions between SNPs and current use of MHT on mammographic density.No significant interactions were identified after adjustment for multiple testing. The strongest SNP-MHT interaction (unadjusted P int <0.0004) was observed with rs9358531 6.5kb 5' of PRL. Furthermore, three SNPs in PLCG2 that had previously been shown to modify the association of MHT use with breast cancer risk were found to modify also the association of MHT use with mammographic density (unadjusted P int <0.002), but solely among cases (unadjusted P int SNP×MHT×case-status <0.02).The study identified potential interactions on mammographic density between current use of MHT and SNPs near PRL and in PLCG2, which require confirmation. Given the moderate size of the interactions observed, larger studies are needed to identify genetic modifiers of the association of MHT use with mammographic density.
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A content-based review of mobile health applications for breast cancer prevention and education: Characteristics, quality and functionality analysis - Altmannshofer, Stefanie; Flaucher, Madeleine; Beierlein, Milena; Eskofier, Björn; Beckmann, Matthias; Fasching, Peter; Hübner, Hanna (Digital Health, 2024)
Objective: Mobile Health apps could be a feasible and effective tool to raise awareness for breast cancer prevention and to support women to change their behaviour to a healthier lifestyle. The aim of this study was to analyse the characteristics and quality of apps designed for breast cancer prevention and education. Methods: We conducted a systematic search for apps covering breast cancer prevention topics in the Google Play and Apple App Store accessible from Germany using search terms either in German or in English. Only apps with a last update after June 2020 were included. The apps identified were downloaded and evaluated by two independent researchers. App quality was analysed using the Mobile Application Rating Scale (MARS). Associations of app characteristics and MARS rating were analysed. Results: We identified 19 apps available in the Google Play Store and seven apps available in the Apple App Store that met all inclusion criteria. The mean MARS score was 3.07 and 3.50, respectively. Functionality was the highest-scoring domain. Operating system, developer (healthcare), download rates and time since the last update were significantly associated with overall MARS score. In addition, the presence of the following app functions significantly influenced MARS rating: breast self-examination tutorial, reminder for self-examination, documentation feature and education about breast cancer risk factors. Conclusions: Although most of the apps offer important features for breast cancer prevention, none of the analysed apps combined all functions. The absence of healthcare professionals’ expertise in developing apps negatively affects the overall quality.
CRIS-Team Scopus Importer:2024-03-29
Keywords: Breast cancer; MARS; mHealth; mobile apps; prevention; quality; rating

A Cross-Sectional Multicenter Study of Multidimensional Body Image in Adolescents and Adults with Gender Dysphoria Before and After Transition-Related Medical Interventions - Becker, Inga; Auer, Matthias; Barkmann, Claus; Fuss, Johannes; Moeller, Birgit; Nieder, Timo O.; Fahrenkrug, Saskia; Hildebrandt, Thomas; Richter-Appelt, Hertha (Archives of Sexual Behavior, 2018)
Persistent feelings of gender dysphoria (GD) are accompanied by distress and body dissatisfaction in most clinically referred adolescents and adults. Transition-related medical interventions (e.g., puberty suppression, hormones, or surgery) may alleviate body dissatisfaction. The aim of the present cross-sectional study was to compare multidimensional body image across clinically referred adolescents and adults undergoing different transition-related medical interventions. Two clinical samples of adolescents (n = 82) and adults (n = 120) referred to specialized departments of four different transgender health services in Germany participated in the study. In total, 202 individuals from the female-to-male (FtM individuals) and male-to-female (MtF individuals) spectrum aged 14-74 years were included at different stages of their transition. Four scales assessing multidimensional aspects of body image (measured by the Body Image Assessment Questionnaire, FBeK) were compared across three groups: sample, gender, and medical interventions (while controlling for age and treatment duration). The results indicated less favorable body image scores compared with the norm in both adolescents and adults with GD. Individuals who had undergone transition-related medical interventions presented a significantly better body image on two of the four scales. Differences according to gender and age were also present. These findings suggest that medical interventions, especially gender-affirming hormones and surgery, are generally beneficial to the body image in individuals with GD. However, not all of the less favorable outcomes in multidimensional body image were positively influenced by the treatment conditions and may thus benefit from additional integrative counseling before and during transition.
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Active Participation, Mind–Body Stabilization, and Coping Strategies with Integrative Medicine in Breast Cancer Patients - Theuser, Anna-Katharin; Antoniadis, Sophia; Langemann, Hanna; Wasner, Sonja; Grasruck, Katharina; Dietzel-Drentwett, Svenja; Fasching, Peter; Beckmann, Matthias; Hack, Carolin (Integrative Cancer Therapies, 2021)
Purpose: Increasing numbers of breast cancer survivors have led to a growing demand for integrative medicine. When patients have completed treatments associated with severe side effects, attention turns to reducing psychological symptoms, coping behavior, and self-care. The aim of this study was to assess patient-reported benefits in relation to active participation, mind–body stabilization, and coping strategies in breast cancer patients receiving integrative medicine. Methods: In a cross-sectional study, health counseling and treatment provided by a standardized integrative medicine consultancy service at the University Breast Center of Franconia were evaluated in 75 breast cancer patients over a 15-month period. At the baseline, the patients answered a questionnaire on their medical history, symptoms, and the treatment goals they were hoping to achieve with integrative medicine. Patient-reported outcomes relative to active participation, mind–body stabilization, and coping strategies were analyzed. Results: A large majority of the patients had previous experience with integrative medicine (91%). Most reported that they achieved their treatment goals with integrative medicine. Ninety-one percent achieved active participation in cancer treatment, 90% mind–body stabilization, and 79% improvement in coping strategies. Besides active participation, which was greatest in patients with stable disease, the success of integrative therapy was independent of age, concomitant diseases, previous integrative medicine experience, treatment state, and systemic cancer therapy. Conclusion: Breast cancer patients benefit from the counseling and treatment provided with integrative medicine in mind–body stabilization and coping with cancer. Active participation in cancer treatment is important for the patients. Integrative treatment services should form part of routine patient care.
CRIS-Team Scopus Importer:2021-03-19
Keywords: active participation; breast cancer; complementary and alternative medicine; coping; integrative medicine; mind–body; oncology

Addition of triple negativity of breast cancer as an indicator for germline mutations in predisposing genes increases sensitivity of clinical selection criteria - Hoyer, Juliane; Vasileiou, Georgia; Uebe, Steffen; Wunderle, Marius; Kraus, Cornelia; Fasching, Peter; Thiel, Christian; Hartmann, Arndt; Beckmann, Matthias; Lux, Michael P.; Reis, André (BMC Cancer, 2018)
BACKGROUND: Breast cancer is the most common cancer in women. 12-15% of all tumors are triple-negative breast cancers (TNBC). So far, TNBC has been mainly associated with mutations in BRCA1. The presence of other predisposing genes seems likely since DNA damage repair is a complex process that involves several genes. Therefore we investigated if mutations in other genes are involved in cancer development and whether TNBC is an additional indicator of mutational status besides family history and age of onset. METHODS: We performed a germline panel-based screening of 10 high and low-moderate penetrance breast cancer susceptibility genes (BRCA1, BRCA2, ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D and TP53) in 229 consecutive individuals affected with TNBC unselected for age, family history or bilateral disease. Within this cohort we compared the number of mutation carriers fulfilling clinical selection criteria with the total number of carriers identified. RESULTS: Age at diagnosis ranged from 23 to 80 years with an average age of 50.2 years. In 57 women (24.9%) we detected a pathogenic mutation, with a higher frequency (29.7%) in the group manifesting cancer before 60 years. Deleterious BRCA1 mutations occurred in 14.8% of TNBC patients. These were predominantly recurrent frameshift mutations (24/34, 70.6%). Deleterious BRCA2 mutations occurred in 5.7% of patients, all but one (c.1813dupA) being unique. While no mutations were found in CDH1 and TP53, 10 mutations were detected in one of the six other predisposition genes. Remarkably, neither of the ATM, RAD51D, CHEK2 and PALB2 mutation carriers had a family history. Furthermore, patients with non-BRCA1/2 mutations were not significantly younger than mutation negative women (p = 0.3341). Most importantly, among the 57 mutation carriers, ten (17.5%) would be missed using current clinical testing criteria including five (8%) with BRCA1/2 mutations. CONCLUSIONS: In summary, our data confirm and expand previous studies of a high frequency of germline mutations in genes associated with ineffective repair of DNA damage in women with TNBCs. Neither age of onset, contralateral disease nor family history were able to discern all mutation positive individuals. Therefore, TNBC should be considered as an additional criterion for panel based genetic testing.
EVALuna2:34811

A diet rich in Mailllard reaction products protects LDL against copper induced oxidation ex vivo, a human intervention trial - Dittrich, Ralf; Dragonas, Charalampos; Kannenkeril, D.; Hoffmann, Inge; Müller, Andreas; Beckmann, Matthias; Pischetsrieder, Monika (Food Research International, 2009)
Maillard reaction products (MRPs) have antioxidative properties in vitro but the influence of a diet rich in MRPs on oxidative damage in vivo remains unknown. In this study, the influence of thermally processed foods rich in MRPs on copper induced oxidation of human low-density lipoprotein (LDL) in vitro was examined. Moreover, oxidative resistance of LDL (OR) in blood plasma of eight healthy subjects was monitored, who consumed diets poor and rich in MRPs in weekly turn for 3 weeks. Dark beer, bread crust, and roasted coffee led to a statisticaIly significant increased OR in vitro compared to pale beer, bread crumb, and raw coffee. The consumption of a diet rich in MRPS significantly increased plasma OR compared to the diet poor in MRPs by 35.5%. This study indicates that thermally processed foods rich in MRPs inhibit the LDL oxidation in vitro and have the ability to reduce oxidative modification of LDL in vivo.
UnivIS-Import:2015-04-14:Pub.2009.nat.dchph.llmch.adietr
Keywords: Beer; Coffee; Diet; LDL oxidation; Maillard reaction products

Adjuvant radiotherapy and local recurrence in vulvar cancer – a subset analysis of the AGO-CaRE-1 study - Woelber, Linn; Prieske, Katharina; Eulenburg, Christine zu; Corradini, Stefanie; Petersen, Cordula; Bommert, Mareike; Blankenstein, Thomas; Hilpert, Felix; de Gregorio, Nikolaus; Iborra, Severine; Sehouli, Jalid; Ignatov, Atanas; et al. (Gynecologic Oncology, 2021)
Background: The impact of adjuvant radiotherapy (RT) to the vulva with regard to prognosis and local recurrence in patients with vulvar squamous cell cancer (VSCC) is poorly described. Patients and methods: In the AGO-CaRE-1 study 1618 patients with primary VSCC FIGO stage ≥ IB, treated between 1998-2008, were documented. In this retrospective subanalysis, 360 patients were included based on the following criteria: nodal involvement (pN+), known RT treatment and known radiation fields. Results: The majority had pT1b/pT2 tumors (n=299; 83.1%). In 76.7%, R0 resection was achieved. 57/360 (15.8%) N+ patients were treated with adjuvant RT to the groins/pelvis and 146/360 (40.5%) received adjuvant RT to the vulva and groins/pelvis. 157/360 (43.6%) patients did not receive any adjuvant RT. HPV status was available in 162/360 patients (45.0%), 75/162 tumors were HPV+(46.3%), 87/162 (53.7%) HPV-. During a median follow-up of 17.2 months, recurrence at the vulva only occurred in 25.5% of patients without adjuvant RT, in 22.8% of patients with adjuvant RT to groins/pelvis and in 15.8% of patients with adjuvant RT to the vulva and groins/pelvis respectively. The risk reducing effect of local RT was independent of the resection margin status. 50% disease free survival time (50% DFST) indicated a stronger impact of adjuvant RT to the vulva in HPV+ compared to HPV- patients (50% DFST 20.7 months vs. 17.8 months). Conclusion: Adjuvant RT to the vulva was associated with a lower risk for local recurrence in N+ VSCC independent of the resection margin status. This observation was more pronounced in patients with HPV+ tumors in comparison to HPV– tumors.
CRIS-Team Scopus Importer:2021-11-26
Keywords: Adjuvant radiotherapy; HPV; Local recurrence; Prognosis; Vulvar cancer

ADSCs and adipocytes are the main producers in the autotaxin-lysophosphatidic acid axis of breast cancer and healthy mammary tissue in vitro - Schmid, Rafael; Wolf, Katharina; Robering, Jan Willem; Strauss, Selina; Strissel, Pamela; Strick, Reiner; Rübner, Matthias; Fasching, Peter; Horch, Raymund E.; Kremer, Andreas; Boos, Anja; Weigand, Annika (BMC Cancer, 2018)
BACKGROUND: Breast cancer is the most common malignancy in women affecting one out of eight females throughout their lives. Autotaxin (ATX) is upregulated in breast cancer which results in increased lysophosphatidic acid (LPA) formation within the tumor. This study's aim was to identify the role of different mammary cell populations within the ATX-LPA axis. METHODS: Epithelial-cell-adhesion-molecule-positive (EpCAM) and -negative cells from breast tumors, adipose-derived stem cells (ADSCs) of tumor-adjacent and tumor-distant mammary fat were isolated and compared to healthy ADSCs, mammary epithelial cells (HMECs), and mesenchymal cells (MES) of healthy mammary tissue (n = 4 each) and further to well-established breast (cancer) cell lines. RESULTS: mRNA expression analyses revealed that ADSCs and MES largely expressed LPA receptor 1 (LPAR1) while epithelial cells mainly expressed LPAR6. LPA 18:1 activated all the cell populations and cell lines by rise in cytosolic free calcium concentrations. MES and ADSCs expressed ATX whereas epithelial cells did not. ADSCs revealed the highest expression in ATX with a significant decline after adipogenic differentiation in healthy ADSCs, whereas ATX expression increased in ADSCs from tumor patients. Breast (cancer) cell lines did not express ATX. Transmigration of MES was stimulated by LPA whereas an inhibitory effect was observed in epithelial cells with no differences between tumors and healthy cells. Triple-negative breast cancer (TNBC) cell lines were also stimulated and the transmigration partly inhibited using the LPA receptor antagonist Ki16425. CONCLUSIONS: We here show that each mammary cell population plays a different role in the ATX-LPA axis with ADSCs and adipocytes being the main source of ATX in tumor patients in our experimental setting. Inhibitors of this axis may therefore present a valuable target for pharmacological therapies.
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Adult body mass index and risk of ovarian cancer by subtype: a Mendelian randomization study - Dixon, Suzanne C.; Nagle, Christina M.; Thrift, Aaron P.; Pharoah, Paul D. P.; Pearce, Celeste Leigh; Zheng, Wei; Painter, Jodie N.; Chenevix-Trench, Georgia; Fasching, Peter; Beckmann, Matthias; Lambrechts, Diether; Vergote, Ignace; et al. (International Journal of Epidemiology, 2016)
BACKGROUND: Observational studies have reported a positive association between body mass index (BMI) and ovarian cancer risk. However, questions remain as to whether this represents a causal effect, or holds for all histological subtypes. The lack of association observed for serous cancers may, for instance, be due to disease-associated weight loss. Mendelian randomization (MR) uses genetic markers as proxies for risk factors to overcome limitations of observational studies. We used MR to elucidate the relationship between BMI and ovarian cancer, hypothesizing that genetically predicted BMI would be associated with increased risk of non-high grade serous ovarian cancers (non-HGSC) but not HGSC. METHODS: We pooled data from 39 studies (14 047 cases, 23 003 controls) in the Ovarian Cancer Association Consortium. We constructed a weighted genetic risk score (GRS, partial F-statistic = 172), summing alleles at 87 single nucleotide polymorphisms previously associated with BMI, weighting by their published strength of association with BMI. Applying two-stage predictor-substitution MR, we used logistic regression to estimate study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted BMI and risk, and pooled these using random-effects meta-analysis. RESULTS: Higher genetically predicted BMI was associated with increased risk of non-HGSC (pooled OR = 1.29, 95% CI 1.03-1.61 per 5 units BMI) but not HGSC (pooled OR = 1.06, 95% CI 0.88-1.27). Secondary analyses stratified by behaviour/subtype suggested that, consistent with observational data, the association was strongest for low-grade/borderline serous cancers (OR = 1.93, 95% CI 1.33-2.81). CONCLUSIONS: Our data suggest that higher BMI increases risk of non-HGSC, but not the more common and aggressive HGSC subtype, confirming the observational evidence.
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Adult height is associated with increased risk of ovarian cancer: a Mendelian randomisation study - Dixon-Suen, Suzanne C.; Nagle, Christina M.; Thrift, Aaron P.; Pharoah, Paul D. P.; Ewing, Ailith; Pearce, Celeste Leigh; Zheng, Wei; Chenevix-Trench, Georgia; Fasching, Peter; Beckmann, Matthias; Lambrechts, Diether; Vergote, Ignace; et al. (British Journal of Cancer, 2018)
BACKGROUND: Observational studies suggest greater height is associated with increased ovarian cancer risk, but cannot exclude bias and/or confounding as explanations for this. Mendelian randomisation (MR) can provide evidence which may be less prone to bias. METHODS: We pooled data from 39 Ovarian Cancer Association Consortium studies (16,395 cases; 23,003 controls). We applied two-stage predictor-substitution MR, using a weighted genetic risk score combining 609 single-nucleotide polymorphisms. Study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted height and risk were pooled using random-effects meta-analysis. RESULTS: Greater genetically predicted height was associated with increased ovarian cancer risk overall (pooled-OR (pOR) = 1.06; 95% CI: 1.01-1.11 per 5 cm increase in height), and separately for invasive (pOR = 1.06; 95% CI: 1.01-1.11) and borderline (pOR = 1.15; 95% CI: 1.02-1.29) tumours. CONCLUSIONS: Women with a genetic propensity to being taller have increased risk of ovarian cancer. This suggests genes influencing height are involved in pathways promoting ovarian carcinogenesis.
EVALuna2:209946

Age- and Tumor Subtype-Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers - Schmidt, Marjanka K.; Hogervorst, Frans; Van Hien, Richard; Cornelissen, Sten; Broeks, Annegien; Adank, Muriel A.; Meijers, Hanne; Waisfisz, Quinten; Hollestelle, Antoinette; Schutte, Mieke; Van Den Ouweland, Ans; Hooning, Maartje; et al. (Journal of Clinical Oncology, 2016)
PURPOSE: CHEK2*1100delC is a well-established breast cancer risk variant that is most prevalent in European populations; however, there are limited data on risk of breast cancer by age and tumor subtype, which limits its usefulness in breast cancer risk prediction. We aimed to generate tumor subtype- and age-specific risk estimates by using data from the Breast Cancer Association Consortium, including 44,777 patients with breast cancer and 42,997 controls from 33 studies genotyped for CHEK2*1100delC. PATIENTS AND METHODS: CHEK2*1100delC genotyping was mostly done by a custom Taqman assay. Breast cancer odds ratios (ORs) for CHEK2*1100delC carriers versus noncarriers were estimated by using logistic regression and adjusted for study (categorical) and age. Main analyses included patients with invasive breast cancer from population- and hospital-based studies. RESULTS: Proportions of heterozygous CHEK2*1100delC carriers in controls, in patients with breast cancer from population- and hospital-based studies, and in patients with breast cancer from familial- and clinical genetics center-based studies were 0.5%, 1.3%, and 3.0%, respectively. The estimated OR for invasive breast cancer was 2.26 (95%CI, 1.90 to 2.69; P = 2.3 × 10(-20)). The OR was higher for estrogen receptor (ER)-positive disease (2.55 [95%CI, 2.10 to 3.10; P = 4.9 × 10(-21)]) than it was for ER-negative disease (1.32 [95%CI, 0.93 to 1.88; P = .12]; P interaction = 9.9 × 10(-4)). The OR significantly declined with attained age for breast cancer overall (P = .001) and for ER-positive tumors (P = .001). Estimated cumulative risks for development of ER-positive and ER-negative tumors by age 80 in CHEK2*1100delC carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom. CONCLUSION: These CHEK2*1100delC breast cancer risk estimates provide a basis for incorporating CHEK2*1100delC into breast cancer risk prediction models and into guidelines for intensified screening and follow-up.
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A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry - Middha, Pooja; Wang, Xiaoliang; Behrens, Sabine; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Michailidou, Kyriaki; Ahearn, Thomas U.; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Aronson, Kristan J.; et al. (Breast Cancer Research, 2023)
BACKGROUND: Genome-wide studies of gene-environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer. METHODS: Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene-environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs. RESULTS: Assuming a 1 × 10-5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability < 15%, we identified two independent SNP-risk factor pairs: rs80018847(9p13)-LINGO2 and adult height in association with overall breast cancer risk (ORint = 0.94, 95% CI 0.92-0.96), and rs4770552(13q12)-SPATA13 and age at menarche for ER + breast cancer risk (ORint = 0.91, 95% CI 0.88-0.94). CONCLUSIONS: Overall, the contribution of G×E interactions to the heritability of breast cancer is very small. At the population level, multiplicative G×E interactions do not make an important contribution to risk prediction in breast cancer.
CRIS-Team Scopus Importer:2023-08-18
Keywords: Breast cancer; European ancestry; Gene-environment interactions; Genetic epidemiology

A genome-wide transcriptomic analysis of embryos fathered by obese males in a murine model of diet-induced obesity - Bernhardt, Laura; Dittrich, Marcus; El-Merahbi, Rabih; Saliba, Antoine-Emmanuel; Mueller, Tobias; Sumara, Grzegorz; Vogel, Joerg; Nichols-Burns, Stefanie; Mitchell, Megan; Haaf, Thomas; El Hajj, Nady (Scientific Reports, 2021)
Paternal obesity is known to have a negative impact on the male's reproductive health as well as the health of his offspring. Although epigenetic mechanisms have been implicated in the non-genetic transmission of acquired traits, the effect of paternal obesity on gene expression in the preimplantation embryo has not been fully studied. To this end, we investigated whether paternal obesity is associated with gene expression changes in eight-cell stage embryos fathered by males on a high-fat diet. We used single embryo RNA-seq to compare the gene expression profile of embryos generated by males on a high fat (HFD) versus control (CD) diet. This analysis revealed significant upregulation of the Samd4b and Gata6 gene in embryos in response to a paternal HFD. Furthermore, we could show a significant increase in expression of both Gata6 and Samd4b during differentiation of stromal vascular cells into mature adipocytes. These findings suggest that paternal obesity may induce changes in the male germ cells which are associated with the gene expression changes in the resulting preimplantation embryos.
CRIS-Team WoS Importer:2021-03-12

Age, treatment and prognosis of patients with squamous cell vulvar cancer (VSCC) - analysis of the AGO-CaRE-1 study - Prieske, Katharina; Woelber, Linn; Muallem, Mustafa Zelal; Eulenburg, Christine; Jueckstock, Julia Kathrin; Hilpert, Felix; de Gregorio, Nikolaus; Iborra, Severine; Ignatov, Atanas; Hillemanns, Peter; Fuerst, Sophie; Strauss, Hans Georg; et al. (Gynecologic Oncology, 2021)
Background: Despite an increasing incidence with simultaneous decreasing age of onset, vulvar squamous cell carcinoma (VSCC) is still a disease that mainly effects the elderly population. Data on the association of age with prognosis and treatment patterns in VSCC are sparse. Methods: This is an analysis of the AGO-CaRE-1 cohort. Patients with VSCC (FIGO stage ≥1B), treated at 29 cancer centers in Germany from 1998 to 2008, were included in a centralized database (n = 1618). In this subgroup analysis patients were analyzed according to age [<50 yrs. (n = 220), 50–69 yrs. (n = 506), ≥70 yrs. (n = 521)] with regard to treatment patterns and prognosis. Only patients with documented age, surgical groin staging and known nodal status were included (n = 1247). Median follow-up was 27.5 months. Results: At first diagnosis, women ≥70 yrs. presented with more advanced tumor stages (<0.001), larger tumor diameter (<0.001), poorer ECOG status (<0.001), more frequent HPV negative tumors (p = 0.03) as well as a higher rate of nodal involvement (<0.001). Disease recurrence occurred significantly more often in elderly patients (p = 0.001) and age as well as ECOG status, microscopic residual resection, tumor stage, grading, and (chemo)radiation were independent prognostic factors for death or recurrence in multivariate analysis. 2-year disease-free survival rates were 59.3% (≥70 yrs), 65.8% (50–69 yrs) and 81.1% (<50 yrs), respectively (p < 0.001). Conclusions: Older women with VSCC present with advanced tumor stages at first diagnosis and have an increased risk of recurrence as well as a decreased 2-year DFS in comparison to younger patients. Potential reasons could be self-awareness and/or more aggressive tumor biology due to HPV independent disease.
CRIS-Team Scopus Importer:2021-03-12
Keywords: Age; Elderly; HPV; Lichen sclerosus; TP53; Vulvar cancer

Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry - Mueller, Stefanie H.; Lai, Alvina G.; Valkovskaya, Maria; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Lush, Michael; Abu-Ful, Zomoruda; Ahearn, Thomas U.; Andrulis, Irene L.; Anton-Culver, Hoda; et al. (Genome Medicine, 2023)
Background: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. Methods: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes’ coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. Results: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 × 10−6) and AC058822.1 (P = 1.47 × 10−4), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C. Conclusions: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10−5), demonstrating the importance of diversifying study cohorts.
CRIS-Team Scopus Importer:2023-02-10
Keywords: Breast cancer susceptibility; Diverse ancestry; Gene regulation; Genome-wide association study; Rare variants

AGO Algorithms for the Treatment of Breast Cancer: Update 2021 AGO-Algorithmen zur Behandlung von Brustkrebs: Update 2021 - Schneeweiss, Andreas; Fasching, Peter; Fehm, Tanja; Gerber, Bernd; Jackisch, Christian; Loibl, Sibylle; Schmidt, Marcus; Stickeler, Elmar; Wockel, Achim; Janni, Wolfgang; Mueller, Volkmar (Geburtshilfe und Frauenheilkunde, 2021)
Therapy options shown in the algorithms are based on the current AGO recommendations, but cannot represent all evidence-based treatment options, since prior therapies, performance status, comorbidities, patient preference, etc. must be taken into account for the actual treatment choice. In individual cases, other evidence-based treatment options may also be appropriate and justified. Regardless of approval status, the algorithms only take into account drugs that were available in Germany at the time the algorithm was last updated. Here we present the 2021 update of AGO treatment algorithms for early and metastatic breast cancer, which are intended to intensify structured treatment decision by providing reproducible and evidence-based treatment paths and may be helpful for a broad treatment landscape.
CRIS-Team Scopus Importer:2021-11-05
Keywords: breast cancer guidelines; evidence-based treatment; therapy algorithms

AGO Recommendations for the Diagnosis and Treatment of Patients with Early Breast Cancer: Update 2019 - Ditsch, Nina; Untch, Michael; Thill, Marc; Müller, Volkmar; Janni, Wolfgang; Albert, Ute Susann; Bauerfeind, Ingo; Blohmer, Jens; Budach, Wilfried; Dall, Peter; Diel, Ingo; Fasching, Peter; et al. (Breast Care, 2019)
CRIS-Team Scopus Importer:2019-08-23
Keywords: Early breast cancer; Local therapy; Systemic therapy; Treatment recommendations

AGO Recommendations for the Diagnosis and Treatment of Patients with Early Breast Cancer: Update 2021 - Ditsch, Nina; Kolberg-Liedtke, Cornelia; Friedrich, Michael; Jackisch, Christian; Albert, Ute Susann; Banys-Paluchowski, Maggie; Bauerfeind, Ingo; Blohmer, Jens Uwe; Budach, Wilfried; Dall, Peter; Fallenberg, Eva M.; Fasching, Peter; et al. (Breast Care, 2021)
CRIS-Team Scopus Importer:2021-06-18

AGO Recommendations for the Diagnosis and Treatment of Patients with Early Breast Cancer: Update 2022. - Ditsch, Nina; Woecke, Achim; Untch, Michael; Jackisch, Christian; Albert, Ute-Susann; Banys-Paluchowski, Maggie; Bauerfeind, Ingo; Blohmer, Jens-Uwe; Budach, Wilfried; Dall, Peter; Fallenberg, Eva Maria; Fasching, Peter; et al. (Breast Care, 2022)
INTRODUCTION: The AGO (Arbeitsgemeinschaft Gynäkologische Onkologie, German Gynecological Oncology Group) Task Force on Diagnosis and Treatment of Breast Cancer as an interdisciplinary team consists of specialists from gynecological oncology, pathology, diagnostic radiology, medical oncology, and radiation oncology with a special focus on breast cancer. METHODS: The updated evidence-based treatment recommendation 2022 for early breast cancer (EBC) and metastatic breast cancer of the AGO Task Force has been released. RESULTS AND CONCLUSION: This paper captures the update of EBC.
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AGO Recommendations for the Diagnosis and Treatment of Patients with Locally Advanced and Metastatic Breast Cancer: Update 2019 - Thill, Marc; Jackisch, Christian; Janni, Wolfgang; Müller, Volkmar; Albert, Ute Susann; Bauerfeind, Ingo; Blohmer, Jens; Budach, Wilfried; Dall, Peter; Diel, Ingo; Fasching, Peter; Fehm, Tanja; et al. (Breast Care, 2019)
Every year the Breast Committee of the Arbeitsgemeinschaft Gynäkologische Onkologie (German Gynecological Oncology Group, AGO), a group of gynecological oncologists specialized in breast cancer and interdisciplinary members specialized in pathology, radiologic diagnostics, medical oncology, and radiation oncology, prepares and updates evidence-based recommendations for the diagnosis and treatment of patients with early and metastatic breast cancer. Every update is performed according to a documented rule-fixed algorithm, by thoroughly reviewing and scoring the recent publications for their scientific validity and clinical relevance. This current publication presents the 2019 update on the recommendations for metastatic breast cancer.
CRIS-Team Scopus Importer:2019-08-23
Keywords: AGO grades of recommendation; Bone health; Early and metastatic breast cancer; Locoregional recurrence; Oxford level of evidence; Therapy

AGO Recommendations for the Diagnosis and Treatment of Patients with Locally Advanced and Metastatic Breast Cancer: Update 2020. - Ditsch, Nina; Untch, Michael; Kolberg-Liedtke, Cornelia; Jackisch, Christian; Krug, David; Friedrich, Michael; Janni, Wolfgang; Mueller, Volkmar; Albert, Ute-Susann; Banys-Paluchowski, Malgorzata; Bauerfeind, Ingo; Blohmer, Jens-Uwe; et al. (Breast Care, 2020)
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AGO Recommendations for the Diagnosis and Treatment of Patients with Locally Advanced and Metastatic Breast Cancer: Update 2021 - Thill, Marc; Friedrich, Michael; Kolberg-Liedtke, Cornelia; Albert, Ute Susann; Banys-Paluchowski, Maggie; Bauerfeind, Ingo; Blohmer, Jens Uwe; Budach, Wilfried; Dall, Peter; Fallenberg, Eva M.; Fasching, Peter; Fehm, Tanja; et al. (Breast Care, 2021)
CRIS-Team Scopus Importer:2021-06-18

AGO Recommendations for the Diagnosis and Treatment of Patients with Locally Advanced and Metastatic Breast Cancer: Update 2022. - Thill, Marc; Lueftner, Diana; Kolberg-Liedtke, Cornelia; Albert, Ute-Susann; Banys-Paluchowski, Maggie; Bauerfeind, Ingo; Blohmer, Jens-Uwe; Budach, Wilfried; Dall, Peter; Fallenberg, Eva Maria; Fasching, Peter; Fehm, Tanja; et al. (Breast Care, 2022)
The Breast Committee of the Arbeitsgemeinschaft Gynäkologische Onkologie (German Gynecological Oncology Group, AGO) presents the 2022 update of the evidence-based recommendations for the diagnosis and treatment of patients with locally advanced and metastatic breast cancer.
EVALuna2:514465

AGO Recommendations for the Diagnosis and Treatment of Patients with Locally Advanced and Metastatic Breast Cancer: Update 2023. - Thill, Marc; Kolberg-Liedtke, Cornelia; Albert, Ute Susann; Banys-Paluchowski, Maggie; Bauerfeind, Ingo; Blohmer, Jens Uwe; Budach, Wilfried; Dall, Peter; Ditsch, Nina; Fallenberg, Eva Maria; Fasching, Peter; Fehm, Tanja; et al. (Breast Care, 2023)
The Breast Committee of the Arbeitsgemeinschaft Gynäkologische Onkologie (German Gynecological Oncology Group, AGO) presents the 2023 update of the evidence-based recommendations for the diagnosis and treatment of patients with locally advanced and metastatic breast cancer (mBC).
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AGO Recommendations for the Surgical Therapy of Breast Cancer: Update 2022 AGO-Empfehlungen zur operativen Therapie des Mammakarzinoms: Update 2022 - Banys-Paluchowski, Maggie; Thill, Marc; Kuhn, Thorsten; Ditsch, Nina; Heil, Jorg; Woeckel, Achim; Fallenberg, Eva; Friedrich, Michael; Kuemmel, Sherko; Mueller, Volkmar; Janni, Wolfgang; Albert, Ute-Susann; et al. (Geburtshilfe und Frauenheilkunde, 2022)
The recommendations of the AGO Breast Committee on the surgical therapy of breast cancer were last updated in March 2022 (www.ago-online.de). Since surgical therapy is one of several partial steps in the treatment of breast cancer, extensive diagnostic and oncological expertise of a breast surgeon and good interdisciplinary cooperation with diagnostic radiologists is of great importance. The most important changes concern localization techniques, resection margins, axillary management in the neoadjuvant setting and the evaluation of the meshes in reconstructive surgery. Based on meta-analyses of randomized studies, the level of recommendation of an intraoperative breast ultrasound for the localization of non-palpable lesions was elevated to ++. Thus, the technique is considered to be equivalent to wire localization, provided that it is a lesion which can be well represented by sonography, the surgeon has extensive experience in breast ultrasound and has access to a suitable ultrasound device during the operation. In invasive breast cancer, the aim is to reach negative resection margins (no tumor on ink), regardless of whether an extensive intraductal component is present or not. Oncoplastic operations can also replace a mastectomy in selected cases due to the large number of existing techniques, and are equivalent to segmental resection in terms of oncological safety at comparable rates of complications. Sentinel node excision is recommended for patients with cN0 status receiving neoadjuvant chemotherapy after completion of chemotherapy. Minimally invasive biopsy is recommended for initially suspect lymph nodes. After neoadjuvant chemotherapy, patients with initially 1-3 suspicious lymph nodes and a good response (ycN0) can receive the targeted axillary dissection and the axillary dissection as equivalent options.
CRIS-Team Scopus Importer:2022-11-04
Keywords: breast cancer; breast surgery; guidelines; neoadjuvant chemotherapy; surgical therapy

AGO Recommendations for the Surgical Therapy of the Axilla After Neoadjuvant Chemotherapy: 2021 Update - Friedrich, Michael; Kühn, Thorsten; Janni, Wolfgang; Müller, Volkmar; Banys-Pachulowski, Maggie; Kolberg-Liedtke, Cornelia; Jackisch, Christian; Krug, David; Albert, Ute Susann; Bauerfeind, Ingo; Blohmer, Jens; Budach, Wilfried; et al. (Geburtshilfe und Frauenheilkunde, 2021)
For many decades, the standard procedure to treat breast cancer included complete dissection of the axillary lymph nodes. The aim was to determine histological node status, which was then used as the basis for adjuvant therapy, and to ensure locoregional tumour control. In addition to the debate on how to optimise the therapeutic strategies of systemic treatment and radiotherapy, the current discussion focuses on improving surgical procedures to treat breast cancer. As neoadjuvant chemotherapy is becoming increasingly important, the surgical procedures used to treat breast cancer, whether they are breast surgery or axillary dissection, are changing. Based on the currently available data, carrying out SLNE prior to neoadjuvant chemotherapy is not recommended. In contrast, surgical axillary management after neoadjuvant chemotherapy is considered the procedure of choice for axillary staging and can range from SLNE to TAD and ALND. To reduce the rate of false negatives during surgical staging of the axilla in pN+ CNBstage before NACT and ycN0 after NACT, targeted axillary dissection (TAD), the removal of > 2 SLNs (SLNE, no untargeted axillary sampling), immunohistochemistry to detect isolated tumour cells and micro-metastases, and marking positive lymph nodes before NACT should be the standard approach. This most recent update on surgical axillary management describes the significance of isolated tumour cells and micro-metastasis after neoadjuvant chemotherapy and the clinical consequences of low volume residual disease diagnosed using SLNE and TAD and provides an overview of this year's AGO recommendations for surgical management of the axilla during primary surgery and in relation to neoadjuvant chemotherapy.
CRIS-Team Scopus Importer:2021-10-29
Keywords: breast cancer; neoadjuvant chemotherapy; sentinel LNE; targeted axillary dissection

AGR3 in breast cancer: prognostic impact and suitable serum-based biomarker for early cancer detection - Garczyk, Stefan; Von Stillfried, Saskia; Antonopoulos, Wiebke; Hartmann, Arndt; Schrauder, Michael G.; Fasching, Peter; Anzeneder, Tobias; Tannapfel, Andrea; Ergoenenc, Yavuz; Knuechel, Ruth; Rose, Michael; Dahl, Edgar (PLoS ONE, 2015)
Blood-based early detection of breast cancer has recently gained novel momentum, as liquid biopsy diagnostics is a fast emerging field. In this study, we aimed to identify secreted proteins which are up-regulated both in tumour tissue and serum samples of breast cancer patients compared to normal tissue and sera. Based on two independent tissue cohorts (n = 75 and n = 229) and one serum cohort (n = 80) of human breast cancer and healthy serum samples, we characterised AGR3 as a novel potential biomarker both for breast cancer prognosis and early breast cancer detection from blood. AGR3 expression in breast tumours is significantly associated with oestrogen receptor ? (P<0.001) and lower tumour grade (P<0.01). Interestingly, AGR3 protein expression correlates with unfavourable outcome in low (G1) and intermediate (G2) grade breast tumours (multivariate hazard ratio: 2.186, 95% CI: 1.008-4.740, P<0.05) indicating an independent prognostic impact. In sera analysed by ELISA technique, AGR3 protein concentration was significantly (P<0.001) elevated in samples from breast cancer patients (n = 40, mainly low stage tumours) compared to healthy controls (n = 40). To develop a suitable biomarker panel for early breast cancer detection, we measured AGR2 protein in human serum samples in parallel. The combined AGR3/AGR2 biomarker panel achieved a sensitivity of 64.5% and a specificity of 89.5% as shown by receiver operating characteristic (ROC) curve statistics. Thus our data clearly show the potential usability of AGR3 and AGR2 as biomarkers for blood-based early detection of human breast cancer.
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A hybrid method towards automated nipple detection in 3D breast ultrasound images - Wang, Lei; Böhler, Tobias; Zöhrer, Fabian; Georgii, Joachim; Rauh, Claudia; Fasching, Peter; Brehm, Barbara; Schulz-Wendtland, Rüdiger; Beckmann, Matthias; Uder, Michael; Hahn, Horst K. (Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS, 2014)
In clinical work-up of breast cancer, nipple position is an important marker to locate lesions. Moreover, it serves as an effective landmark to register a 3D automated breast ultrasound (ABUS) images to other imaging modalities, e.g., X-ray mammography, tomosynthesis or magnetic resonance imaging (MRI). However, the presence of speckle noises caused by the interference waves and variant imaging directions poses challenges to automatically identify nipple positions. In this work, a hybrid fully automatic method to detect nipple positions in ABUS images is presented. The method extends the multi-scale Laplacian-based method that we proposed previously, by integrating a specially designed Hessian-based method to locate the shadow area beneath the nipple and areola. Subsequently, the likelihood maps of nipple positions generated by both methods are combined to build a joint-likelihood map, where the final nipple position is extracted. To validate the efficiency and robustness, the extended hybrid method was tested on 926 ABUS images, resulting in a distance error of 7.08±10.96 mm (mean±standard deviation).
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Akt and p53 are potential mediators of reduced mammary tumor growth by Chloroquine and the mTOR inhibitor RAD001 - Löhberg, Christian; Strissel, Pamela; Dittrich, Ralf; Strick, Reiner; Dittmer, Jürgen; Dittmer, Angela; Fabry, Ben; Kalender, Willi Alfred; Koch, Thorsten; Wachter, David; Groh, Nicole; Polier, Astrid; et al. (Biochemical Pharmacology, 2012)

Aktuelle Strategien zur Systemtherapie des frühen Mammakarzinoms von der 18. Internationalen St.-Gallen-Konsensuskonferenz - Lüftner, Diana; Banys-Paluchowski, Maggie; Ditsch, Nina; Fasching, Peter; Jackisch, Christian; Janni, Wolfgang; Krug, David; Untch, Michael; Harbeck, Nadia; Huober, Jens (Die Onkologie, 2023)
Background: For more than 30 years, The St. Gallen (SG) International Consensus Conference on the treatment of patients with primary breast cancer (SGBCC) has been taking place regularly. As the St. Gallen consensus panel consists of experts from different countries and disciplines, the votes represent an international cross-section of opinions Rationale: From the German perspective it is considered useful to discuss the results of the votes with respect to the clinical routine in Germany Basis: The discussion is related to the German guidelines of the ‚Arbeitsgemeinschaft Gynäkologische Onkologie‘ (AGO Organkommission Mamma, Version 2023.1D) which is updated every year, most recently in March 2023. Results: This year’s 18th SGBCC focused on practice-oriented issues. The individual disease situation and benefit-risk assessment were mainly based on patient cases and put in the context of current data. Here, we discuss the most important voting results on systemic therapy with a focus on endocrine therapy plus CDK4/6 inhibition, immunotherapy and PARP inhibition together with germline BRCA testing.
CRIS-Team Scopus Importer:2023-11-17
Keywords: (neo)adjuvant systemic treatment; Early breast cancer; Endocrine-based therapy; Immunotherapy; St. Gallen Consensus 2023

Aktuelles zum gesetzlichen Früherkennungsprogramm des Zervixkarzinoms in Deutschland - Behrens, Annika; Beckmann, Matthias; Stübs, Frederik (gynäkologische praxis, 2023)
The statutory cancer screening program (GKFP) covers regulations for early detection and screening of cancer for men and women in Germany. Costs for these assessments are covered by the health insurance. The G-BA is in charge of the organized screening, in which women between 20 and 34 years of age are entitled to a yearly screening assessment based on cytology smears. Women of 35 years and older are offered a combination of HPV testing and cytology every 3 years. Data showed a reduced incidence of invasive carcinoma of the cervix as well as of precancerous lesions and overall mortality. Participation in screening assessments for cervical cancer is recommended independently of HPV vaccination status for all women in the according age range. Prophylactic vaccination against HPV high risk types are recommended for all children and adolescents independently of the gender between 9–14 years of age, but before the first sexual intercourse. However, the license according to the European Medicines Agency (EMA) covers all children irrespective of the gender starting at 9 years of age without defining an upper age limit. At the moment, two HPV vaccines are available. For both vaccines, a 2-dose-vaccination regimen is recommended. HPV vaccination can also be valuable for adolescents and adults older than 17 years and to reduce reinfection rates after HPV infection. In this case, HPV vaccination is solely a prophylactic measure and has no therapeutic effect.
CRIS-Team Scopus Importer:2023-10-20
Keywords: cervical carcinoma; primary prevention; prophylactic vaccination; screening

A large-scale assessment of two-way SNP interactions in breast cancer susceptibility using 46 450 cases and 42 461 controls from the breast cancer association consortium - Milne, Roger L.; Herranz, Jesus; Michailidou, Kyriaki; Dennis, Joe; Tyrer, Jonathan P.; Zamora, M. Pilar; Arias-Perez, Jose Ignacio; Gonzalez-Neira, Anna; Pita, Guillermo; Alonso, M. Rosario; Wang, Qin; Bolla, Manjeet K.; et al. (Human Molecular Genetics, 2014)
Part of the substantial unexplained familial aggregation of breast cancer may be due to interactions between common variants, but few studies have had adequate statistical power to detect interactions of realistic magnitude. We aimed to assess all two-way interactions in breast cancer susceptibility between 70 917 single nucleotide polymorphisms (SNPs) selected primarily based on prior evidence of a marginal effect. Thirty-eight international studies contributed data for 46 450 breast cancer cases and 42 461 controls of European origin as part of a multi-consortium project (COGS). First, SNPs were preselected based on evidence (P < 0.01) of a per-allele main effect, and all two-way combinations of those were evaluated by a per-allele (1 d.f.) test for interaction using logistic regression. Second, all 2.5 billion possible two-SNP combinations were evaluated using Boolean operation-based screening and testing, and SNP pairs with the strongest evidence of interaction (P < 10(-4)) were selected for more careful assessment by logistic regression. Under the first approach, 3277 SNPs were preselected, but an evaluation of all possible two-SNP combinations (1 d.f.) identified no interactions at P < 10(-8). Results from the second analytic approach were consistent with those from the first (P > 10(-10)). In summary, we observed little evidence of two-way SNP interactions in breast cancer susceptibility, despite the large number of SNPs with potential marginal effects considered and the very large sample size. This finding may have important implications for risk prediction, simplifying the modelling required. Further comprehensive, large-scale genome-wide interaction studies may identify novel interacting loci if the inherent logistic and computational challenges can be overcome.
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A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants: Application to BRCA1 and BRCA2 - Zanti, Maria; O'Mahony, Denise G.; Parsons, Michael T.; Li, Hongyan; Dennis, Joe; Aittomäkkiki, Kristiina; Andrulis, Irene L.; Anton-Culver, Hoda; Aronson, Kristan J.; Augustinsson, Annelie; Becher, Heiko; Bojesen, Stig E.; et al. (Human Mutation, 2023)
A large number of variants identified through clinical genetic testing in disease susceptibility genes are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion) can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analysis of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC) and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared with classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and preformatted Excel calculators for implementation of the method for rare variants in BRCA1, BRCA2, and other high-risk genes with known penetrance.
CRIS-Team Scopus Importer:2023-11-24

Amniotic-Umbilical-to-Cerebral Ratio-A Novel Ratio Combining Doppler Parameters and Amniotic Fluid Volume to Predict Adverse Perinatal Outcome in SGA Fetuses at Term - Stumpfe, Florian; Faschingbauer, Florian; Kehl, Sven; Pretscher, Jutta; Emons, Julius; Gaß, Paul; Mayr, Andreas; Schmid, Matthias; Beckmann, Matthias; Stelzl, Patrick (Ultraschall in der Medizin, 2020)
Purpose â Introduction of a novel ratio-the amniotic-umbilical-to-cerebral ratio (AUCR)-to predict adverse perinatal outcome in SGA fetuses at term and comparison of its predictive accuracy with established parameters. Materials and Methods â This retrospective cohort study included 165 singleton pregnancies with SGA fetuses (birth weight <âŠ10 thpercentile) at term. Cases with planned vaginal delivery and documented pulsatility indices (PI) of the umbilical artery (UA), middle cerebral artery (MCA), and single deepest pocket (SDP) were included. CPR was calculated as the ratio between MCA PI and UA PI, UCR as the ratio between UA PI and MCA PI. AUCR was defined as follows: SDP/(UA PI/MCA PI). Adverse perinatal outcomes were defined as operative intervention (OI), OI due to fetal distress, admission to the neonatal intensive care unit (NICU), and composite adverse perinatal outcome (CAPO). Associations between Doppler parameters and these outcomes were estimated using regression analyses. Results â OI was statistically significantly associated with UCR, SDP, and AUCR, whereas no association was observed for UA PI, MCA PI, and CPR. Fetuses requiring OI due to fetal distress revealed a significantly higher UA PI and UCR as well as a lower MCA PI, CPR, and AUCR. With regard to NICU admission and CAPO, a significantly higher UA PI and lower CPR were found. Furthermore, a significant association was shown for SDP, UCR, and AUCR. AUCR achieved the best area under the curve for all outcome parameters. Conclusion â AUCR leads to an improvement in the prediction of unfavorable outcome in SGA fetuses at term. Furthermore, results of our study show that UCR might be superior to CPR.
CRIS-Team Scopus Importer:2020-11-13
Keywords: amniotic fluid; AUCR; CPR; SDP; UCR

A multicenter, randomized, double-blind, phase II study to evaluate the tolerability of an induction dose escalation of everolimus in patients with metastatic breast cancer (mBC) (DESIREE) - Loibl, S.; Schmidt, M.; Luebbe, K.; Decker, T.; Thill, M.; Bauer, L.; Mueller, V.; Link, T.; Furlanetto, J.; Kuemmel, S.; Mundhenke, Christoph; Hoffmann, O.; et al. (ANNALS OF ONCOLOGY, 2021)
CRIS-Team WoS Importer:2021-10-15

A multicentre, randomised, double-blind, phase II study to evaluate the tolerability of an induction dose escalation of everolimus in patients with metastatic breast cancer (DESIREE) - Schmidt, M.; Lübbe, K.; Decker, T.; Thill, M.; Bauer, L.; Müller, V.; Link, T.; Furlanetto, J.; Reinisch, M.; Mundhenke, Christoph; Hoffmann, O.; Zahn, M. O.; et al. (ESMO Open, 2022)
Background: Stomatitis is one of the main reasons to discontinue everolimus in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2–) metastatic breast cancer (mBC). To decrease stomatitis and subsequently early treatment discontinuations or dose reductions, the DESIREE trial investigated the use of a stepwise dose-escalation schedule of everolimus (EVE esc). Patients and methods: DESIREE is a phase II, multicentre, randomised, double-blind, placebo-controlled trial in patients with HR+/HER2– mBC and progression/relapse after nonsteroidal aromatase inhibitor treatment. Patients were randomised to EVE esc (2.5 mg/day, week 1; 5 mg/day, week 2; 7.5 mg/day, week 3; 10 mg/day, weeks 4-24) or everolimus 10 mg/day (EVE 10mg) for 24 weeks plus exemestane. The primary endpoint was the incidence of stomatitis episodes grade ≥2 within 12 weeks of treatment. The secondary endpoints included toxicity, relative total dose intensity (RTDI) and quality of life (QoL). Results: A total of 160 patients were randomised and 156 started treatment (EVE esc: 80; EVE 10mg: 76). The median age of patients was 64 years (range 33-85), 56.3% patients in the EVE esc arm versus 42.1% in the EVE 10mg arm had liver metastasis (P = 0.081) and 62.5% versus 51.3% received over one metastatic therapy line (P = 0.196). Within 12 weeks, the incidence of stomatitis episodes grade ≥2 was significantly lower in the EVE esc arm compared with the EVE 10mg arm (28.8% versus 46.1%; odds ratio 0.47, 95% confidence interval 0.24-0.92; P = 0.026). Toxicity was in line with the known safety profile without new safety concerns. The median RTDI was 91.1% in the EVE esc arm versus 80.0% in the EVE 10mg arm (P = 0.329). Discontinuation rate in the first 3 weeks was 6.3% versus 15.8%, respectively (P = 0.073). QoL was comparable between the two treatment arms. Conclusions: A dose-escalation schema of everolimus over 3 weeks can be successfully used to reduce the incidence of high-grade stomatitis in the first 12 weeks of treatment in patients with HR+/HER2– mBC. Trial registration: ClinicalTrials.gov NCT02387099; https://clinicaltrials.gov/ct2/show/NCT02387099
CRIS-Team Scopus Importer:2022-11-25
Keywords: everolimus; exemestane; metastatic breast cancer; stomatitis

Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci - Glubb, Dylan M.; Johnatty, Sharon E.; Quinn, Michael C. J.; O'Mara, Tracy A.; Tyrer, Jonathan P.; Gao, Bo; Fasching, Peter; Beckmann, Matthias; Lambrechts, Diether; Vergote, Ignace; Edwards, Digna R. Velez; Beeghly-Fadiel, Alicia; et al. (Oncotarget, 2017)
We previously identified associations with ovarian cancer outcome at five genetic loci. To identify putatively causal genetic variants and target genes, we prioritized two ovarian outcome loci (1q22 and 19p12) for further study. Bioinformatic and functional genetic analyses indicated that MEF2D and ZNF100 are targets of candidate outcome variants at 1q22 and 19p12, respectively. At 19p12, the chromatin interaction of a putative regulatory element with the ZNF100 promoter region correlated with candidate outcome variants. At 1q22, putative regulatory elements enhanced MEF2D promoter activity and haplotypes containing candidate outcome variants modulated these effects. In a public dataset, MEF2D and ZNF100 expression were both associated with ovarian cancer progression-free or overall survival time. In an extended set of 6,162 epithelial ovarian cancer patients, we found that functional candidates at the 1q22 and 19p12 loci, as well as other regional variants, were nominally associated with patient outcome; however, no associations reached our threshold for statistical significance (p<1×10-5). Larger patient numbers will be needed to convincingly identify any true associations at these loci.
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Analysis and classification of oncology activities on the way to workflow based single source documentation in clinical information systems - Wagner, Stefan; Beckmann, Matthias; Wullich, Bernd; Seggewies, Christof; Ries, Markus; Buerkle, Thomas; Prokosch, Hans-Ulrich (BMC Medical Informatics and Decision Making, 2015)
Today, cancer documentation is still a tedious task involving many different information systems even within a single institution and it is rarely supported by appropriate documentation workflows.In a comprehensive 14 step analysis we compiled diagnostic and therapeutic pathways for 13 cancer entities using a mixed approach of document analysis, workflow analysis, expert interviews, workflow modelling and feedback loops. These pathways were stepwise classified and categorized to create a final set of grouped pathways and workflows including electronic documentation forms.A total of 73 workflows for the 13 entities based on 82 paper documentation forms additionally to computer based documentation systems were compiled in a 724 page document comprising 130 figures, 94 tables and 23 tumour classifications as well as 12 follow-up tables. Stepwise classification made it possible to derive grouped diagnostic and therapeutic pathways for the three major classes - solid entities with surgical therapy - solid entities with surgical and additional therapeutic activities and - non-solid entities. For these classes it was possible to deduct common documentation workflows to support workflow-guided single-source documentation.Clinical documentation activities within a Comprehensive Cancer Center can likely be realized in a set of three documentation workflows with conditional branching in a modern workflow supporting clinical information system.
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Analysis of GDF15 and IGFBP7 in Hyperemesis Gravidarum Support Causality - Fejzo, Marlena S.; Fasching, Peter; Schneider, Michael; Schwitulla, Judith; Beckmann, Matthias; Schwenke, Eva; Macgibbon, Kimber W.; Mullin, Patrick M. (Geburtshilfe und Frauenheilkunde, 2019)
Objective Hyperemesis gravidarum, severe nausea and vomiting in pregnancy, occurs in up to 2% of pregnancies and leads to significant weight loss, dehydration, electrolyte imbalance, and ketonuria. It is associated with both maternal and fetal morbidity. Familial aggregation studies and twin studies suggest a genetic component. In a recent GWAS, we showed that placentation, appetite, and cachexia genes GDF15 and IGFBP7 are linked to hyperemesis gravidarum (HG). The purpose of this study is to determine whether GDF15 and IGFBP7 are upregulated in HG patients. Methods We compared serum levels of GDF15 and IGFBP7 at 12 and 24 weeks' gestation in women hospitalized for HG, and two control groups, women with nausea and vomiting of pregnancy (NVP), and women with no NVP. Results We show GDF15 and IGFBP7 serum levels are significantly increased in women with HG at 12 weeks' gestation. Serum levels of hCG are not significantly different between cases and controls. At 24 weeks gestation, when symptoms have largely resolved, there is no difference in GDF15 and IGFBP7 serum levels between cases and controls. Conclusion This study supports GDF15 and IGFBP7 in the pathogenesis of HG and may be useful for prediction and diagnosis. The GDF15-GFRAL brainstem-activated pathway was recently identified and therapies to treat conditions of abnormal appetite are under intense investigation. Based on our findings, HG should be included.
CRIS-Team Scopus Importer:2019-05-02
Keywords: GDF15; GFRAL; hyperemesis gravidarum; IGFBP7; nausea and vomiting of pregnancy

Analysis of motives and patient satisfaction in oncological second opinions provided by a certified university breast and gynecological cancer center - Löhberg, Christian; Meyer, Julia; Häberle, Lothar; Hack, Carolin; Jud, Sebastian; Hein, Alexander; Wunderle, Marius; Emons, Julius; Gaß, Paul; Fasching, Peter; Egloffstein, Sainab; Krebs, Jessica; et al. (Archives of Gynecology and Obstetrics, 2020)
Purpose: Second opinions in oncology are becoming increasingly important in an era of more complex treatments and a growing demand for information by patients. Therefore, we analyzed their effects and influencing factors like patients’ motives, subjective extent of information and satisfaction with communications. Methods: This prospective study evaluated second opinions for patients with breast cancer or gynecological malignancy. The patients received a questionnaire before and two months after, which inquired expectations, reasons, and satisfaction with the second opinion and the attending physicians. Results: A total of 164 patients were included and the majority had breast cancer (75.0%). Receiving the second opinion made 89.7% feel better informed, their need for information decreased (from 75.3% to 39.2%, P < 0.0001), and satisfaction with doctor–patient communications increased (from 61.9 to 91.8%, P = 0.0002). There were various reasons for requesting a second opinion, e.g., the extremely stressful situation of a cancer diagnosis, hope for change in the treatment recommendation or dissatisfaction with the initial physicians. Conclusions: Second opinions can lead to significantly greater patient satisfaction, meeting the need for information and leading to better management of patients in the extremely stressful situation of a cancer diagnosis. Doctor–patient communications play a key role.
CRIS-Team Scopus Importer:2020-04-28
Keywords: Breast cancer; Doctor–patient communication; Gynecological malignancy; Oncology center; Patient satisfaction; Second opinion

Analysis of Oncological Second Opinions in a Certified University Breast and Gynecological Cancer Center in Relation to Complementary and Alternative Medicine - Hack, Carolin; Wasner, Sonja; Meyer, Julia; Häberle, Lothar; Jud, Sebastian; Hein, Alexander; Wunderle, Marius; Emons, Julius; Gaß, Paul; Fasching, Peter; Egloffstein, Sainab; Beckmann, Matthias; et al. (Complementary Medicine Research, 2020)
Introduction: Oncological second opinions are becoming increasingly important given more complex treatment strategies, simultaneously more patients use complementary and alternative medicine (CAM), and many comprehensive cancer centers initiate integrative medicine programs. The present study focuses on analyzing the effects of a second opinion in relation to attitudes toward CAM. Methods: In this prospective study patients (n = 97) with a diagnosis of breast cancer or gynecological malignancies who had requested a second opinion received a questionnaire before and after the second opinion concerning their attitudes toward CAM. Results: The majority of patients had breast cancer (72.2%, n = 70). Only 6.2% (n = 6) stated that they had been informed about CAM by the doctors who treated them first, 21.6% (n = 21) had received information about it when seeking the second opinion. After the first opinion, 42.3% (n = 41) wanted to try CAM, the same proportion trusted orthodox medicine alone. After the second opinion, 24 patients (24.7%) wanted to try CAM, while 38.1% (n = 37) relied exclusively on orthodox medicine. There was a significant correlation between an increased patients' need for information and interest in CAM (p = 0.02). Conclusions: Today, aspects of CAM still are very often no part of oncological first and second opinions. This might hence lead to discouraging patients to try out CAM and therefore integrative medicine programs in comprehensive cancer centers might be problem-solving.
CRIS-Team Scopus Importer:2020-09-04
Keywords: Breast cancer; Complementary and alternative medicine; Gynecological malignancies; Integrative medicine; Oncological center; Second opinion

Analysis of Oncological Second Opinions in a Certified University Breast and Gynecological Cancer Center Regarding Consensus between the First and Second Opinion and Conformity with the Guidelines - Lux, Michael P.; Wasner, Sonja; Meyer, Julia; Häberle, Lothar; Hack, Carolin; Jud, Sebastian; Hein, Alexander; Wunderle, Marius; Emons, Julius; Gaß, Paul; Fasching, Peter; Egloffstein, Sainab; et al. (Breast Care, 2020)
Introduction: Oncological second opinions are becoming increasingly important in the era of complex treatments and established certified cancer centers. Oncological guidelines with the highest levels of evidence are available, but these can only be effective to the extent that they are implemented. Therefore, we analyzed the effects of second opinions with regard to their agreement with first opinions and conformity with guidelines. Methods: In 164 patients with a diagnosis of breast cancer or gynecological malignancy who requested a second opinion, the first and second opinions, established at the interdisciplinary tumor conference, and conformity with the guidelines were evaluated. Results: The first opinion was not in agreement with the guidelines in 34.8% (15.2% diagnosis, 12.8% surgical therapy, 13.4% systemic therapy, and 5.5% radiotherapy), and the recommendations were optimized in the second opinion in 56.7% (28.7% diagnosis, 15.9% surgical therapy, 30.5% systemic therapy, and 8.5% radiotherapy). Conclusions: Oncological second opinions showed significant effects and one-third of first opinions were not in conformity with the guidelines. In a significant proportion of cases, the existing treatment plan was changed or supplemented to allow modern and individualized treatment approaches.
CRIS-Team Scopus Importer:2020-09-04

Anastrozole has an Association between Degree of Estrogen Suppression and Outcomes in Early Breast Cancer and is a Ligand for Estrogen Receptor α - Ingle, James N.; Cairns, Junmei; Suman, Vera J.; Shepherd, Lois E.; Fasching, Peter; Hoskin, Tanya L.; Singh, Ravinder J.; Desta, Zeruesenay; Kalari, Krishna R.; Ellis, Matthew J.; Goss, Paul E.; Chen, Bingshu E.; et al. (Clinical Cancer Research, 2020)
PURPOSE: To determine if the degree of estrogen suppression with aromatase inhibitors (AI: anastrozole, exemestane, letrozole) is associated with efficacy in early-stage breast cancer, and to examine for differences in the mechanism of action between the three AIs. EXPERIMENTAL DESIGN: Matched case-control studies [247 matched sets from MA.27 (anastrozole vs. exemestane) and PreFace (letrozole) trials] were undertaken to assess whether estrone (E1) or estradiol (E2) concentrations after 6 months of adjuvant therapy were associated with risk of an early breast cancer event (EBCE). Preclinical laboratory studies included luciferase activity, cell proliferation, radio-labeled ligand estrogen receptor binding, surface plasmon resonance ligand receptor binding, and nuclear magnetic resonance assays. RESULTS: Women with E1 ≥1.3 pg/mL and E2 ≥0.5 pg/mL after 6 months of AI treatment had a 2.2-fold increase in risk (P = 0.0005) of an EBCE, and in the anastrozole subgroup, the increase in risk of an EBCE was 3.0-fold (P = 0.001). Preclinical laboratory studies examined mechanisms of action in addition to aromatase inhibition and showed that only anastrozole could directly bind to estrogen receptor α (ERα), activate estrogen response element-dependent transcription, and stimulate growth of an aromatase-deficient CYP19A1-/- T47D breast cancer cell line. CONCLUSIONS: This matched case-control clinical study revealed that levels of estrone and estradiol above identified thresholds after 6 months of adjuvant anastrozole treatment were associated with increased risk of an EBCE. Preclinical laboratory studies revealed that anastrozole, but not exemestane or letrozole, is a ligand for ERα. These findings represent potential steps towards individualized anastrozole therapy.
CRIS-Team Scopus Importer:2020-06-26

Androgen receptor expression and response to chemotherapy in breast cancer patients treated in the neoadjuvant TECHNO and PREPARE trial - Witzel, Isabell; Loibl, Sibylle; Wirtz, Ralph; Fasching, Peter; Denkert, Carsten; Weber, Karsten; Lück, Hans Joachim; Huober, Jens; Karn, Thomas; Mackelenbergh, Marion von; Marmé, Frederik; Schem, Christian; et al. (British Journal of Cancer, 2019)
Background: The androgen receptor (AR) is discussed as a prognostic and/or predictive marker in breast cancer patients. Methods: AR mRNA expression was analysed by RT-qPCR in breast cancer patients treated in the neoadjuvant TECHNO (n = 118, HER2-positive) and PREPARE trial (n = 321, HER2-positive and -negative). In addition, mRNA expression of the AR transcript variants 1 (AR1) and 2 (AR2) was measured. Results: Regarding subtypes, high AR mRNA levels were frequent in HER2-positive (61.3%, 92/150) and luminal tumours (60.0%, 96/160) but almost absent in triple-negative tumours (4.3%, 3/69) (p < 0.0001). Overall, high AR mRNA levels were found to be associated with lower pathological complete remission (pCR) rates (OR 0.77 per unit, 95% CI 0.67–0.88, p = 0.0002) but also with better prognosis in terms of longer disease-free survival (DFS) (HR 0.57, 95% CI 0.39–0.85, p = 0.0054) and overall survival (OS) (HR 0.43, 95% CI, 0.26–0.71, p = 0.0011). In the PREPARE trial, a survival difference for patients with high and low AR1 mRNA levels could only be seen in the standard chemotherapy arm but not in the dose-dense treatment arm (OS: HR 0.41; 95% CI 0.22–0.74 vs. HR 1.05; 95% CI 0.52–2.13; p = 0.0459). Conclusions: We provide evidence that AR mRNA predicts response to chemotherapy in breast cancer patients.
CRIS-Team Scopus Importer:2019-11-29

An Electronic Patient-Reported Outcome Tool for the FACT-B (Functional Assessment of Cancer Therapy-Breast) Questionnaire for Measuring the Health-Related Quality of Life in Patients With Breast Cancer: Reliability Study - Matthies, Lina Maria; Taran, Florin-Andrei; Keilmann, Lucia; Schneeweiss, Andreas; Simoes, Elisabeth; Hartkopf, Andreas D.; Sokolov, Alexander N.; Walter, Christina B.; Sickenberger, Nina; Wallwiener, Stephanie; Feisst, Manuel; Gaß, Paul; et al. (Journal of Medical Internet Research, 2019)
BACKGROUND: The most frequent malignant disease in women is breast cancer. In the metastatic setting, quality of life is the primary therapeutic goal, and systematic treatment has only a limited effect on survival rates; therefore, the concept of the health-related quality of life (HRQoL) and measurement of patient-reported outcomes (PROs) are gaining more and more importance in the therapy setting of diseases such as breast cancer. One of the frequently used questionnaires for measuring the HRQoL in patients with breast cancer is the Functional Assessment of Cancer Therapy-Breast (FACT-B). Currently, paper-based surveys still predominate, as only a few reliable and validated electronic-based questionnaires are available. ePRO tools for the FACT-B questionnaire with proven reliability are missing so far. OBJECTIVE: The aim of this study was to analyze the reliability of tablet-based measurement of FACT-B in the German language in adjuvant (curative) and metastatic breast cancer patients. METHODS: Paper- and tablet-based questionnaires were completed by a total of 106 female adjuvant and metastatic breast cancer patients. All patients were required to complete the electronically based (ePRO) and paper-based version of the FACT-B. A frequency analysis was performed to determine descriptive sociodemographic characteristics. Both dimensions of reliability (parallel forms reliability using Wilcoxon test and test of internal consistency using Spearman ρ) and agreement rates for single items, Kendall tau for each subscale, and total score were analyzed. RESULTS: High correlations were shown for both dimensions of reliability (parallel forms reliability and internal consistency) in the patients' response behavior between paper-based and electronically based questionnaires. Regarding the reliability test of parallel forms, no significant differences were found in 35 of 37 single items, while significant correlations in the test for consistency were found in all 37 single items, in all 5 sum individual item subscale scores, as well as in total FACT-B score. CONCLUSIONS: The ePRO version of the FACT-B questionnaire is reliable for patients with breast cancer in both adjuvant and metastatic settings, showing highly significant correlations with the paper-based version in almost all questions all subscales and the total score.
CRIS-Team Scopus Importer:2019-05-07
Keywords: breast cancer; ePRO measurement; FACT-B; HRQoL; patient-reported outcomes; reliability of ePRO

A network analysis to identify mediators of germline-driven differences in breast cancer prognosis - Escala-Garcia, Maria; Abraham, Jean; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Ashworth, Alan; Auer, Paul L.; Auvinen, Päivi; Beckmann, Matthias; Beesley, Jonathan; Behrens, Sabine; Benitez, Javier; et al. (Nature Communications, 2020)
Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies 7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.
CRIS-Team Scopus Importer:2020-01-24

A New Sonographic Weight Estimation Formula for Fetuses with Congenital Diaphragmatic Hernia - Faschingbauer, Florian; Mayr, Andreas; Geipel, A.; Gembruch, U.; Dammer, U.; Raabe, E.; Beckmann, Matthias; Kehl, Sven; Schild, R. L.; Siemer, J.; Schmid, M. (Ultraschall in der Medizin, 2015)
The accuracy of the sonographic weight estimation (WE) of fetuses with congenital diaphragmatic hernia (CDH) is significantly lower than that of fetuses without any malformations. The objective of this study was to develop and evaluate the first specific sonographic weight formula for fetuses with CDH.In a retrospective, multicenter, cohort study, a statistical estimation technique known as "multivariable fractional polynomial regression" was applied to a group of 146 fetuses with CDH. Each fetus underwent an ultrasound examination with complete biometric parameters within 7 days of delivery. A new formula was derived using the obtained data and was then compared with other commonly used equations. The accuracy of the different formulas was compared using means of signed percentage errors (SPE), medians of absolute percentage errors (MAPE), and fractions of estimates within prespecified error bounds.The new derived formula is: EFW = 10^(4.6729 107 371 + 0.2365 011 768 * HC + 0.2228 897 682 * FL^2 - 0.0129 895 773 * FL^3 - 1.0470 039 072 * (FL * HC)^0.5 + 0.0004 314 661 * (AC * HC) - [in case of liver herniation] 0.0062 112 122), where EFW is the estimated fetal weight, HC is the head circumference, AC is the abdominal circumference, and FL is the femur length. The new formula proved to be superior to other established equations, showing both the lowest median absolute percentage error (MAE: 6.97) and mean signed percentage error (SPE: 0.40), and the best distribution of absolute percentage errors within prespecified error bounds.This new formula significantly improves weight estimation in fetuses with CDH.
EVALuna2:5474

A New Sonographic Weight Estimation Formula for Small-for-Gestational-Age Fetuses - Faschingbauer, Florian; Dammer, Ulf; Raabe, Eva; Kehl, Sven; Schmid, Matthias; Schild, Ralf L.; Beckmann, Matthias; Mayr, Andreas (Journal of Ultrasound in Medicine, 2016)
The purpose of this study was to develop a new specific weight estimation formula for small-for-gestational-age (SGA) fetuses that differentiated between symmetric and asymmetric growth patterns.A statistical estimation technique known as component-wise gradient boosting was applied to a group of 898 SGA fetuses (symmetric, n = 750; asymmetric, n = 148). A new formula was derived from the data obtained and was then compared to other commonly used equations.The new formula derived is as follows: estimated fetal weight = e^[1.3734627 + 0.0057133 × biparietal diameter + 0.0011282 × head circumference + 0.0201147 × abdominal circumference + 0.0183081 × femur length - 0.0000177 × biparietal diameter(2) - 0.0000018 × head circumference(2) - 0.0000297 × abdominal circumference(2) -0.0001007 × femur length(2) + 0.0397563 × I(sex = male) + 0.0064505 × gestational age (days) + 0.0096528 × I(SGA = asymmetric)], where the function I denotes an indicator function, which is 1 if the expression is fulfilled (sex = male; SGA type = asymmetric) and otherwise 0. In the whole study group and the 2 subgroups, the new formula showed the lowest median absolute percentage error, mean percentage error, and random error and the best distribution of absolute percentage errors within prespecified error bounds.The new formula substantially improves weight estimation in SGA fetuses.
EVALuna2:5572

An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression - Wyszynski, Asaf; Hong, Chi-Chen; Lam, Kristin; Michailidou, Kyriaki; Lytle, Christian; Yao, Song; Zhang, Yali; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Hopper, John L.; Southey, Melissa C.; et al. (Human Molecular Genetics, 2016)
Breast cancer is the most diagnosed malignancy and the second leading cause of cancer mortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression. We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERα-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated with modified ERα binding and monoallelic-repression of IGFBP5 following oestrogen treatment. We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from 41 case control studies and 11 GWAS. We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR = 0.68 95%CI 0.55-0.83, P = 0.0002; replication OR = 0.77 95% CI 0.73-0.82, P = 2.1 × 10-19) and identify 13 additional linked variants (r2 > 0.8) in the 20Kb linkage block containing the enCNV (P = 3.2 × 10-15- 5.6 × 10-17). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk loci may be mediating their effect through IGFBP5.
EVALuna2:33321

A novel serum extracellular vesicle protein signature to monitor glioblastoma tumor progression - Tzaridis, Theophilos; Weller, Johannes; Bachurski, Daniel; Shakeri, Farhad; Schaub, Christina; Hau, Peter; Buness, Andreas; Schlegel, Uwe; Steinbach, Joachim-Peter; Seidel, Clemens; Goldbrunner, Roland; Schaefer, Niklas; et al. (International Journal of Cancer, 2022)
Detection of tumor progression in patients with glioblastoma remains a major challenge. Extracellular vesicles (EVs) are potential biomarkers and can be detected in the blood of patients with glioblastoma. In our study, we evaluated the potential of serum-derived EVs from glioblastoma patients to serve as biomarker for tumor progression. EVs from serum of glioblastoma patients and healthy volunteers were separated by size exclusion chromatography and ultracentrifugation. EV markers were defined by using a proximity-extension assay and bead-based flow cytometry. Tumor progression was defined according to modified RANO criteria. EVs from the serum of glioblastoma patients (n = 67) showed an upregulation of CD29, CD44, CD81, CD146, C1QA and histone H3 as compared to serum EVs from healthy volunteers (P value range: <.0001 to .08). For two independent cohorts of glioblastoma patients, we noted upregulation of C1QA, CD44 and histone H3 upon tumor progression, but not in patients with stable disease. In a multivariable logistic regression analysis, a combination of CD29, CD44, CD81, C1QA and histone H3 correlated with RANO-defined tumor progression with an AUC of 0.76. Measurement of CD29, CD44, CD81, C1QA and histone H3 in serum-derived EVs of glioblastoma patients, along with standard MRI assessment, has the potential to improve detection of true tumor progression and thus could be a useful biomarker for clinical decision making.
CRIS-Team WoS Importer:2022-09-23

Anticancer effect of bacteria on cervical cancer: Molecular aspects and therapeutic implications - Pourmollaei, Soraya; Barzegari, Abolfazl; Farshbaf-Khalili, Azizeh; Nouri, Mohammad; Fattahi, Amir; Shahnazi, Mahnaz; Dittrich, Ralf (Life Sciences, 2020)
Cervical cancer is the second common cancer and the third leading cause of cancer deaths among women in less developed countries. It has been indicated that changes in vaginal microbiome play an important role in the occurrence and development of cervical cancer. However, studies have shown that probiotics play an effective role in fighting cancer by affecting pathogenic bacteria, inducing cancer cells apoptosis, and other anticancer activities. Therefore, the purpose of the present study is reviewing the anticancer effect of cervicovaginal bacteria and their potential for cervical cancer treatment.
CRIS-Team Scopus Importer:2020-02-25
Keywords: Bacteria; Cancer; Cancer treatment; Cervix

Anti-Müllerian hormone (AMH) levels in premenopausal breast cancer patients treated with taxane-based adjuvant chemotherapy - A translational research project of the SUCCESS A study - Trapp, Elisabeth; Steidl, J.; Rack, B.; Kupka, M. S.; Andergassen, U.; Jueckstock, J.; Kurt, A.; Vilsmaier, T.; De Gregorio, A.; De Gregorio, N.; Tzschaschel, M.; Lato, C.; et al. (BREAST, 2017)
BACKGROUND: Premenopausal women undergoing chemotherapy are at high risk for premature ovarian failure and its long-term consequences. Data on potential markers to evaluate ovarian reserve pre- and posttreatment are limited. Anti-Müllerian hormone (AMH) known for ovarian reserve in reproductive medicine could be a surrogate marker and was assessed in premenopausal breast cancer patients of the SUCCESS A study (EUDRA-CT no. 2005-000490-21). METHODS: We identified 170 premenopausal patients, age ≤ 40 years at trial entry, who received FEC-Doc as taxane-anthracylince based chemotherapy. Blood samples were taken at three time points: Before, four weeks after and two years after adjuvant chemotherapy. Serum AMH-levels were evaluated in a central laboratory by a quantitative immunoassay AMH Gen II ELISA (Beckman Coulter, Brea, USA). RESULTS: Median age was 36 years (21-40 years). Median serum AMH-level before chemotherapy was 1.37 ng/ml (range < 0.1-11.3 ng/ml). Four weeks after chemotherapy AMH-levels dropped in 98.6% of the patients to <0.1 ng/ml (range < 0.1-0.21 ng/ml). After two years, 73.3% (n = 101) showed no evidence of ovarian function recovery (AMH <0.1 ng/ml, range < 0.1-3.9 ng/ml). Permanent chemotherapy induced amenorrhea occurred only in 50.6% of the patients. CONCLUSIONS: In this analysis, premenopausal patients showed a high rate of ovarian impairment reflected by low AMH-levels after chemotherapy.
EVALuna2:36126

Antimullerian Hormone as a Serum Biomarker for Risk of Chemotherapy-Induced Amenorrhea - Ruddy, Kathryn J.; Schaid, Daniel J.; Batzler, Anthony; Cecchini, Reena S.; Partridge, Ann H.; Norman, Aaron; Fehrenbacher, Louis; Stewart, Elizabeth A.; Trabuco, Emanuel; Ginsburg, Elizabeth; Couch, Fergus J.; Fasching, Peter; et al. (Journal of the National Cancer Institute, 2021)
Antimullerian hormone (AMH) is a promising biomarker for ovarian reserve. In this study, we assessed AMH before and 1 year after initiation of adjuvant chemotherapy on National Surgical Adjuvant Breast and Bowel Project (NSABP)/NRG Oncology B-47 in female participants aged 42 years and younger (median age = 39 years). At baseline, median AMH was 1.2 ng/mL; 13 (4.7%) values were less than 0.1 ng/mL (the threshold for detectable levels, in the perimenopause and menopause range), and 57 values (20.6%) were less than 0.5 ng/mL. At 1 year, 215 (77.6%) were less than 0.1 ng/mL, and 264 (95.3%) were less than 0.5 ng/mL. Postchemotherapy menses were reported by 46.2% of participants. Multivariable logistic regression found that the odds of having postchemotherapy menses increased with younger age, higher body mass index, and higher prechemotherapy AMH, but not by trastuzumab administration or by the choice of chemotherapy (doxorubicin-cyclophosphamide followed by paclitaxel vs docetaxel-cyclophosphamide). We conclude that higher prechemotherapy AMH predicts a lower risk of chemotherapy-induced amenorrhea and that AMH 1 year after chemotherapy initiation is not informative in this setting because it is likely to be very low.
CRIS-Team Scopus Importer:2021-09-10

Antioxidant effect of aqueous extract of four plants with therapeutic potential on gynecological diseases; Semen persicae, Leonurus cardiaca, Hedyotis diffusa, and Curcuma zedoaria - Ji, Shaojian; Fattahi, Amir; Raffel, Nathalie; Hoffmann, Inge; Beckmann, Matthias; Dittrich, Ralf; Schrauder, Michael G. (European Journal of Medical Research, 2017)
BACKGROUND: Little information is available concerning antioxidant effects of plant teas (water boiled) which are used more commonly in traditional Chinese medicine than other extracts. Thus, we addressed this issue by evaluating the ability of teas from four different plants with therapeutic potential on gynecological diseases. METHODS: The aqueous extracts of Semen persicae, Leonurus cardiaca, Hedyotis diffusa, and Curcuma zedoaria rhizome were prepared and then their effects on copper-induced low-density lipoprotein cholesterol (LDL-C) oxidation were evaluated by spectrophotometric method. Density gradient ultracentrifugation method was recruited to isolate LDL-C from healthy individuals. RESULTS: Our results showed that adding 10, 20, and 30 µl S. persicae could increase the lag phase duration of LDL-C oxidation compared with control reaction 12, 21, and 33%, respectively. The most effective delay (87%) was observed when 30 µl H. diffusa was added to the reaction. In cases of L. cardiaca and C. zedoaria, we found no significant influence on the lag phase duration (p > 0.05). Moreover, our findings about starting point of the decomposition phase were almost in parallel with the lag phase results, as 30 µl of S. persicae or H. diffusa teas could significantly increase the initiation time of decomposition (p < 0.05). CONCLUSIONS: In conclusion our results showed that both S. persicae and H. diffusa teas and not L. cardiaca and C. zedoaria could have medicinal therapeutic effects partly through direct oxidation prevention.
EVALuna2:36118

An update on platelet-rich plasma (PRP) therapy in endometrium and ovary related infertilities: clinical and molecular aspects - Hajipour, Hamed; Farzadi, Laya; Latifi, Zeinab; Keyhanvar, Neda; Navali, Nazli; Fattahi, Amir; Nouri, Mohammad; Dittrich, Ralf (Systems Biology in Reproductive Medicine, 2021)
Administration of platelet-rich plasma (PRP) is one of the well-recommended strategies for the treatment of endometrium- and ovary-associated infertility. Due to the autologous source of PRP, minimal risks for disease transmission and immunogenic and allergic responses are expected in this method. Despite the extensive use of PRP in medicine, its precise mechanism of action in endometrial and ovarian tissues is still unknown. Nevertheless, the induction of cell proliferation, chemotaxis, regeneration, extracellular matrix synthesis, remodeling, angiogenesis, and epithelialization are the main pathways for PRP to affect female reproductive organs. Given the promising results of previous studies, it is necessary to standardize PRP preparation protocols for different therapeutic purposes and also clearly determine appropriate inclusion and exclusion criteria for recruiting patients. In the current review, we presented a summary of studies on PRP therapy for endometrium- and ovary-associated infertility with a focus on the possible mechanisms by which PRP enhances endometrial receptivity and regenerates ovarian function.
CRIS-Team WoS Importer:2021-03-19

A phase II randomized study of neoadjuvant letrozole plus alpelisib for hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer (NeO-ORB) - Mayer, Ingrid A.; Prat, Aleix; Egle, Daniel; Blau, Sibel; Alejandro Perez Fidalgo, J.; Gnant, Michael; Fasching, Peter; Colleoni, Marco; Wolff, Antonio C.; Winer, Eric P.; Singer, Christian F.; Hurvitz, Sara; et al. (Clinical Cancer Research, 2019)
Purpose: Addition of alpelisib to fulvestrant significantly extended progression-free survival in PIK3CA-mutant, hormone receptor–positive (HR þ ) advanced/metastatic breast cancer in the phase III SOLAR-1 study. The combination of alpelisib and letrozole also had promising activity in phase I studies of HR þ advanced/metastatic breast cancer. NEO-ORB aimed to determine whether addition of alpelisib to letrozole could increase response rates in the neoadjuvant setting. Patients and Methods: Postmenopausal women with HR þ , human epidermal growth factor receptor 2-negative, T1c-T3 breast cancer were assigned to the PIK3CA-wild-type or PIK3CA-mutant cohort according to their tumor PIK3CA status, and randomized (1:1) to 2.5 mg/day letrozole with 300 mg/day alpelisib or placebo for 24 weeks. Primary endpoints were objective response rate (ORR) and pathologic complete response (pCR) rate for both PIK3CA cohorts. Results: In total, 257 patients were assigned to letrozole plus alpelisib (131 patients) or placebo (126 patients). Grade 3 adverse events (5% of patients) in the alpelisib arm were hyperglycemia (27%), rash (12%), and maculopapular rash (8%). The primary objective was not met; ORR in the alpelisib versus placebo arm was 43% versus 45% and 63% versus 61% in the PIK3CA-mutant and wild-type cohorts, respectively. pCR rates were low in all groups. Decreases in Ki-67 were similar across treatment arms and cohorts. In PIK3CA-mutant tumors, alpelisib plus letrozole treatment induced a greater decrease in phosphorylated AKT versus placebo plus letrozole. Conclusions: In contrast to initial results in advanced/metastatic disease, addition of alpelisib to 24-week neoadjuvant letrozole treatment did not improve response in patients with HR þ early breast cancer.
CRIS-Team Scopus Importer:2019-05-28

A Phase II Study of Talazoparib after Platinum or Cytotoxic Nonplatinum Regimens in Patients with Advanced Breast Cancer and Germline BRCA1/2 Mutations (ABRAZO) - Turner, Nicholas C.; Telli, Melinda L.; Rugo, Hope S.; Mailliez, Audrey; Ettl, Johannes; Grischke, Eva-Maria; Mina, Lida A.; Balmana, Judith; Fasching, Peter; Hurvitz, Sara A.; Wardley, Andrew M.; Chappey, Colombe; et al. (Clinical Cancer Research, 2019)
PURPOSE: To assess talazoparib activity in germline BRCA1/2 mutation carriers with advanced breast cancer. PATIENTS AND METHODS: ABRAZO (NCT02034916) was a two-cohort, two-stage, phase II study of talazoparib (1 mg/day) in germline BRCA mutation carriers with a response to prior platinum with no progression on or within 8 weeks of the last platinum dose (cohort 1) or ≥3 platinum-free cytotoxic regimens (cohort 2) for advanced breast cancer. Primary endpoint was confirmed objective response rate (ORR) by independent radiological assessment. RESULTS: We enrolled 84 patients (cohort 1, n = 49; cohort 2, n = 35) from May 2014 to February 2016. Median age was 50 (range, 31-75) years. Triple-negative breast cancer (TNBC) incidence was 59% (cohort 1) and 17% (cohort 2). Median number of prior cytotoxic regimens for advanced breast cancer was two and four, respectively. Confirmed ORR was 21% [95% confidence interval (CI), 10-35; cohort 1] and 37% [95% CI, 22-55; cohort 2]. Median duration of response was 5.8 and 3.8 months, respectively. Confirmed ORR was 23% (BRCA1), 33% (BRCA2), 26% (TNBC), and 29% (hormone receptor-positive). The most common all-grade adverse events (AE) included anemia (52%), fatigue (45%), and nausea (42%). Talazoparib-related AEs led to drug discontinuation in 3 (4%) patients. In an exploratory analysis, longer platinum-free interval was associated with higher response rate in cohort 1 (0% ORR with interval <8 weeks; 47% ORR with interval >6 months). CONCLUSIONS: Talazoparib exhibited promising antitumor activity in patients with advanced breast cancer and germline BRCA mutation.
CRIS-Team Scopus Importer:2019-05-21

Appraising the role of previously reported risk factors in epithelial ovarian cancer risk: A Mendelian randomization analysis - Yarmolinsky, James; Relton, Caroline L.; Lophatananon, Artitaya; Muir, Kenneth; Menon, Usha; Gentry-Maharaj, Aleksandra; Walther, Axel; Zheng, Jie; Fasching, Peter; Zheng, Wei; Yin Ling, Woo; Park, Sue K.; et al. (Plos Medicine, 2019)
BACKGROUND: Various risk factors have been associated with epithelial ovarian cancer risk in observational epidemiological studies. However, the causal nature of the risk factors reported, and thus their suitability as effective intervention targets, is unclear given the susceptibility of conventional observational designs to residual confounding and reverse causation. Mendelian randomization (MR) uses genetic variants as proxies for risk factors to strengthen causal inference in observational studies. We used MR to evaluate the association of 12 previously reported risk factors (reproductive, anthropometric, clinical, lifestyle, and molecular factors) with risk of invasive epithelial ovarian cancer, invasive epithelial ovarian cancer histotypes, and low malignant potential tumours. METHODS AND FINDINGS: Genetic instruments to proxy 12 risk factors were constructed by identifying single nucleotide polymorphisms (SNPs) that were robustly (P < 5 × 10-8) and independently associated with each respective risk factor in previously reported genome-wide association studies. These risk factors included genetic liability to 3 factors (endometriosis, polycystic ovary syndrome, type 2 diabetes) scaled to reflect a 50% higher odds liability to disease. We obtained summary statistics for the association of these SNPs with risk of overall and histotype-specific invasive epithelial ovarian cancer (22,406 cases; 40,941 controls) and low malignant potential tumours (3,103 cases; 40,941 controls) from the Ovarian Cancer Association Consortium (OCAC). The OCAC dataset comprises 63 genotyping project/case-control sets with participants of European ancestry recruited from 14 countries (US, Australia, Belarus, Germany, Belgium, Denmark, Finland, Norway, Canada, Poland, UK, Spain, Netherlands, and Sweden). SNPs were combined into multi-allelic inverse-variance-weighted fixed or random effects models to generate effect estimates and 95% confidence intervals (CIs). Three complementary sensitivity analyses were performed to examine violations of MR assumptions: MR-Egger regression and weighted median and mode estimators. A Bonferroni-corrected P value threshold was used to establish strong evidence (P < 0.0042) and suggestive evidence (0.0042 < P < 0.05) for associations. In MR analyses, there was strong or suggestive evidence that 2 of the 12 risk factors were associated with invasive epithelial ovarian cancer and 8 of the 12 were associated with 1 or more invasive epithelial ovarian cancer histotypes. There was strong evidence that genetic liability to endometriosis was associated with an increased risk of invasive epithelial ovarian cancer (odds ratio [OR] per 50% higher odds liability: 1.10, 95% CI 1.06-1.15; P = 6.94 × 10-7) and suggestive evidence that lifetime smoking exposure was associated with an increased risk of invasive epithelial ovarian cancer (OR per unit increase in smoking score: 1.36, 95% CI 1.04-1.78; P = 0.02). In analyses examining histotypes and low malignant potential tumours, the strongest associations found were between height and clear cell carcinoma (OR per SD increase: 1.36, 95% CI 1.15-1.61; P = 0.0003); age at natural menopause and endometrioid carcinoma (OR per year later onset: 1.09, 95% CI 1.02-1.16; P = 0.007); and genetic liability to polycystic ovary syndrome and endometrioid carcinoma (OR per 50% higher odds liability: 0.89, 95% CI 0.82-0.96; P = 0.002). There was little evidence for an association of genetic liability to type 2 diabetes, parity, or circulating levels of 25-hydroxyvitamin D and sex hormone binding globulin with ovarian cancer or its subtypes. The primary limitations of this analysis include the modest statistical power for analyses of risk factors in relation to some less common ovarian cancer histotypes (low grade serous, mucinous, and clear cell carcinomas), the inability to directly examine the association of some ovarian cancer risk factors that did not have robust genetic variants available to serve as proxies (e.g., oral contraceptive use, hormone replacement therapy), and the assumption of linear relationships between risk factors and ovarian cancer risk. CONCLUSIONS: Our comprehensive examination of possible aetiological drivers of ovarian carcinogenesis using germline genetic variants to proxy risk factors supports a role for few of these factors in invasive epithelial ovarian cancer overall and suggests distinct aetiologies across histotypes. The identification of novel risk factors remains an important priority for the prevention of epithelial ovarian cancer.
CRIS-Team Scopus Importer:2019-09-20

A prediction model for pathological complete response after neoadjuvant chemotherapy of HER2-negative breast cancer patients - Häberle, Lothar; Erber, Ramona; Gaß, Paul; Hein, Alexander; Jud, Sebastian; Langemann, Hanna; Rauh, C.; Hack, Caroline; Schulz-Wendtland, Rüdiger; Hartmann, Arndt; Beckmann, Matthias; Lux, Michael P.; et al. (ANNALS OF ONCOLOGY, 2018)
CRIS-Team WoS Importer:2019-03-08

A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: Clinical results and biomarker analysis of GeparNuevo study - Loibl, S.; Untch, M.; Burchardi, N.; Huober, J.; Sinn, B. V.; Blohmer, J. U.; Grischke, E. M.; Furlanetto, J.; Tesch, H.; Hanusch, C.; Engels, K.; Rezai, M.; et al. (Annals of Oncology, 2019)
Background: Combining immune-checkpoint inhibitors with chemotherapy yielded an increased response rates in patients with metastatic triple-negative breast cancer (TNBC). Therefore, we evaluated the addition of durvalumab to standard neoadjuvant chemotherapy (NACT) in primary TNBC. Patients and methods: GeparNuevo is a randomised phase II double-blind placebo-controlled study randomising patients with TNBC to durvalumab or placebo given every 4 weeks in addition to nab-paclitaxel followed by standard EC. In the window-phase durvalumab/placebo alone was given 2 weeks before start of nab-paclitaxel. Randomisation was stratified by stromal tumour-infiltrating lymphocyte (sTILs). Patients with primary cT1b-cT4a-d disease, centrally confirmed TNBC and sTILs were included. Primary objective was pathological complete response (PCR) (ypT0 ypN0). Results: A total of 174 patients were randomised, 117 participated in the window-phase. Median age was 49.5 years (range 23-76); 47 patients (27%) were younger than 40 years; 113 (65%) had stage ≥IIA disease, 25 (14%) high sTILs, 138 of 158 (87%) were PD-L1-positive. PCR rate with durvalumab was 53.4% (95% CI 42.5% to 61.4%) versus placebo 44.2% (95% CI 33.5% to 55.3%; unadjusted continuity corrected χ2P = 0.287), corresponding to OR = 1.45 (95% CI 0.80-2.63, unadjusted Wald P = 0.224). Durvalumab effect was seen only in the window cohort (PCR 61.0% versus 41.4%, OR = 2.22, 95% CI 1.06-4.64, P = 0.035; interaction P = 0.048). In both arms, significantly increased PCR (P < 0.01) were observed with higher sTILs. There was a trend for increased PCR rates in PD-L1-positive tumours, which was significant for PD-L1-tumour cell in durvalumab (P = 0.045) and for PD-L1-immune cell in placebo arm (P = 0.040). The most common immune-related adverse events were thyroid dysfunction any grade in 47%. Conclusions: Our results suggest that the addition of durvalumab to anthracycline-/taxane-based NACT increases PCR rate particularly in patients treated with durvalumab alone before start of chemotherapy. Trial registration: ClinicalTrials.gov number: NCT02685059.
CRIS-Team Scopus Importer:2019-10-08
Keywords: durvalumab; immunotherapy; neoadjuvant; TNBC

A Randomized, Double-Blind, Phase III Trial of Neoadjuvant Chemotherapy (NACT) with atezolizumab/Placebo in Patients with Triple-Negative Breast Cancer (TNBC) Followed by Adjuvant Continuation of atezolizumab/Placebo (Gepardouze) - Loibl, Sibylle; Jackisch, Christian; Seiler, Sabine; Rastogi, Priya; Huober, Lens; Denkert, Carsten; Schneeweiss, Andreas; Hanusch, Claus; Fasching, Peter; Blohmer, Jens-Uwe; Untch, Michael; Rhiem, Kerstin; et al. (ONCOLOGY RESEARCH AND TREATMENT, 2020)
CRIS-Team WoS Importer:2020-03-20

A Randomized, Open-label, Presurgical, Window-of-Opportunity Study Comparing the Pharmacodynamic Effects of the Novel Oral SERD AZD9496 with Fulvestrant in Patients with Newly Diagnosed ER+ HER2(-) Primary Breast Cancer - Robertson, John F. R.; Evans, Abigail; Henschen, Stephan; Kirwan, Cliona C.; Jahan, Ali; Kenny, Laura M.; Dixon, J. Michael; Schmid, Peter; Kothari, Ashutosh; Mohamed, Omar; Fasching, Peter; Cheung, Kwok-Leung; et al. (Clinical Cancer Research, 2020)
Purpose: Fulvestrant, the first-in-class selective estrogen receptor (ER) degrader (SERD), is clinically effective in patients with ER+ breast cancer, but it has administration and pharmacokinetic limitations. Pharmacodynamic data suggest complete ER degradation is not achieved at fulvestrant's clinically feasible dose. This presurgical study (NCT03236974) compared the pharmacodynamic effects of fulvestrant with AZD9496, a novel, orally bioavailable, nonsteroidal, potent SERD, in treatment-naive patients with ER+ HER2(-) primary breast cancer awaiting curative intent surgery.
CRIS-Team WoS Importer:2020-08-28

A randomized phase III study evaluating pegylated liposomal doxorubicin versus capecitabine as first-line therapy for metastatic breast cancer: results of the PELICAN study - Harbeck, Nadia; Saupe, Steffen; Jaeger, Elke; Schmidt, Marcus; Kreienberg, Rolf; Mueller, Lothar; Otremba, Burkhard Joerg; Waldenmaier, Dirk; Dorn, Julia; Warm, Mathias; Scholz, Michael; Untch, Michael; et al. (Breast Cancer Research and Treatment, 2017)
PURPOSE: The PELICAN trial evaluates for the first time efficacy and safety of pegylated liposomal doxorubicin (PLD) versus capecitabine as first-line treatment of metastatic breast cancer (MBC). METHODS: This randomized, phase III, open-label, multicenter trial enrolled first-line MBC patients who were ineligible for endocrine or trastuzumab therapy. Cumulative adjuvant anthracyclines of 360 mg/m2 doxorubicin or equivalent were allowed. Left ventricular ejection fraction of >50 % was required. Patients received PLD 50 mg/m2 every 28 days or capecitabine 1250 mg/m2 twice daily for 14 days every 21 days. The primary endpoint was time-to-disease progression (TTP). RESULTS: 210 patients were randomized (n = 105, PLD and n = 105, capecitabine). Adjuvant anthracyclines were given to 37 % (PLD) and 36 % (capecitabine) of patients. No significant difference was observed in TTP [HR = 1.21 (95 % confidence interval, 0.838-1.750)]. Median TTP was 6.0 months for both PLD and capecitabine. Comparing patients with or without prior anthracyclines, no significant difference in TTP was observed in the PLD arm (log-rank P = 0.64). For PLD versus capecitabine, respectively, overall survival (median, 23.3 months vs. 26.8 months) and time-to-treatment failure (median, 4.6 months vs. 3.7 months) were not statistically significantly different. Compared to PLD, patients on capecitabine experienced more serious adverse events (P = 0.015) and more cardiac events among patients who had prior anthracycline exposure (18 vs. 8 %; P = 0.31). CONCLUSION: Both PLD and capecitabine are effective first-line agents for MBC.
EVALuna2:36160

Arbeitsgemeinschaft Gynäkologische Onkologie Recommendations for the Diagnosis and Treatment of Patients with Early Breast Cancer: Update 2023 - Park-Simon, Tjoung Won; Müller, Volkmar; Jackisch, Christian; Albert, Ute Susann; Banys-Paluchowski, Maggie; Bauerfeind, Ingo; Blohmer, Jens Uwe; Budach, Wilfried; Dall, Peter; Ditsch, Nina; Fallenberg, Eva Maria; Fasching, Peter; et al. (Breast Care, 2023)
Background: Each year the interdisciplinary Arbeitsgemeinschaft Gynäkologische Onkologie (AGO), German Gynecological Oncology Group Breast Committee on Diagnosis and Treatment of Breast Cancer provides updated state-of-the-art recommendations for early and metastatic breast cancer. Summary: The updated evidence-based treatment recommendation for early and metastatic breast cancer has been released in March 2023. Key Messages: This paper concisely captures the updated recommendations for early breast cancer chapter by chapter.
CRIS-Team Scopus Importer:2023-09-15
Keywords: (Post)(neo)adjuvant; Breast surgery; Communication; Early breast cancer; Radiotherapy; Reconstruction

A Review of Integrative Medicine in Gynaecological Oncology - Kalder, M.; Mueller, T.; Fischer, D.; Mueller, A.; Bader, W.; Beckmann, Matthias; Brucker, C.; Hack, Carolin; Hanf, V.; Hasenburg, A.; Hein, Alexander; Jud, Sebastian; et al. (Geburtshilfe und Frauenheilkunde, 2016)
In recent years complementary and alternative medicine (CAM) has increasingly been the focus of international research. Numerous subsidised trials (7903) and systematic reviews (651) have been published, and the evidence is starting to be integrated into treatment guidelines. However, due to insufficient evidence and/or insufficient good quality evidence, this has mostly not translated to practice recommendations in reviews by the Cochrane collaboration gynaecology group. There is nevertheless a not insignificant number of CAM providers and users. The percentage of oncology patients who use CAM varies between 5 and 90 %. Doctors have been identified as the main providers of CAM. Half of gynaecologists offer CAM because of personal conviction or on suggestion from colleagues. This must be viewed in a critical light, since CAM is mostly practiced without appropriate training, often without sufficient evidence for a given method - and where evidence exists, practice guidelines are lacking - and lack of safety or efficacy testing. The combination of patient demand and lucrativeness for doctors/alternative medicine practitioners, both based on supposed effectiveness CAM, often leads to its indiscriminate use with uncertain outcomes and significant cost for patients. On the other hand there is published, positive level I evidence for a number of CAM treatment forms. The aim of this article is therefore to review the available evidence for CAM in gynaecological oncology practice. The continued need for research is highlighted, as is the need to integrate practices supported by good evidence into conventional gynaecological oncology.
EVALuna2:32999

A small hypoxia signature predicted pCR response to bevacizumab in the neoadjuvant GeparQuinto breast cancer trial - Karn, Thomas; Meissner, Tobias; Weber, Karsten E.; Solbach, Christine; Denkert, Carsten; Engels, Knut; Fasching, Peter; Sinn, Bruno V.; Schrader, Iris; Budczies, Jan; Marmé, Frederik; Müller, Volkmar; et al. (Clinical Cancer Research, 2020)
Purpose: In breast cancer, bevacizumab increased pCR rate but not long-term survival and no predictive markers are available to identify patients with long-term benefit from the drug. Experimental Design: We profiled 289 pretherapeutic formalinfixed, paraffin-embedded (FFPE) biopsies of HER2-negative patients from the GeparQuinto trial of neoadjuvant chemotherapy bevacizumab by exome-capture RNA-sequencing (RNA-seq). In a prospectively planned study, we tested molecular signatures for response prediction. IHC validation was performed using tissue microarrays. Results: We found strong agreement of molecular and pathologic parameters as hormone receptors, grading, and lymphocyte infiltration in 221 high-quality samples. Response rates (49.3% pCR overall) were higher in basal-like (68.9%) and HER2-enriched (45.5%) than in luminal B (35.7%), luminal A (17.9%), and normal-like (20.0%) subtypes. T-cell (OR = 1.60; 95% confidence interval, 1.21-2.12; P = 0.001), proliferation (OR = 2.88; 95% CI, 2.00-4.15; P < 0.001), and hypoxia signatures (OR = 1.92; 95% CI, 1.41-2.60; P < 0.001) significantly predicted pCR in univariate analysis. In a prespecified multivariate logistic regression, a small hypoxia signature predicted pCR (OR = 2.40; 95% CI, 1.28-4.51; P = 0.006) with a significant interaction with bevacizumab treatment (P = 0.020). IHC validation using NDRG1 as marker revealed highly heterogenous expression within tissue leading to profound loss of sensitivity in TMA analysis, still a significant predictive value for pCR was detected (P = 0.025). Conclusions: Exome-capture RNA-seq characterizes small FFPE core biopsies by reliably detecting factors as for example ER status, grade, and tumor-infiltrating lymphocytes levels. Beside molecular subtypes and immune signatures, a small hypoxia signature predicted pCR to bevacizumab,which could be validated by IHC. The signature can have important applications for bevacizumab treatment in different cancer types and might also have a role for novel combination therapies of bevacizumab with immune checkpoint inhibition.
CRIS-Team Scopus Importer:2020-04-28

Assessing the genetic architecture of epithelial ovarian cancer histological subtypes - Cuellar-Partida, Gabriel; Lu, Yi; Dixon, Suzanne C.; Fasching, Peter A.; Hein, Alexander; Burghaus, Stefanie; Beckmann, Matthias; Lambrechts, Diether; Van Nieuwenhuysen, Els; Vergote, Ignace; Vanderstichele, Adriaan; Doherty, Jennifer Anne; et al. (Human genetics, 2016)
Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease ([Formula: see text] = 8.8 ± 1.1 %), endometrioid ([Formula: see text] = 3.2 ± 1.6 %), clear cell ([Formula: see text] = 6.7 ± 3.3 %) and all EOC ([Formula: see text] = 5.6 ± 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.
EVALuna2:33325

Assessment of breast volume changes during human pregnancy using a three-dimensional surface assessment technique in the prospective CGATE study - Bayer, Christian M.; Bani, Mayada; Schneider, Michael; Dammer, Ulf; Raabe, Eva; Haeberle, Lothar; Faschingbauer, Florian; Schneeberger, Sabine; Renner, Stefan; Fischer, Dorothea; Schulz-Wendtland, Rüdiger; Fasching, Peter; et al. (European Journal of Cancer Prevention, 2014)
Pregnancies and breastfeeding are two important protective factors concerning breast cancer risk. Breast volume and breast volume changes might be a breast phenotype that could be monitored during pregnancy and breastfeeding without ionizing radiation or expensive equipment. The aim of the present study was to document changes in breast volume during pregnancy prospectively. In the prospective Clinical Gravidity Association Trial and Evaluation programme, pregnant women were followed up prospectively from gestational week 12 to birth. Three-dimensional breast surface imaging and subsequent volume assessments were performed. Factors influencing breast volume at the end of the pregnancy were assessed using linear regression models. Breast volumes averaged 420 ml at the start of pregnancy and 516 ml at the end of pregnancy. The first, second and third quartiles of the volume increase were 41, 95 and 135 ml, respectively. Breast size increased on average by 96 ml, regardless of the initial breast volume. Breast volume increases during pregnancy, but not all womens' breasts respond to pregnancy in the same way. Breast volume changes during pregnancy are an interesting phenotype that can be easily assessed in further studies to examine breast cancer risk.
EVALuna2:14487

Assessment of mammographic density before and after first full-term pregnancy - Löhberg, Christian; Heusinger, Katharina; Jud, Sebastian; Häberle, Lothar; Hein, Alexander; Rauh, Claudia; Bani, Mayada; Lux, Michael P.; Schrauder, Michael G.; Bayer, Christian M.; Helbig, Cosima; Grolik, Ronald; et al. (European Journal of Cancer Prevention, 2010)
Mammographic density (MD) has consistently been found as one of the strongest breast cancer risk factors. In our study, both qualitative and quantitative density measurements were performed in a hospital-based group of premenopausal women before and after first full-term pregnancy providing an opportunity for direct evaluation of the effects of one pregnancy on MD. Mammograms were obtained from 23 women before and after first full-term pregnancy and from 28 nulliparous controls. MD was determined by a standard qualitative assessment method using the Breast Imaging Reporting and Data System, and a quantitative computer-based threshold method (0-100%). The mean age at mammography before and after pregnancy was 31 and 34 years, respectively, with a mean difference of 40 months between mammographies. The quantitative density assessment showed a significant reduction in relative MD after pregnancy of 12 percentage points (8.6-15.4), compared with 3.1 (0.0-6.2) in the nulliparous control group (P<0.001). A reduction in MD of more than 10% was seen in 52% of the patients, compared with 18% of the controls. The qualitative density assessment confirmed a reduction in MD after pregnancy by one Breast Imaging Reporting and Data System category (P=0.02). This longitudinal study showed that MD can be influenced by one full-term pregnancy. This effect was seen with both quantitative and qualitative assessment methods. It may be hypothesized that breast cancer risk reduction associated with pregnancy is mediated through a direct reduction of MD, and MD assessment might be incorporated in individualizing risk assessment and prevention. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.
CRIS-Team Scopus Importer:2021-07-19
Keywords: Breast cancer risk; mammographic density; pregnancy

Assessment of side effects (SEs) impacting quality of life (QoL) in patients (pts) undergoing treatment (tx) for advanced breast cancer (ABC) in clinical practice: A real-world (RW) multi-country survey - Cardoso, F.; Rihani, J.; Aubel, D.; De Courcy, J.; Harmer, V.; Harbeck, N.; Casas, A.; Rugo, H. S.; Fasching, Peter; Haftchenary, S.; Pathak, P.; Schumacher-Wulf, E. (ANNALS OF ONCOLOGY, 2022)
CRIS-Team WoS Importer:2022-06-03

Assessment of the additional clinical potential of X-ray dark-field imaging for breast cancer in a preclinical setup - Emons, J.; Fasching, Peter; Wunderle, M.; Heindl, F.; Rieger, Jens; Horn, Florian; Pelzer, Georg; Ritter, André; Weber, Thomas; Radicke, M.; Polifka, Iris; Wachter, David Lukas; et al. (GEBURTSHILFE UND FRAUENHEILKUNDE, 2020)
CRIS-Team WoS Importer:2020-10-30

Assessment of the additional clinical potential of X-ray dark-field imaging for breast cancer in a preclinical setup - Emons, Julius; Fasching, Peter; Wunderle, Marius; Heindl, Felix; Rieger, Jens; Horn, Florian; Pelzer, Georg; Ritter, André; Weber, Thomas; Radicke, Marcus; Polifka, Iris; Wachter, David; et al. (Therapeutic Advances in Medical Oncology, 2020)
Background: Mammography can identify calcifications up to 50–100 μm in size as a surrogate parameter for breast cancer or ductal carcinoma in situ (DCIS). Microcalcifications measuring <50 µm are also associated with breast cancer or DCIS and are frequently not detected on mammography, although they can be detected with dark-field imaging. This study examined whether additional breast examination using X-ray dark-field imaging can increase the detection rate of calcifications. Advances in knowledge: (1) evaluation of additional modality of breast imaging; (2) specific evaluation of breast calcifications. Implications for patient care: the addition of X-ray dark-field imaging to conventional mammography could detect additional calcifications. Methods: Talbot–Lau X-ray phase–contrast imaging and X-ray dark-field imaging were used to acquire images of breast specimens. The radiation dosage with the technique is comparable with conventional mammography. Three X-ray gratings with periods of 5–10 µm between the X-ray tube and the flat-panel detector provide three different images in a single sequence: the conventional attenuation image, differential phase image, and dark-field image. The images were read by radiologists. Radiological findings were marked and examined pathologically. The results were described in a descriptive manner. Results: A total of 81 breast specimens were investigated with the two methods; 199 significant structures were processed pathologically, consisting of 123 benign and 76 malignant lesions (DCIS or invasive breast cancer). X-ray dark-field imaging identified 15 additional histologically confirmed carcinoma lesions that were visible but not declared suspicious on digital mammography alone. Another four malignant lesions that were not visible on mammography were exclusively detected with X-ray dark-field imaging. Conclusions: Adding X-ray dark-field imaging to digital mammography increases the detection rate for breast cancer and DCIS associated lesions with micrometer-sized calcifications. The use of X-ray dark-field imaging may be able to provide more accurate and detailed radiological classification of suspicious breast lesions. Adding X-ray dark-field imaging to mammography may be able to increase the detection rate and improve preoperative planning in deciding between mastectomy or breast-conserving therapy, particularly in patients with invasive lobular breast cancer.
CRIS-Team Scopus Importer:2020-09-25
Keywords: breast cancer; interferometry; mammography; microcalcifications

Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with prognosis of estrogen receptor-negative breast cancer after chemotherapy - Lei, Jieping; Rudolph, Anja; Moysich, Kirsten B.; Rafiq, Sajjad; Behrens, Sabine; Goode, Ellen L.; Pharoah, Paul Pd; Seibold, Petra; Fasching, Peter; Andrulis, Irene L.; Kristensen, Vessela N.; Couch, Fergus J.; et al. (Breast Cancer Research, 2015)
Tumor lymphocyte infiltration is associated with clinical response to chemotherapy in estrogen receptor (ER) negative breast cancer. To identify variants in immunosuppressive pathway genes associated with prognosis after adjuvant chemotherapy for ER-negative patients, we studied stage I-III invasive breast cancer patients of European ancestry, including 9,334 ER-positive (3,151 treated with chemotherapy) and 2,334 ER-negative patients (1,499 treated with chemotherapy).We pooled data from sixteen studies from the Breast Cancer Association Consortium (BCAC), and employed two independent studies for replications. Overall 3,610 single nucleotide polymorphisms (SNPs) in 133 genes were genotyped as part of the Collaborative Oncological Gene-environment Study, in which phenotype and clinical data were collected and harmonized. Multivariable Cox proportional hazard regression was used to assess genetic associations with overall survival (OS) and breast cancer-specific survival (BCSS). Heterogeneity according to chemotherapy or ER status was evaluated with the log-likelihood ratio test.Three independent SNPs in TGFBR2 and IL12B were associated with OS (P <10?³) solely in ER-negative patients after chemotherapy (267 events). Poorer OS associated with TGFBR2 rs1367610 (G > C) (per allele hazard ratio (HR) 1.54 (95% confidence interval (CI) 1.22 to 1.95), P = 3.08 × 10??) was not found in ER-negative patients without chemotherapy or ER-positive patients with chemotherapy (P for interaction <10-3). Two SNPs in IL12B (r² = 0.20) showed different associations with ER-negative disease after chemotherapy: rs2546892 (G > A) with poorer OS (HR 1.50 (95% CI 1.21 to 1.86), P = 1.81 × 10??), and rs2853694 (A > C) with improved OS (HR 0.73 (95% CI 0.61 to 0.87), P = 3.67 × 10??). Similar associations were observed with BCSS. Association with TGFBR2 rs1367610 but not IL12B variants replicated using BCAC Asian samples and the independent Prospective Study of Outcomes in Sporadic versus Hereditary Breast Cancer Study and yielded a combined HR of 1.57 ((95% CI 1.28 to 1.94), P = 2.05 × 10??) without study heterogeneity.TGFBR2 variants may have prognostic and predictive value in ER-negative breast cancer patients treated with adjuvant chemotherapy. Our findings provide further insights into the development of immunotherapeutic targets for ER-negative breast cancer.
EVALuna2:9270

Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer - Hampras, Shalaka S.; Sucheston-Campbell, Lara E.; Cannioto, Rikki; Chang-Claude, Jenny; Modugno, Francesmary; Doerk, Thilo; Hillemanns, Peter; Preus, Leah; Knutson, Keith L.; Wallace, Paul K.; Hong, Chi-Chen; Friel, Grace; et al. (Oncotarget, 2016)
Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer.In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients.The most significant global associations for all genes in the pathway were seen in endometrioid (p = 0.082) and clear cell (p = 0.083), with the most significant gene level association seen with TGFBR2 (p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 (p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA (p = 0.035, endometrioid and mucinous), LGALS1 (p = 0.03, mucinous), STAT5B (p = 0.022, clear cell), TGFBR1 (p = 0.021 endometrioid) and TGFBR2 (p = 0.017 and p = 0.025, endometrioid and mucinous, respectively).Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.
EVALuna2:9345

Association analysis identifies 65 new breast cancer risk loci - Michailidou, Kyriaki; Lindstrom, Sara; Dennis, Joe; Beesley, Jonathan; Hui, Shirley; Kar, Siddhartha; Lemacon, Audrey; Soucy, Penny; Glubb, Dylan; Rostamianfar, Asha; Bolla, Manjeet K.; Wang, Qin; et al. (Nature, 2017)
Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.
EVALuna2:9385

Association between breast cancer risk factors and molecular type in postmenopausal patients with hormone receptor-positive early breast cancer - Wunderle, Marius; Pretscher, Jutta; Brucker, Sara Y.; Volz, Bernhard; Hartmann, Arndt; Fießler, Cornelia; Hein, Alexander; Häberle, Lothar; Jud, Sebastian; Lux, Michael P.; Janni, Wolfgang; Löhberg, Christian; et al. (Breast Cancer Research and Treatment, 2019)
PurposeEvidence shows that genetic and non-genetic risk factors for breast cancer (BC) differ relative to the molecular subtype. This analysis aimed to investigate associations between epidemiological risk factors and immunohistochemical subtypes in a cohort of postmenopausal, hormone receptor-positive BC patients.MethodsThe prospective, single-arm, multicenter phase IV PreFace study (Evaluation of Predictive Factors Regarding the Effectivity of Aromatase Inhibitor Therapy) included 3529 postmenopausal patients with hormone receptor-positive early BC. Data on their epidemiological risk factors were obtained from patients' diaries and their medical histories. Data on estrogen receptor, progesterone receptor, and HER2 receptor status were obtained from pathology reports. Patients with incomplete information were excluded. Data were analyzed using conditional inference regression analysis, analysis of variance, and the chi-squared test.ResultsIn a cohort of 3392 patients, the strongest association with the molecular subtypes of BC was found for hormone replacement therapy (HRT) before diagnosis of early BC. The analysis showed that patients who took HRT at diagnosis had luminal A-like BC more often (83.7%) than those who had never taken HRT or had stopped taking it (75.5%). Luminal B-like BC and HER2-positive BC were diagnosed more often in women who had never taken HRT or had stopped taking it (13.3% and 11.2%, respectively) than in women who were taking HRT at diagnosis of BC (8.3% and 8.0%, respectively).ConclusionsThis analysis shows an association between HRT and the distribution of molecular subtypes of BC. However, no associations between other factors (e.g., age at diagnosis, body mass index, smoking status, age at menopause, number of deliveries, age at first delivery, breastfeeding history, or family history) were noted.
CRIS-Team WoS Importer:2019-03-29

Association between mammographic density and pregnancies relative to age and BMI: a breast cancer case-only analysis - Hack, Carolin; Emons, Julius; Jud, Sebastian; Heusinger, Katharina; Adler, Werner; Gaß, Paul; Haeberle, Lothar; Heindl, Felix; Hein, Alexander; Schulz-Wendtland, Rüdiger; Uder, Michael; Hartmann, Arndt; et al. (Breast Cancer Research and Treatment, 2017)
Percentage mammographic density (PMD) is a major risk factor for breast cancer (BC). It is strongly associated with body mass index (BMI) and age, which are themselves risk factors for breast cancer. This analysis investigated the association between the number of full-term pregnancies and PMD in different subgroups relative to age and BMI.Patients were identified in the breast cancer database of the University Breast Center for Franconia. A total of 2410 patients were identified, for whom information on parity, age, and BMI, and a mammogram from the time of first diagnosis were available for assessing PMD. Linear regression analyses were conducted to investigate the influence on PMD of the number of full-term pregnancies (FTPs), age, BMI, and interaction terms between them.As in previous studies, age, number of FTPs, and BMI were found to be associated with PMD in the expected direction. However, including the respective interaction terms improved the prediction of PMD even further. Specifically, the association between PMD and the number of FTPs differed in young patients under the age of 45 (mean decrease of 0.37 PMD units per pregnancy) from the association in older age groups (mean decrease between 2.29 and 2.39 PMD units). BMI did not alter the association between PMD and the number of FTPs.The effect of pregnancies on mammographic density does not appear to become apparent before the age of menopause. The mechanism that drives the effect of pregnancies on mammographic density appears to be counter-regulated by other influences on mammographic density in younger patients.
EVALuna2:14710

Association Between Obesity and Circulating Tumor Cells in Early Breast Cancer Patients - Tzschaschel, Marie; Friedl, Thomas W.P.; Schochter, Fabienne; Schütze, Sabine; Polasik, Arkadius; Fehm, Tanja; Pantel, Klaus; Schindlbeck, Christian; Schneeweiss, Andreas; Schreier, Jörg; Tesch, Hans; Lorenz, Ralf; et al. (Clinical Breast Cancer, 2023)
Background: Obesity and the presence of circulating tumor cells (CTCs) before and/or after chemotherapy are associated with poor outcome in breast cancer (BC) patients. The activation of oncogenic pathways in fatty tissue leads to cell proliferation, suggesting a possible link between obesity and CTCs. Materials and Methods: In the phase III SUCCESS A trial, 3754 patients with early BC were randomized to 3 cycles of fluorouracil, epirubicin and cyclophosphamide followed by 3 cycles of docetaxel with or without gemcitabine. Data of 1088 patients with CTC assessments (CellSearch-System; Menarini Silicon Biosystems, Italy) and body mass index (BMI) measurements both before and after chemotherapy were available. Patients were classified according to the WHO's international definitions as underweight, normal weight, overweight, or obese, and according to their weight-change during chemotherapy into a weight-loss group (> 5% decrease), stable-weight group (≤ 5% weight-change) or weight-gain group (>5% increase). Associations between CTC positivity and, BMI or weight-change group were analyzed using frequency-table methods. Results: At study entry, 47.4% patients were underweight or normal weight, 33.6% were overweight and 18.9% were obese. Before and after chemotherapy, CTCs were detected in 20.1% and 22.6% of patients, respectively. There was no association between CTC positivity and BMI before (P = 0.104) or after (P = 0.051) chemotherapy. Furthermore, there was no association between weight-change group and CTC status before/after chemotherapy (P = 0.332). Conclusions: According to our analysis, the risk factors obesity and prevalence of CTCs are not associated and may represent independent prognostic factors.
CRIS-Team Scopus Importer:2023-06-30
Keywords: CTCs; EBC; Overweight

Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21 - Hamdi, Yosr; Soucy, Penny; Adoue, Veronique; Michailidou, Kyriaki; Canisius, Sander; Lemacon, Audrey; Droit, Arnaud; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Baynes, Caroline; Blomqvist, Carl; et al. (Oncotarget, 2016)
There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10-6). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS), encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ (P = 8.28x10-14), MRPS18C (P = 1.94x10-27) and FAM175A (P = 3.83x10-3), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas.
EVALuna2:33314

Association of CA27.29 and Circulating Tumor Cells Before and at Different Times After Adjuvant Chemotherapy in Patients with Early-stage Breast Cancer - The SUCCESS Trial - Hepp, Philip; Andergassen, Ulrich; Jaezger, Bernadette; Trapp, Elisabeth; Alunni-Fabbroni, Marianna; Friedl, Thomas W. P.; Hecker, Nadeschda; Lorenz, Ralf; Fasching, Peter; Schneeweiss, Andreas; Fehm, Tanja; Janni, Wolfgang; et al. (Anticancer Research, 2016)
BACKGROUND: Evidence for the prognostic value of circulating tumor cells (CTCs) in early-stage breast cancer is swiftly increasing. An alternative approach for identifying patients at risk for recurrence is based on the detection of the mucin-1 (MUC1)-based tumor marker CA27.29. Here we report the association of these two prognostic markers before and immediately after chemotherapy (CHT), as well as after 2 and 5 years of follow-up. PATIENTS AND METHODS: The SUCCESS trial compared fluorouracil, epirubicin and cyclophosphamide followed by docetaxel vs. FEC followed by docetaxel plus gemcitabine, and 2 vs. 5 years of treatment with zoledronic acid in 3,754 patients with node-positive or high-risk node-negative early-stage breast cancer. CA27.29 was measured with the ST AIA-PACK CA27.29 reagent (Tosoh Bioscience, Belgium). The cutoff for CA27.29 positivity was >31 U/ml. CTCs were assessed with the CellSearch System (Veridex, USA). The cutoff for CTC positivity was ≥1 CTC/15 ml whole blood. The relationship between CTC positivity and CA27.29 positivity was assessed based on Chi-square statistics and Cramer's V, which varies from 0 (no association between the variables) to 1 (complete association). Samples for CA27.29 and CTC determinations during follow-up were only drawn from patients that had no relapse. RESULTS: Both CA27.29 and CTC data were available for 1,981, 1,602, 1,159 and 707 patients before, immediately after and at 2 and 5 years after CHT, respectively. Positivity rates for CTC were 21.3%, 22.8%, 18.6% and 8.5%, respectively. CA27.29 was positive in 7.9%, 21.0%, 2.8%and 7.5%, respectively. Positivity for both CA27.29 and CTC was found in 2.4%, 4.2%, 0.7% and 1.8% of patients, respectively. The association between CA27.29 and CTC was significant but weak before CHT (p=0.0015; Cramer's V=0.063) and 5 years after CHT (p<0.001; Cramer's V=0.164), and not significant immediately after CHT (p=0.162; Cramer's V=0.035) and 2 years after (p=0.349; Cramer's V=0.028). CONCLUSION: We showed that CTC and CA27.29 positivity were significantly, but only weakly associated before CHT and 5 years after CHT, while no significant association was found immediately or 2 years after CHT during the course of early-stage breast cancer. It, therefore, seems reasonable to further evaluate the prognostic value of CTCs and CA27.29 as a combined prognostic test of two potentially independent markers that might provide complementary prognostic information.
EVALuna2:33535

Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry - Zhao, Zhiguo; Wen, Wanqing; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Zhang, Ben; Long, Jirong; Shu, Xiao-Ou; Schmidt, Marjanka K.; Milne, Roger L.; Garcia-Closas, Montserrat; Chang-Claude, Jenny; et al. (Cancer Causes & Control, 2016)
PURPOSE: Type 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors. METHODS: We constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry. Unconditional logistic regression models were used to derive adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) to measure the association of breast cancer risk with T2D GRS or T2D-associated genetic risk variants. Meta-analyses were conducted to obtain summary ORs across all studies. RESULTS: The T2D GRS was not found to be associated with breast cancer risk, overall, by menopausal status, or for estrogen receptor positive or negative breast cancer. Three T2D associated risk variants were individually associated with breast cancer risk after adjustment for multiple comparisons using the Bonferroni method (at p < 0.001), rs9939609 (FTO) (OR 0.94, 95 % CI = 0.92-0.95, p = 4.13E-13), rs7903146 (TCF7L2) (OR 1.04, 95 % CI = 1.02-1.06, p = 1.26E-05), and rs8042680 (PRC1) (OR 0.97, 95 % CI = 0.95-0.99, p = 8.05E-04). CONCLUSIONS: We have shown that several genetic risk variants were associated with the risk of both T2D and breast cancer. However, overall genetic susceptibility to T2D may not be related to breast cancer risk.
EVALuna2:32983

Association of genomic variants at PAX8 and PBX2 with cervical cancer risk - Ramachandran, Dhanya; Wang, Yingying; Schuermann, Peter; Huelse, Fabienne; Mao, Qianqian; Jentschke, Matthias; Boehmer, Gerd; Strauss, Hans-Georg; Hirchenhain, Christine; Schmidmayr, Monika; Mueller, Florian; Runnebaum, Ingo; et al. (International Journal of Cancer, 2021)
Cervical malignancy is triggered by human papillomavirus infection but the risk for cervical cancer has a hereditary component. From a recent Genome Wide Association Study meta-analysis, 2q14.1 (PAX8) and 6p21.32 (PBX2) have been proposed as novel cervical cancer susceptibility loci. We investigated the two main signals at these loci in an independent case-control series of 2578 cases with cervical dysplasia or carcinoma and 1483 healthy females. We find significant associations for both variants, rs10175462 at PAX8 and rs2856437 at PBX2, with overall cervical disease (rs10175462: odds ratio [OR] 0.82, 95% confidence interval [CI] 0.74-0.91, P = 2.4 × 10−4; rs2856437: OR 1.52, 95% CI 1.14-2.02, P =.004). Both variants showed evidence of association with invasive squamous cervical cancer (rs10175462: OR 0.80, 95% CI 0.68-0.94, P =.006; rs2856437: OR 1.56, 95% CI 1.03-2.36, P =.036) and with high-grade dysplasia (rs10175462: OR 0.79, 95%CI 0.70-0.90, P = 1.9 × 10−4; rs2856437: OR 1.58, 95% CI 1.15-2.17, P =.005). A combined analysis of high-grade dysplasia and invasive cervical cancer also showed significant associations for both variants (rs10175462: OR 0.81, 95% CI 0.73-0.91, P = 2.4 × 10−4; rs2856437: OR 1.57, 95% CI 1.18-2.10, P =.002). No association was detected for rs2856437 with low-grade dysplasia, while rs10175462 showed weak evidence of association (P =.05). RNA analyses in cervical samples revealed that PAX8 transcripts were upregulated in HPV-positive lesions (P =.008) but this was not observed in the presence of the protective minor allele of rs10175462. The rs10175462 genotype also correlated with reduced levels of the lncRNA PAX8-AS1 (P <.001). Taken together, our results extend the evidence for a link between genomic risk variants at the HLA region (PBX2) with cervical disease and support PAX8 as the first consistent non-HLA cervical cancer susceptibility locus.
CRIS-Team Scopus Importer:2021-05-21
Keywords: association study; cervical malignancy; eQTL; HPV infection; single nucleotide polymorphism

Association of genomic variants at the human leukocyte antigen locus with cervical cancer risk,HPVstatus and gene expression levels - Ramachandran, Dhanya; Schuermann, Peter; Mao, Qianqian; Wang, Yingying; Bretschneider, Lisa-Marie; Speith, Lisa-Marie; Huelse, Fabienne; Enssen, Julia; Bousset, Kristine; Jentschke, Matthias; Boehmer, Gerd; Strauss, Hans-Georg; et al. (International Journal of Cancer, 2020)
The human leukocyte antigen (HLA) locus on chromosome 6 has been reported to be associated with cervical cancer. We investigated two independent single-nucleotide polymorphisms in a large case-control series of cervical dysplasia and carcinoma that has been newly established by the German Cervigen Consortium, comprising a total of 2481 cases and 1556 healthy females. We find significant associations for both variants, rs9272117 atHLA-DQA1and rs2844511 atMICAandHCP5, with cervical disease. Both variants showed evidence of association with invasive cervical cancer (rs9272117: OR 0.89, 95% CI 0.79-0.99,P= .036; rs2844511: OR 1.17, 95% CI 1.04-1.31,P= .008) and with high-grade dysplasia (rs9272117: OR 0.78, 95% CI 0.70-0.87,P= 7.1 x 10(-6); rs2844511: OR 1.13, 95% CI 1.01-1.26,P= .035), as well as in a combined analysis of both groups (rs9272117: OR 0.83, 95% CI 0.75-0.91,P= 6.9 x 10(-5); rs2844511: OR 1.14, 95% CI 1.04-1.26,P= .005). Variant rs2844511, but not rs9272117, also showed modest evidence of association with low-grade dysplasia (OR 1.26, 95% CI 1.04-1.54,P= .019). In case-only analyses, rs2844511 tended to predict HPV status (P= .044) and rs9272117 tended to associate with HPV16 (P= .022). RNA studies in cervical samples showed a significant correlation in the transcript levels ofMICA,HCP5andHLA-DQA1, suggesting extensive co-regulation. All three genes were upregulated in HPV16-positive samples. In stratified analyses, rs9272117 was associated withHLA-DQA1levels, specifically in HPV-positive samples, while rs2844511 was associated withMICAandHCP5levels. The risk allele of rs2844511 was required for correlations betweenMICAorHCP5withHLA-DQA1. Altogether, our results support 6p21.32-33 as the first consistent cervical cancer susceptibility locus and provide evidence for a link between genetic risk variants, HPV16 status and transcript levels ofHLA-DQA1,HCP5andMICA, which may contribute to tumor immune evasion.
CRIS-Team WoS Importer:2020-07-24

Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment - Morra, Anna; Escala-Garcia, Maria; Beesley, Jonathan; Keeman, Renske; Canisius, Sander; Ahearn, Thomas U.; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Auer, Paul L.; Augustinsson, Annelie; Freeman, Laura E. Beane; et al. (BREAST CANCER RES, 2021)
Background Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. Methods We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15). Results Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. Conclusions We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.
CRIS-Team WoS Importer:2021-09-03

Association of Germline Variant Status with Therapy Response in High-risk Early-Stage Breast Cancer: A Secondary Analysis of the GeparOcto Randomized Clinical Trial - Pohl-Rescigno, Esther; Hauke, Jan; Loibl, Sibylle; Möbus, Volker; Denkert, Carsten; Fasching, Peter; Kayali, Mohamad; Ernst, Corinna; Weber-Lassalle, Nana; Hanusch, Claus; Tesch, Hans; Müller, Volkmar; et al. (JAMA Oncology, 2020)
Importance: The GeparOcto randomized clinical trial compared the efficacy of 2 neoadjuvant breast cancer (BC) treatment regimens: Sequential intense dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddEPC) vs weekly paclitaxel and nonpegylated liposomal doxorubicin (PM) in patients with different biological BC subtypes. Patients with triple-negative BC (TNBC) randomized to the PM arm received additional carboplatin (PMCb). Overall, no difference in pathologic complete response (PCR) rates was observed between study arms. It remained elusive whether the germline variant status of BRCA1/2 and further BC predisposition genes are associated with treatment outcome. Objective: To determine treatment outcome for BC according to germline variant status. Design, Setting, and Participants: This retrospective biomarker study is a secondary analysis of the GeparOcto multicenter prospective randomized clinical trial conducted between December 2014 and June 2016. Genetic analyses assessing for variants in BRCA1/2 and 16 other BC predisposition genes in 914 of 945 women were performed at the Center for Familial Breast and Ovarian Cancer, Cologne, Germany, from August 2017 through December 2018. Main Outcomes and Measures: Proportion of patients who achieved PCR (ypT0/is ypN0 definition) after neoadjuvant treatment according to germline variant status. Results: In the study sample of 914 women with different BC subtypes with a mean (range) age at BC diagnosis of 48 (21-76) years, overall higher PCR rates were observed in patients with BRCA1/2 variants than in patients without (60.4% vs 46.7%; odds ratio [OR], 1.74; 95% CI, 1.13-2.68; P =.01); variants in non-BRCA1/2 BC predisposition genes were not associated with therapy response. Patients with TNBC with BRCA1/2 variants achieved highest PCR rates. In the TNBC subgroup, a positive BRCA1/2 variant status was associated with therapy response in both the PMCb arm (74.3% vs 47.0% without BRCA1/2 variant; OR, 3.26; 95% CI, 1.44-7.39; P =.005) and the iddEPC arm (64.7% vs 45.0%; OR, 2.24; 95% CI, 1.04-4.84; P =.04). A positive BRCA1/2 variant status was also associated with elevated PCR rates in patients with ERBB2-negative, hormone receptor-positive BC (31.8% vs 11.9%; OR, 3.44; 95% CI, 1.22-9.72; P =.02). Conclusions and Relevance: Effective chemotherapy for BRCA1/2-mutated TNBC is commonly suggested to be platinum based. With a PCR rate of 64.7%, iddEPC may also be effective in these patients, though further prospective studies are needed. The elevated PCR rate in BRCA1/2-mutated ERBB2-negative, hormone receptor-positive BC suggests that germline BRCA1/2 testing should be considered prior to treatment start. Trial Registration: ClinicalTrials.gov Identifier: NCT02125344.
CRIS-Team Scopus Importer:2020-03-27

Association of Maternal Smoking during Pregnancy with Neurophysiological and ADHD-Related Outcomes in School-Aged Children - Jansone, Karina; Eichler, Anna; Fasching, Peter; Kornhuber, Johannes; Kaiser, Anna; Millenet, Sabina; Banaschewski, Tobias; Nees, Frauke; On Behalf Of The Imac-Mind Consortium, (International Journal of Environmental Research and Public Health, 2023)
Data of a longitudinal cohort study were analyzed to investigate the association between prenatal tobacco exposure and electroencephalographical (EEG) power spectrum in healthy, school-aged children as well as its relationship with attention deficit hyperactivity disorder (ADHD)-related symptoms. Group comparisons (exposed, non-exposed) were performed to test whether prenatal tobacco exposure was associated with brain activity and ADHD symptoms, with adjustments made for covariates including child's sex, child's age, maternal age, maternal smoking habit before pregnancy, alcohol consumption during pregnancy, gestation age, and maternal psychopathology. Tobacco-exposed children showed higher brain activity in the delta and theta frequency bands. This effect was independent of the considered covariates. However, the effects on hyperactivity were found to significantly depend on maternal age and alcohol consumption during pregnancy, but not on the amount of exposure. In summary, smoking during pregnancy significantly affected the resting-state brain activity in children, independent of socio-demographic factors, indicating potential long-lasting effects on brain development. Its impact on ADHD-related behavior was shown to be influenced by socio-demographic confounding factors, such as maternal alcohol consumption and the age of the mother.
CRIS-Team Scopus Importer:2023-04-07
Keywords: ADHD; EEG; hyperactivity; maternal smoking; pregnancy; resting-state brain activity

Association of molecular subtypes with breast cancer risk factors: a case-only analysis - Rauh, Claudia; Gaß, Paul; Heusinger, Katharina; Haeberle, Lothar; Jud, Sebastian; Hein, Alexander; Löhberg, Christian; Lux, Michael P.; Wachter, David; Heimrich, Jutta; Strehl, Johanna D.; Haller, Florian; et al. (European Journal of Cancer Prevention, 2015)
As breast cancer (BC) screening identifies many BCs with a good prognosis, which might be overdiagnosed and therefore overtreated, the identification of subgroups with a high risk for aggressive subtypes might be helpful. The aim of this case-case analysis was to investigate the association between epidemiological risk factors and molecular subtypes in a cohort of BC patients. Epidemiological risk factors for 2587 BC patients were obtained using a structured questionnaire and from the patients' charts. The histopathological information (estrogen and progesterone receptor, HER2 and Ki-67) used in the analysis was retrieved from the original pathology reports. Analyses using conditional inference regression trees were carried out on these data. The strongest influence factor on the distribution of the molecular subtypes was age at first diagnosis of BC. An influence of BMI was also identified in patients aged either more than 42 years or 49.6 years or less. Older patients aged more than 49.6 years and perimenopausal women with a BMI of 32.4 kg/m or less were most likely to develop luminal A-like BC. Young patients aged 42 years or less and perimenopausal patients with a BMI more than 32.4 kg/m more often developed triple-negative BC. The study confirmed that age at diagnosis is an important factor influencing the distribution of molecular subtypes. In the perimenopausal group, it may be postulated that BMI plays a critical role in the pathogenesis of BC, defining a subgroup that is more likely to develop triple-negative BC or luminal B-like disease and another group in which there is a more postmenopausal distribution pattern.
EVALuna2:5482

Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study - Rambau, Peter F.; Vierkant, Robert A.; Intermaggio, Maria P.; Kelemen, Linda E.; Goodman, Marc T.; Herpel, Esther; Pharoah, Paul D.; Kommoss, Stefan; Jimenez-Linan, Mercedes; Karlan, Beth Y.; Gentry-Maharaj, Aleksandra; Menon, Usha; et al. (Journal of Pathology: Clinical Research, 2018)
We aimed to validate the prognostic association of p16 expression in ovarian high-grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical-grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis-associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47-2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30-2.75, p = 0.004), while absence was associated with shorter OS in low-grade serous carcinomas (HR: 2.95, 95% CI 1.61-5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype-specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low-grade serous carcinoma justifies CDK4 inhibition.
EVALuna2:50246

Association of Pathologic Complete Response with Long-Term Survival Outcomes in Triple-Negative Breast Cancer: A Meta-Analysis - Huang, Min; O'Shaughnessy, Joyce; Zhao, Jing; Haiderali, Amin; Cortes, Javier; Ramsey, Scott D.; Briggs, Andrew; Hu, Peter; Karantza, Vassiliki; Aktan, Gursel; Qi, Cynthia Z.; Gu, Chenyang; et al. (Cancer Research, 2020)
Pathologic complete response (pCR) following neoadjuvant therapy has been associated with improved event-free survival (EFS) and overall survival (OS) in early-stage breast cancer. The magnitude of this association varies by breast cancer subtype, yet further research focusing on subtype-specific populations is limited. Here we provide an updated and comprehensive evaluation of the association between pCR and survival outcomes in triple-negative breast cancer (TNBC). A literature review identified neoadjuvant studies, including clinical trials, real-world cohort studies, and studies that pooled multiple trials or cohorts, which reported EFS/OS results by pCR in patients with early-stage TNBC. Meta-analyses were performed to evaluate the association between pCR and EFS/OS and to predict long-term survival outcomes based on pCR status. Sensitivity analyses were conducted to assess the impact of cross-study variations. Twenty-five studies with over 4,000 patients with TNBC were identified. A synthesis of evidence from these studies suggested substantial improvement in EFS and OS for pCR versus non-pCR [EFS HR (95% confidence interval): 0.24 (0.20-0.29); OS: 0.19 (0.15-0.24)]; consistent results were reported in sensitivity analyses. Collectively, our findings suggest that adjuvant therapy is associated with improved EFS/OS in patients with TNBC who received neoadjuvant therapy, regardless of pCR status.
CRIS-Team WoS Importer:2021-01-29

Association of prenatal alcohol exposure and prenatal maternal depression with offspring low-grade inflammation in early adolescence - Maschke, Janina; Roetner, Jakob; Bösl, Sophia; Plank, Anne-Christine; Rohleder, Nicolas; Goecke, Tamme W.; Fasching, Peter; Beckmann, Matthias; Kratz, Oliver; Moll, Gunther; Lenz, Bernd; Kornhuber, Johannes; et al. (International Journal of Environmental Research and Public Health, 2021)
(1) This longitudinal study aimed to investigate the link between prenatal alcohol exposure and prenatal maternal depression with the offspring’s low-grade inflammatory status. (2) Prenatal alcohol exposure was determined via maternal self-report during the 3rd trimester of pregnancy (self-report+: n = 29) and the meconium alcohol metabolite Ethyl Glucuronide (EtG), collected at birth (≥30 ng/g: n = 23). The Edinburgh Postnatal Depression Scale (EPDS) was used to screen for prenatal maternal depressive symptoms during the 3rd trimester (≥10: n = 35). Fifteen years later, 122 adolescents (M = 13.32 years; 48.4% female) provided blood samples for the analysis of high sensitivity C-reactive protein (hsCRP; M = 0.91; SD = 1.28). (3) Higher hsCRP levels were found in EtG positive adolescents (p = 0.036, ηp2 = 0.04) and an inverse non-significant dose–response relation with hsCRP (r = −0.35, p = 0.113). For maternal self-reported prenatal alcohol consumption (p = 0.780, ηp2 = 0.00) and prenatal depressive symptoms (p = 0.360, ηp2 = 0.01) no differences for hsCRP levels between the affected and unaffected groups were found. (4) Adolescents with prenatal alcohol exposure are at risk for low-grade systemic inflammation. The EtG biomarker may be more accurate compared to self-reports. The findings suggest that prenatal maternal depression does not evoke low-grade systemic inflammation.
CRIS-Team Scopus Importer:2021-08-06
Keywords: Early adolescence; High-sensitivity C-reactive protein (hsCRP); Low-grade systemic inflammation; Maternal self-report; Meconium ethyl glucuronide (EtG); Pregnancy; Prenatal alcohol exposure (PAE); Prenatal depression

Association of quality of life (QOL) with overall survival (OS) in patients (pts) with HR+/HER2-advanced breast cancer (ABC) treated with ribociclib (RIB) plus endocrine therapy (ET) in the MONALEESA-3 (ML-3) and ML-7 trials - Fasching, Peter; Harbeck, N.; Jerusalem, G.; Colleoni, M. A.; Neven, P.; Franke, F.; De Laurentiis, M.; Tripathy, D.; Martin, M.; Babu, G.; Yardley, D.; Wheatley-Price, P.; et al. (ANNALS OF ONCOLOGY, 2021)
CRIS-Team WoS Importer:2021-10-15

Association of RAD51 with homologous recombination deficiency (HRD) and clinical outcomes in untreated triple-negative breast cancer (TNBC): analysis of the GeparSixto randomized clinical trial - Llop-Guevara, A.; Loibl, S.; Villacampa, G.; Vladimirova, V.; Schneeweiss, A.; Karn, T.; Zahm, D. M.; Herencia-Ropero, A.; Jank, P.; van Mackelenbergh, M.; Fasching, Peter; Marmé, F.; et al. (Annals of Oncology, 2021)
Background: Current genetic and genomic tests measuring homologous recombination deficiency (HRD) show limited predictive value. This study compares the performance of an immunohistology-based RAD51 test with genetic/genomic tests to identify patients with HRD primary triple-negative breast cancer (TNBC) and evaluates its accuracy to select patients sensitive to platinum-based neoadjuvant chemotherapy (NACT). Patients and methods: This is a retrospective, blinded, biomarker analysis from the GeparSixto randomized clinical trial. TNBC patients received neoadjuvant paclitaxel plus Myocet®-nonpegylated liposomal doxorubicin (PM) or PM plus carboplatin (PMCb), both arms including bevacizumab. Formalin-fixed paraffin-embedded (FFPE) tumor samples were laid on tissue microarrays. RAD51, BRCA1 and γH2AX were quantified using an immunofluorescence assay. The predictive value of RAD51 was assessed by regression models. Concordance analyses were carried out between RAD51 score and tumor BRCA (tBRCA) status or genomic HRD score (Myriad myChoice®). Associations with pathological complete response (pCR) and survival were studied. Functional HRD was predefined as a RAD51 score ≤10% (RAD51-low). Results: Functional HRD by RAD51-low was evidenced in 81/133 tumors (61%). RAD51 identified 93% tBRCA-mutated tumors and 45% non-tBRCA mutant cases as functional HRD. The concordance between RAD51 and genomic HRD was 87% [95% confidence interval (CI) 79% to 93%]. In patients with RAD51-high tumors, pCR was similar between treatment arms [PMCb 31% versus PM 39%, odds ratio (OR) 0.71, 0.23-2.24, P = 0.56]. Patients with RAD51-low tumors benefited from PMCb (pCR 66% versus 33%, OR 3.96, 1.56-10.05, P = 0.004; interaction test P = 0.02). This benefit maintained statistical significance in the multivariate analysis. Carboplatin addition showed similar disease-free survival in the RAD51-high [hazard ratio (HR) 0.40, log-rank P = 0.11] and RAD51-low (0.45, P = 0.11) groups. Conclusions: The RAD51 test identifies tumors with functional HRD and is highly concordant with tBRCA mutation and genomic HRD. RAD51 independently predicts clinical benefit from adding Cb to NACT in TNBC. Our results support further development to incorporate RAD51 testing in clinical decision-making.
CRIS-Team Scopus Importer:2021-10-22
Keywords: BRCA1; BRCA2; HRD biomarkers; personalized medicine; platinum-based neoadjuvant chemotherapy; RAD51; triple-negative breast cancer

Association of RAD51 with homologous recombination deficiency (HRD) and clinical outcomes in untreated triple-negative breast cancer (TNBC): Analysis of the GeparSixto randomized clinical trial - Llop-Guevara, A.; Vladimirova, V.; Schneeweiss, A.; Villacampa, G.; Karn, T.; Zahm, D-M.; Herencia-Ropero, A.; Jank, P.; Van Mackelenbergh, M.; Fasching, Peter; Marme, F.; Stickeler, E.; et al. (Annals of Oncology, 2021)
CRIS-Team WoS Importer:2021-05-28

Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival. - Morra, Anna; Schreurs, Maartje A.C.; Andrulis, Irene L.; Anton-Culver, Hoda; Augustinsson, Annelie; Beckmann, Matthias; Behrens, Sabine; Bojesen, Stig E.; Bolla, Manjeet K.; Brauch, Hiltrud; Broeks, Annegien; Buys, Saundra S.; et al. (Cancer Medicine, 2023)
BACKGROUND: Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers. AIM: To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. METHODS: Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. RESULTS: There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55-0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09-1.56)]. CONCLUSION: Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.
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Association of two genomic variants with HPV type-specific risk of cervical cancer - Seifert, Finja; Eisenblätter, Rieke; Beckmann, Julia; Schürmann, Peter; Hanel, Patricia; Jentschke, Matthias; Böhmer, Gerd; Strauß, Hans Georg; Hirchenhain, Christine; Schmidmayr, Monika; Müller, Florian; Fasching, Peter; et al. (Tumour Virus Research, 2023)
Problem: Human papillomavirus infection is integral to developing invasive cervical cancer in the majority of patients. In a recent genome-wide association study, rs9357152 and rs4243652 have been associated with seropositivity for HPV16 or HPV18, respectively. It is unknown whether these variants also associate with cervical cancer triggered by either HPV16 or HPV18. Methods: We investigate whether the two HPV susceptibility variants show association with type-specific cervical cancer in a genetic case-control study with cases stratified by HPV16 or HPV18, respectively. We further tested whether rs9357152 modulates gene expression of any of 36 genes at the human leukocyte antigen locus in 256 cervical tissues. Results: rs9357152 was associated with invasive HPV16-positive cervical cancer (OR 1.33, 95%CI 1.03–1.70, p = 0.03), and rs4243652 was associated with HPV18-positive adenocarcinomas (OR 2.96, 95%CI 1.18–7.41, p = 0.02). These associations remained borderline significant after testing against different sets of controls. rs9357152 was found to be an eQTL for HLA-DRB1 in HPV-positive cervical tissues (pANOVA = 0.0009), with the risk allele lowering mRNA levels. Conclusions: We find evidence that HPV seropositivity variants at chromosome 6 and 14 may modulate type-specific cervical cancer risk. rs9357152 may exert its effect through regulating HLA-DRB1 induction in the presence of HPV. In regard of multiple testing, these results need to be confirmed in larger studies.
CRIS-Team Scopus Importer:2023-08-11
Keywords: Association study; eQTL; HPV infection; Human leukocyte antigen; Single nucleotide polymorphism; VASH1

Association of vitamin D levels and risk of ovarian cancer: a Mendelian randomization study - Ong, Jue-Sheng; Cuellar-Partida, Gabriel; Lu, Yi; Fasching, Peter A.; Hein, Alexander; Burghaus, Stefanie; Beckmann, Matthias; Lambrechts, Diether; Van Nieuwenhuysen, Els; Vergote, Ignace; Vanderstichele, Adriaan; Doherty, Jennifer Anne; et al. (International Journal of Epidemiology, 2016)
BACKGROUND: In vitro and observational epidemiological studies suggest that vitamin D may play a role in cancer prevention. However, the relationship between vitamin D and ovarian cancer is uncertain, with observational studies generating conflicting findings. A potential limitation of observational studies is inadequate control of confounding. To overcome this problem, we used Mendelian randomization (MR) to evaluate the association between single nucleotide polymorphisms (SNPs) associated with circulating 25-hydroxyvitamin D [25(OH)D] concentration and risk of ovarian cancer. METHODS: We employed SNPs with well-established associations with 25(OH)D concentration as instrumental variables for MR: rs7944926 (DHCR7), rs12794714 (CYP2R1) and rs2282679 (GC). We included 31 719 women of European ancestry (10 065 cases, 21 654 controls) from the Ovarian Cancer Association Consortium, who were genotyped using customized Illumina Infinium iSelect (iCOGS) arrays. A two-sample (summary data) MR approach was used and analyses were performed separately for all ovarian cancer (10 065 cases) and for high-grade serous ovarian cancer (4121 cases). RESULTS: The odds ratio for epithelial ovarian cancer risk (10 065 cases) estimated by combining the individual SNP associations using inverse variance weighting was 1.27 (95% confidence interval: 1.06 to 1.51) per 20 nmol/L decrease in 25(OH)D concentration. The estimated odds ratio for high-grade serous epithelial ovarian cancer (4121 cases) was 1.54 (1.19, 2.01). CONCLUSIONS: Genetically lowered 25-hydroxyvitamin D concentrations were associated with higher ovarian cancer susceptibility in Europeans. These findings suggest that increasing plasma vitamin D levels may reduce risk of ovarian cancer.
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Associations between genetically predicted circulating protein concentrations and endometrial cancer risk - Zhu, Jingjing; O’mara, Tracy A.; Liu, Duo; Setiawan, Veronica Wendy; Glubb, Dylan; Spurdle, Amanda B.; Fasching, Peter; Lambrechts, Diether; Buchanan, Daniel; Kho, Pik Fang; Cook, Linda S.; Friedenreich, Christine; et al. (Cancers, 2021)
Endometrial cancer (EC) is the leading female reproductive tract malignancy in developed countries. Currently, genome-wide association studies (GWAS) have identified 17 risk loci for EC. To identify novel EC-associated proteins, we used previously reported protein quantitative trait loci for 1434 plasma proteins as instruments to evaluate associations between genetically predicted circulating protein concentrations and EC risk. We studied 12,906 cases and 108,979 controls of European descent included in the Endometrial Cancer Association Consortium, the Epidemiology of Endometrial Cancer Consortium, and the UK Biobank. We observed associations between genetically predicted concentrations of nine proteins and EC risk at a false discovery rate of <0.05 (p-values range from 1.14 × 10−10 to 3.04 × 10−4). Except for vascular cell adhesion protein 1, all other identified proteins were independent from known EC risk variants identified in EC GWAS. The respective odds ratios (95% confidence intervals) per one standard deviation increase in genetically predicted circulating protein concentrations were 1.21 (1.13, 1.30) for DNA repair protein RAD51 homolog 4, 1.27 (1.14, 1.42) for desmoglein-2, 1.14 (1.07, 1.22) for MHC class I polypeptide-related sequence B, 1.05 (1.02, 1.08) for histo-blood group ABO system transferase, 0.77 (0.68, 0.89) for intestinal-type alkaline phosphatase, 0.82 (0.74, 0.91) for carbohydrate sulfotransferase 15, 1.07 (1.03, 1.11) for D-glucuronyl C5-epimerase, and 1.07 (1.03, 1.10) for CD209 antigen. In conclusion, we identified nine potential EC-associated proteins. If validated by additional studies, our findings may contribute to understanding the pathogenesis of endometrial tumor development and identifying women at high risk of EC along with other EC risk factors and biomarkers.
CRIS-Team Scopus Importer:2021-05-07
Keywords: Endometrial cancer; Genetic instrument; Protein biomarker; Risk

Associations of a Breast Cancer Polygenic Risk Score With Tumor Characteristics and Survival - Lopes Cardozo, Josephine M.N.; Andrulis, Irene L.; Bojesen, Stig E.; Dörk, Thilo; Eccles, Diana M.; Fasching, Peter; Hooning, Maartje J.; Keeman, Renske; Nevanlinna, Heli; Rutgers, Emiel J.T.; Easton, Douglas F.; Hall, Per; et al. (Journal of Clinical Oncology, 2023)
PURPOSE: A polygenic risk score (PRS) consisting of 313 common genetic variants (PRS313) is associated with risk of breast cancer and contralateral breast cancer. This study aimed to evaluate the association of the PRS313 with clinicopathologic characteristics of, and survival following, breast cancer. METHODS: Women with invasive breast cancer were included, 98,397 of European ancestry and 12,920 of Asian ancestry, from the Breast Cancer Association Consortium (BCAC), and 683 women from the European MINDACT trial. Associations between PRS313 and clinicopathologic characteristics, including the 70-gene signature for MINDACT, were evaluated using logistic regression analyses. Associations of PRS313 (continuous, per standard deviation) with overall survival (OS) and breast cancer-specific survival (BCSS) were evaluated with Cox regression, adjusted for clinicopathologic characteristics and treatment. RESULTS: The PRS313 was associated with more favorable tumor characteristics. In BCAC, increasing PRS313 was associated with lower grade, hormone receptor-positive status, and smaller tumor size. In MINDACT, PRS313 was associated with a low risk 70-gene signature. In European women from BCAC, higher PRS313 was associated with better OS and BCSS: hazard ratio (HR) 0.96 (95% CI, 0.94 to 0.97) and 0.96 (95% CI, 0.94 to 0.98), but the association disappeared after adjustment for clinicopathologic characteristics (and treatment): OS HR, 1.01 (95% CI, 0.98 to 1.05) and BCSS HR, 1.02 (95% CI, 0.98 to 1.07). The results in MINDACT and Asian women from BCAC were consistent. CONCLUSION: An increased PRS313 is associated with favorable tumor characteristics, but is not independently associated with prognosis. Thus, PRS313 has no role in the clinical management of primary breast cancer at the time of diagnosis. Nevertheless, breast cancer mortality rates will be higher for women with higher PRS313 as increasing PRS313 is associated with an increased risk of disease. This information is crucial for modeling effective stratified screening programs.
CRIS-Team Scopus Importer:2023-04-07

Associations of obesity and circulating insulin and glucose with breast cancer risk: a Mendelian randomization analysis - Shu, Xiang; Wu, Lang; Khankari, Nikhil K.; Shu, Xiao-Ou; Wang, Thomas J.; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Milne, Roger L.; Schmidt, Marjanka K.; Pharoah, Paul D. P.; et al. (International Journal of Epidemiology, 2019)
Background: In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear.
CRIS-Team WoS Importer:2019-10-08

Associations of prenatal depressive symptoms with DNA methylation of HPA axis-related genes and diurnal cortisol profiles in primary school-aged children - Stonawski, Valeska; Frey, Stefan; Golub, Yulia; Rohleder, Nicolas; Kriebel, Jennifer; Goecke, Tamme W.; Fasching, Peter; Beckmann, Matthias; Kornhuber, Johannes; Kratz, Oliver; Moll, Gunther; Heinrich, Hartmut; et al. (Development and Psychopathology, 2018)

Associations of prenatal depressive symptoms with DNA methylation of HPA axis-related genes and diurnal cortisol profiles in primary school-aged children - Stonawski, Valeska; Frey, Stefan; Golub, Yulia; Rohleder, Nicolas; Kriebel, Jennifer; Goecke, Tamme W.; Fasching, Peter; Beckmann, Matthias; Kornhuber, Johannes; Kratz, Oliver; Heinrich, Hartmut; Moll, Gunther; et al. (Development and Psychopathology, 2019)
Epigenetic DNA modifications in genes related to the hypothalamic-pituitary-adrenal (HPA) axis are discussed as a mechanism underlying the association between prenatal depression and altered child HPA activity. In a longitudinal study, DNA methylation changes related to prenatal depressive symptoms were investigated in 167 children aged 6 to 9 years. At six candidate genes, 126 cytosine-guanine dinucleotides were considered without correcting for multiple testing due to the exploratory nature of the study. Further associations with the basal child HPA activity were examined. Children exposed to prenatal depressive symptoms exhibited lower bedtime cortisol (p = .003, ηp2 = 0.07) and a steeper diurnal slope (p = .023, ηp2 = 0.06). For total cortisol release, prenatal exposure was related to lower cortisol release in boys, and higher release in girls. Furthermore, prenatal depressive symptoms were associated with altered methylation in the glucocorticoid receptor gene (NR3C1), the mineralocorticoid receptor gene (NR3C2), and the serotonin receptor gene (SLC6A4), with some sex-specific effects (p = .012-.040, ηp2 = 0.03-0.04). In boys, prenatal depressive symptoms predicted bedtime cortisol mediated by NR3C2 methylation, indirect effect = -0.07, 95% confidence interval [-0.16, -0.02]. Results indicate relations of prenatal depressive symptoms to both child basal HPA activity and DNA methylation, partially fitting a mediation model, with exposed boys and girls being affected differently.
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A Standard Mammography Unit - Standard 3D Ultrasound Probe Fusion Prototype: First Results - Schulz-Wendtland, Rüdiger; Jud, Sebastian; Fasching, Peter; Hartmann, Arndt; Radicke, Marcus; Rauh, Claudia; Uder, Michael; Wunderle, Marius; Gaß, Paul; Langemann, Hanna; Beckmann, Matthias; Emons, Julius (Geburtshilfe und Frauenheilkunde, 2017)
The combination of different imaging modalities through the use of fusion devices promises significant diagnostic improvement for breast pathology. The aim of this study was to evaluate image quality and clinical feasibility of a prototype fusion device (fusion prototype) constructed from a standard tomosynthesis mammography unit and a standard 3D ultrasound probe using a new method of breast compression.Imaging was performed on 5 mastectomy specimens from patients with confirmed DCIS or invasive carcinoma (BI-RADS ((TM)) 6). For the preclinical fusion prototype an ABVS system ultrasound probe from an Acuson S2000 was integrated into a MAMMOMAT Inspiration (both Siemens Healthcare Ltd) and, with the aid of a newly developed compression plate, digital mammogram and automated 3D ultrasound images were obtained.The quality of digital mammogram images produced by the fusion prototype was comparable to those produced using conventional compression. The newly developed compression plate did not influence the applied x-ray dose. The method was not more labour intensive or time-consuming than conventional mammography. From the technical perspective, fusion of the two modalities was achievable.In this study, using only a few mastectomy specimens, the fusion of an automated 3D ultrasound machine with a standard mammography unit delivered images of comparable quality to conventional mammography. The device allows simultaneous ultrasound - the second important imaging modality in complementary breast diagnostics - without increasing examination time or requiring additional staff.
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A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk - Lu, Yingchang; Beeghly-Fadiel, Alicia; Wu, Lang; Guo, Xingyi; Li, Bingshan; Schildkraut, Joellen M.; Im, Hae Kyung; Chen, Yian A.; Permuth, Jennifer B.; Reid, Brett M.; Teer, Jamie K.; Moysich, Kirsten B.; et al. (Cancer Research, 2018)
Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10-6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10-7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10-3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419-30. ©2018 AACR.
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A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer - Wu, Lang; Shi, Wei; Long, Jirong; Guo, Xingyi; Michailidou, Kyriaki; Beesley, Jonathan; Bolla, Manjeet K.; Shu, Xiao-Ou; Lu, Yingchang; Cai, Qiuyin; Al-Ejeh, Fares; Rozali, Esdy; et al. (Nature Genetics, 2018)
The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.
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Attention, cognitive control and motivation in ADHD: Linking event-related brain potentials and DNA methylation patterns in boys at early school age - Heinrich, Hartmut; Grunitz, Juliane; Stonawski, Valeska; Frey, Silke; Wahl, Simone; Albrecht, Bjoern; Goecke, Tamme W.; Beckmann, Matthias; Kornhuber, Johannes; Fasching, Peter; Moll, Gunther; Eichler, Anna (Scientific Reports, 2017)
In order to better understand the underpinnings of attention-deficit/hyperactivity disorder (ADHD), we targeted the relationship of attentional, cognitive control and motivational processes with DNA methylation patterns of 60 candidate genes in boys at early school age. Participants (6 to 8 years; N = 82) were selected from a German longitudinal cohort (FRANCES). ADHD-related behaviour was assessed via maternal ratings. Performance and event-related potential measures (inter alia Cue-P3 and Nogo-P3), which were recorded in a motivational go/nogo task, indicated diminished attentional orienting, reduced inhibitory response control and a larger motivational effect on performance in ADHD already at this relatively young age. Methylation patterns were analysed in buccal cell DNA with the Illumina HumanMethylation 450K array. For CpG sites at genes of the dopaminergic (COMT, ANKK1) and the neurotrophic (BDNF, NGFR) system, associations with the Nogo-P3 as well as ADHD symptom severity were found suggesting that these systems are involved in response control deficits in ADHD. Methylation effects related to both functional aspects and ADHD behaviour were also observed for DPP10 and TPH2. Epigenetic mechanisms may play a role in ADHD-associated deficits but findings need to be replicated in larger samples and are limited by the fact that only peripheral methylation could be considered.
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Automated artifact detection in abbreviated dynamic contrast-enhanced (DCE) MRI-derived maximum intensity projections (MIPs) of the breast - Kapsner, Lorenz; Ohlmeyer, Sabine; Folle, Lukas; Laun, Frederik Bernd; Nagel, Armin Michael; Liebert, Andrzej; Schreiter, Hannes; Beckmann, Matthias; Uder, Michael; Wenkel, Evelyn; Bickelhaupt, Sebastian (European Radiology, 2022)
Objectives To automatically detect MRI artifacts on dynamic contrast-enhanced (DCE) maximum intensity projections (MIPs) of the breast using deep learning. Methods Women who underwent clinically indicated breast MRI between October 2015 and December 2019 were included in this IRB-approved retrospective study. We employed two convolutional neural network architectures (ResNet and DenseNet) to detect the presence of artifacts on DCE MIPs of the left and right breasts. Networks were trained on images acquired up to and including the year 2018 using a 5-fold cross-validation (CV). Ensemble classifiers were built with the resulting CV models and applied to an independent holdout test dataset, which was formed by images acquired in 2019. Results Our study sample contained 2265 examinations from 1794 patients (median age at first acquisition: 50 years [IQR: 17 years]), corresponding to 1827 examinations of 1378 individuals in the training dataset and 438 examinations of 416 individuals in the holdout test dataset with a prevalence of image-level artifacts of 53% (1951/3654 images) and 43% (381/876 images), respectively. On the holdout test dataset, the ResNet and DenseNet ensembles demonstrated an area under the ROC curve of 0.92 and 0.94, respectively. Conclusion Neural networks are able to reliably detect artifacts that may impede the diagnostic assessment of MIPs derived from DCE subtraction series in breast MRI. Future studies need to further explore the potential of such neural networks to complement quality assurance and improve the application of DCE MIPs in a clinical setting, such as abbreviated protocol
Keywords: Artifacts; Magnetic resonance imaging; Breast; Contrast agent; Neural network

Awareness of breast cancer incidence and risk factors among healthy women in Germany: an update after 10 years - Poehls, Uwe G.; Hack, Carolin; Wunderle, Marius; Renner, Stefan P.; Lux, Michael P.; Beckmann, Matthias; Fasching, Peter; Nabieva, Naiba (European Journal of Cancer Prevention, 2019)
Early breast cancer detection programs depend for effectiveness on the participation rate, which is affected by risk factor awareness. This study investigated changes in women's risk factor awareness between 2004 and 2016. Results from a 2004 survey of 2107 healthy women were compared with new data obtained using the same questionnaire in 2016, with 866 participants indicating their knowledge and perceptions regarding breast cancer incidence, risk factors, risk perceptions, and levels of concern. Logistic regression models assessed the influence of time point (2004 vs. 2016) on correct recognition of risk factors such as age at first childbirth, childlessness, lack of breastfeeding, hormone replacement therapy (HRT), and family history. Regression models were adjusted for common sociodemographic characteristics. Reproductive risk factors were regarded as influencing breast cancer risk less often. In 2004, age at first birth, childlessness, and lack of breastfeeding were regarded as risk factors by 24, 32, and 37%, respectively, in comparison with only 15, 18, and 23% in 2016. All changes were statistically significant. Awareness of HRT as a risk factor increased significantly (36-57%), and family history was recognized as a risk by 75 and 73% in 2004 and 2016, respectively. Most women recognized family history as a breast cancer risk factor. This did not change, reflecting the topic's media prominence. Awareness of HRT as a risk factor increased, probably owing to public information after the large HRT studies. It is unclear why reproductive risk factors are less frequently recognized; educational programs should address this information deficit.
CRIS-Team Scopus Importer:2019-10-08

AXSANA (AXillary Surgery After NeoAdjuvant Treatment): A European prospective multicenter cohort study to evaluate different surgical methods of axillary staging (sentinel lymph node biopsy, targeted axillary dissection, axillary dissection) in clinically node-positive breast cancer patients treated with neoadjuvant chemotherapy - Banys-Paluchowski, M.; Stickeler, E.; De Boniface, J.; Gentilini, O.; Thill, M.; Hartmann, S.; Fasching, Peter; Hübner, Hanna; Krawczyk, N.; Blohmer, J-U; Solbach, C.; Untch, M.; et al. (GEBURTSHILFE UND FRAUENHEILKUNDE, 2020)
CRIS-Team WoS Importer:2020-07-31

BACH1 and HIF1 alpha predict response to neoadjuvant nab-paclitaxel (nP) treatment in early breast cancer (BC) - Vladimirova, V.; Schneeweiss, A.; Jackisch, C.; Weber, K. E.; Denkert, C.; Schmatloch, S.; Karn, T.; Fasching, Peter; Braun, S.; Szeto, C.; Sinn, B.; Van Mackelenbergh, M.; et al. (ANNALS OF ONCOLOGY, 2021)
CRIS-Team WoS Importer:2021-05-28

Baseline menopausal status, Ki-67 and stromal tumour-infiltrating lymphocytes (TILs) and association with outcome in triple-negative breast cancer (TNBC): Exploratory analysis in GeparSixto - Labidi-Galy, S. I.; Schneeweiss, A.; Sinn, H. P.; Blohmer, J-U.; Romanens, L.; Zahm, D-M.; Huober, J.; Dohnal, D.; Link, T.; Hanusch, C.; Jackisch, C.; Fasching, Peter; et al. (ANNALS OF ONCOLOGY, 2021)
CRIS-Team WoS Importer:2021-05-28

Becoming a resident in Germany: an experience-based practical guideline - Bogdanyova, Sandra; Lermann, Johannes; Mendes, Miguel De Sousa; Schott, Sarah (Archives of Gynecology and Obstetrics, 2015)
Many young doctors in Europe and beyond are considering different career alternatives. Germany is one of the most sought after countries for medical specialization. Since there is no centralized structured application process, course, or nationwide rotating program, it may seem a little bit easier to find job opportunities in Germany than in other European countries. However, the process of changing country of residence, looking for and finding new employment, and obtaining all the required paperwork is far from easy. It is therefore essential to gather as much information about the application and its process when considering a career move in order to be well prepared about what may come before and after applying for a resident position.The essential information about the application possibilities and process were reviewed and summarized.This article provides a practical guide on how to proceed when considering job opportunities as a resident in Germany, the application process, and what to expect once a job has been found.
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Beeinträchtigung der Gonadenfunktion nach Chemo- und Strahlentherapie im Kindes- und Jugendalter: Handlungsempfehlungen nach der S1 Leitlinie - Borgmann-Staudt, Anja; Jantke, Andreas; Hinz, Stefan; Beckmann, Matthias; Dittrich, Ralf; Lotz, Laura; Balcerek, Magdalena (Monatsschrift Kinderheilkunde, 2023)
CRIS-Team Scopus Importer:2023-05-26

Berlin, 03.01.2017 240th Opinion of DZK in Collaboration with FZB, DGI, DGPI, GPP, DGGG, DRG and DGMP on Tuberculous Screening in Pregnant Women in the Context of 36 (4) Infection Protection Act (IfSG) - Seelbach-Goebe, Birgit; Beckmann, Matthias (Geburtshilfe und Frauenheilkunde, 2017)
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Berlin, 15th July 2016 Report on the Outline of the "Guideline for Obtaining Blood and Blood Components and for the Usage of Blood Products (Guideline of Haemotherapy)" Report of the German Society of Gynaecology and Obstetrics (GSGO) - Wallwiener, Diethelm; Beckmann, Matthias (Geburtshilfe und Frauenheilkunde, 2016)
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Berlin, 16.08.2017 250th Statement of the German Society of Gynecology and Obstetrics e. V. for the Modification of the Cancer Awareness Guidelines (KFE-RL) Mammography Screening: Letters of invitation and decision-making as well as other Changes in Section III B of the CRCD - Seelbach-Goebel, Birgit; Beckmann, Matthias (Geburtshilfe und Frauenheilkunde, 2017)
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Berlin, 17.02.2017 244th Statement of the German Society of Gynecology and Obstetrics e. V. for the Modification of Children's RiLi until the Age of 6: Examination Book for Children for Extended Neonatal Screening and Screening for Cystic Fibrosis - Seelbach-Goebel, Birgit; Beckmann, Matthias (Geburtshilfe und Frauenheilkunde, 2017)
EVALuna2:36124

Berlin, 18th May 2017 245th Opinion of the DGGG on transcervical Radiofrequency Ablation with intrauterine Ultrasound Guidance in Uterine Myomas - Runnebaum, Ingo; Seelbach-Goebel, Birgit; Beckmann, Matthias (Geburtshilfe und Frauenheilkunde, 2017)
EVALuna2:36138

Berlin, 20th April 2016 Statement on the planned Design of the G-BA for Changing of Directives on medical Measures for artificial Insemination (KB -RL) - Semen Analysis Parameter for an Indication for Intracytoplasmic Sperm Injection rather than In-vitro-Fertilization - Wallwiener, Diethelm; Beckmann, Matthias (Geburtshilfe und Frauenheilkunde, 2016)
EVALuna2:32973

Berlin, 20th June 2016 Report for Modification of the Guideline about the Early Detection of Diseases in Children under the Age of 6 Years (Children's Guideline): Screening for critical congenital Heart Disease using Pulse Oximetry in Newborn Report of the German Society of Gynaecology and Obstetrics (GSGO) - Wallwiener, Diethelm; Beckmann, Matthias (Geburtshilfe und Frauenheilkunde, 2016)
EVALuna2:32965

Berlin, 25.05.2016 Opinion for Changes of Early Cancer Detection-Guideline (KFE-RL): Cervical Cancer - screening - Wallwiener, Diethelm; Beckmann, Matthias (Geburtshilfe und Frauenheilkunde, 2016)
EVALuna2:32974

Berlin, 27.01.2017 242nd Statement of the German Society for Gynecology and Obstetrics e. V. in cooperation with the Professional Association of Gynecologists e. V. Amending the DMP - A - RL: Supplement to Annex 3 (DMP Breast Cancer) and Appendix 4 (Breast Cancer Documentation) - Seelbach-Goebel, Birgit; Beckmann, Matthias W.; Beckmann, Matthias (Geburtshilfe und Frauenheilkunde, 2017)
EVALuna2:36123

Berlin, 29 July 2016 Opinion on the Preliminary Report of the IQTiG on the planning-relevant Quality Indicators - Wallwiener, Diethelm; Beckmann, Matthias (Geburtshilfe und Frauenheilkunde, 2016)
EVALuna2:32949

Berlin, 2nd May 2016 Opinion on the Preliminary Report A10-03 - Wallwiener, Diethelm; Beckmann, Matthias; Schulz-Wendtland, Ruediger (Geburtshilfe und Frauenheilkunde, 2016)
EVALuna2:14675

Berlin, January 11, 2016-Opinion for the Assessment on Testing the Magnetic Resonance Imaging-guided focused Ultrasound Surgery for the Treatment of Uterine Myomas (MRgFUS-TUF) - Wallwiener, Diethelm; Beckmann, Matthias (Geburtshilfe und Frauenheilkunde, 2016)
EVALuna2:32984

Berufgruppenspezifische Akzeptanz der elektronischen Patientenakte im Kontext der Geburtshilfe - Sohn, Stefan; Beckmann, Matthias; Raß, Matthias; Schöffski, Oliver; Sippel, Wilfried; Zagel, Christian; Beckmann, Kai (Deutsche Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie., 2009)
WiSo2-Import:2015-10-02:467

Biological and clinical effects of abemaciclib in a phase 2 neoadjuvant study for postmenopausal patients with HR+/HER2-breast cancer - Fasching, Peter; Fernandez Abad, M.; Garcia-Saenz, J. A.; Schneeweiss, A.; Guarneri, V.; Colleoni, M.; Petru, E.; Costigan, T. M.; Caldwell, C. W.; Barriga, S.; Hurvitz, S.; Slamon, D. (2017)
EVALuna2:36188

Biological and clinical effects of abemaciclib in a phase 2 neoadjuvant study for postmenopausal patients with HR+/HER2-breast cancer - Guarneri, V.; Fasching, Peter; Fernandez Abad, M.; Garcia-Saenz, A.; Schneeweiss, A.; Colleoni, M.; Petru, E.; Costigan, T. M.; Caldwell, C. W.; Barriga, S.; Hurvitz, S.; Slamon, D. (2017)
EVALuna2:36183

Biomarker Data from the Phase III KATHERINE Study of Adjuvant T-DM1 versus Trastuzumab for Residual Invasive Disease after Neoadjuvant Therapy for HER2-Positive Breast Cancer - Denkert, Carsten; Lambertini, Chiara; Fasching, Peter; Pogue-Geile, Katherine L.; Mano, Max S.; Untch, Michael; Wolmark, Norman; Huang, Chiun Sheng; Loibl, Sibylle; Mamounas, Eleftherios P.; Geyer, Charles E.; Lucas, Peter C.; et al. (Clinical Cancer Research, 2023)
PURPOSE: In KATHERINE, adjuvant T-DM1 reduced risk of disease recurrence or death by 50% compared with trastuzumab in patients with residual invasive breast cancer after neoadjuvant therapy (NAT) comprised of HER2-targeted therapy and chemotherapy. This analysis aimed to identify biomarkers of response and differences in biomarker expression before and after NAT. EXPERIMENTAL DESIGN: Exploratory analyses investigated the relationship between invasive disease-free survival (IDFS) and HER2 protein expression/gene amplification, PIK3CA hotspot mutations, and gene expression of HER2, PD-L1, CD8, predefined immune signatures, and Prediction Analysis of Microarray 50 intrinsic molecular subtypes, classified by Absolute Intrinsic Molecular Subtyping. HER2 expression on paired pre- and post-NAT samples was examined. RESULTS: T-DM1 appeared to improve IDFS versus trastuzumab across most biomarker subgroups, except the HER2 focal expression subgroup. High versus low HER2 gene expression in residual disease was associated with worse outcomes with trastuzumab [HR, 2.02; 95% confidence interval (CI), 1.32-3.11], but IDFS with T-DM1 was independent of HER2 expression level (HR, 1.01; 95% CI, 0.56-1.83). Low PD-L1 gene expression in residual disease was associated with worse outcomes with trastuzumab (HR, 0.66; 95% CI, 0.44-1.00), but not T-DM1 (HR, 1.05; 95% CI, 0.59-1.87). PIK3CA mutations were not prognostic. Increased variability in HER2 expression was observed in post-NAT versus paired pre-NAT samples. CONCLUSIONS: T-DM1 appears to overcome HER2 resistance. T-DM1 benefit does not appear dependent on immune activation, but these results do not rule out an influence of the tumor immune microenvironment on the degree of response.
CRIS-Team Scopus Importer:2023-04-28

Biomarkers in women's cancers, gynecology, and obstetrics - Fasching, Peter; Konecny, Gottfried E.; Spurdle, Amanda B. (BioMed Research International, 2014)
EVALuna2:17511

Bladder tumor subtype commitment occurs in carcinoma in-situ driven by key signaling pathways including ECM remodeling - Wullweber, Adrian; Strick, Reiner; Lange, Fabienne; Sikic, Danijel; Taubert, Helge; Wach, Sven; Wullich, Bernd; Bertz, Simone; Weyerer, Veronika; Stöhr, Robert; Breyer, J.; Burger, M.; et al. (EUROPEAN UROLOGY, 2021)
CRIS-Team WoS Importer:2021-08-20

Body mass index and breast cancer survival: a Mendelian randomization analysis - Guo, Qi; Burgess, Stephen; Turman, Constance; Bolla, Manjeet K.; Wang, Qin; Lush, Michael; Abraham, Jean; Aittomaki, Kristiina; Andrulis, Irene L.; Apicella, Carmel; Arndt, Volker; Barrdahl, Myrto; et al. (International Journal of Epidemiology, 2017)
Background: There is increasing evidence that elevated body mass index (BMI) is associated with reduced survival for women with breast cancer. However, the underlying reasons remain unclear. We conducted a Mendelian randomization analysis to investigate a possible causal role of BMI in survival from breast cancer. Methods: We used individual-level data from six large breast cancer case-cohorts including a total of 36 210 individuals (2475 events) of European ancestry. We created a BMI genetic risk score (GRS) based on genotypes at 94 known BMI-associated genetic variants. Association between the BMI genetic score and breast cancer survival was analysed by Cox regression for each study separately. Study-specific hazard ratios were pooled using fixed-effect meta-analysis. Results: BMI genetic score was found to be associated with reduced breast cancer-specific survival for estrogen receptor (ER)-positive cases [hazard ratio (HR) = 1.11, per one-unit increment of GRS, 95% confidence interval (CI) 1.01-1.22, P = 0.03). We observed no association for ER-negative cases (HR = 1.00, per one-unit increment of GRS, 95% CI 0.89-1.13, P = 0.95). Conclusions: Our findings suggest a causal effect of increased BMI on reduced breast cancer survival for ER-positive breast cancer. There is no evidence of a causal effect of higher BMI on survival for ER-negative breast cancer cases.
EVALuna2:33863

Brain and breast cancer cells with pten loss of function reveal enhanced durotaxis and rhob dependent amoeboid migration utilizing 3d scaffolds and aligned microfiber tracts - Wieland, Annalena; Strissel, Pamela; Schorle, Hannah; Bakirci, Ezgi; Janzen, Dieter; Beckmann, Matthias; Eckstein, Markus; Dalton, Paul D.; Strick, Reiner (Cancers, 2021)
Background: Glioblastoma multiforme (GBM) and metastatic triple-negative breast cancer (TNBC) with PTEN mutations often lead to brain dissemination with poor patient outcome, thus new therapeutic targets are needed. To understand signaling, controlling the dynamics and mechanics of brain tumor cell migration, we implemented GBM and TNBC cell lines and designed 3D aligned microfibers and scaffolds mimicking brain structures. Methods: 3D microfibers and scaffolds were printed using melt electrowriting. GBM and TNBC cell lines with opposing PTEN genotypes were analyzed with RHO-ROCK-PTEN inhibitors and PTEN rescue using live-cell imaging. RNA-sequencing and qPCR of tumor cells in 3D with microfibers were performed, while scanning electron microscopy and confocal microscopy addressed cell morphology. Results: In contrast to the PTEN wildtype, GBM and TNBC cells with PTEN loss of function yielded enhanced durotaxis, topotaxis, adhesion, amoeboid migration on 3D microfibers and significant high RHOB expression. Functional studies concerning RHOB-ROCK-PTEN signaling confirmed the essential role for the above cellular processes. Conclusions: This study demonstrates a significant role of the PTEN genotype and RHOB expression for durotaxis, adhesion and migration dependent on 3D. GBM and TNBC cells with PTEN loss of function have an affinity for stiff brain structures promoting metastasis. 3D microfibers represent an important tool to model brain metastasizing tumor cells, where RHO-inhibitors could play an essential role for improved therapy.
CRIS-Team Scopus Importer:2021-10-29
Keywords: 3D microfiber; 3D tumor model; Amoeboid cell migration; Brain cancer; Breast cancer; Durotaxis; PTEN; RHO; ROCK; Topotaxis

Branch duct intraductal papillary mucinous neoplasm - contra resection - Brunner, Michaela; Kersting, S.; Grützmann, Robert; Weber, Georg (Chirurg, 2017)
Due to improvements in imaging modalities the diagnosis of branch duct intraductal papillary mucinous neoplasms (BD-IPMN) has been significantly increased in recent years. A BD-IPMN is frequently diagnosed as an incidental finding in asymptomatic patients. The optimal management of BD-IPMN is the subject of controversial discussions. Numerous studies have shown that an individualized therapeutic strategy with a follow-up observation of most BD-IPMNs is feasible and safe, considering age, comorbidities and patient preference. An accurate evaluation of BD-IPMN with a detailed anamnesis, high-resolution imaging techniques and endoscopic ultrasound is necessary. Symptomatic patients as well as patients with so-called high-risk stigmata should undergo resection. Asymptomatic patients with so-called worrisome features can either undergo surveillance or surgical resection, taking age and comorbidities into account. For BD-IPMN patients without high-risk stigmata and worrisome features and showing no symptoms, surveillance of the pancreatic lesion is the preferred approach. The high prevalence of BD-IPMN, limitations in differential diagnostics, an overestimation of the risk of malignancy due to an overrepresentation of symptomatic and suspected BD-IPMN in resected cohorts, an overestimated role of BD-IPMN as precursor lesions for pancreatic carcinoma and evidence of the safety of follow-up surveillance, underline the enormous importance of surveillance. Based on this and considering the background of a notable mortality and morbidity of pancreatic surgery, aggressive management with prophylactic surgical resection is not justified for all BD-IPMN, in particular for low-risk lesions.
EVALuna2:15288

BRCA1/2 Mutations and Bevacizumab in the Neoadjuvant Treatment of Breast Cancer: Response and Prognosis Results in Patients With Triple-Negative Breast Cancer From the GeparQuinto Study - Fasching, Peter; Loibl, Sibylle; Hu, Chunling; Hart, Steven N.; Shimelis, Hermela; Moore, Raymond; Schem, Christian; Tesch, Hans; Untch, Michael; Hilfrich, Joern; Rezai, Mahdi; Gerber, Bernd; et al. (Journal of Clinical Oncology, 2018)
Purpose BRCA1/2 mutations are frequent in patients with triple-negative breast cancer (TNBC). These patients are often treated with primary systemic chemotherapy. The aim of this study was to analyze the effects of BRCA1/2 mutations on pathologic complete response (pCR) and disease-free survival (DFS) in a cohort of patients with TNBC treated with anthracycline and taxane-containing chemotherapy, with or without bevacizumab. Patients and Methods Germline DNA was sequenced to identify mutations in BRCA1 and BRCA2 in 493 patients with TNBC from the GeparQuinto study. The pCR rates were compared in patients with and without mutation, as well as in patients treated with and without bevacizumab. In addition, the influence of BRCA1/2 mutation status and pCR status on DFS was evaluated relative to treatment. Results BRCA1/2 mutations were detected in 18.3% of patients with TNBC. Overall, patients with mutations had a pCR rate of 50%, compared with 31.5% in patients without a mutation (odds ratio [OR], 2.17; 95% CI, 1.37 to 3.46; P = .001). The pCR rate among patients treated with bevacizumab was 61.5% for BRCA1/2 mutation carriers and 35.6% for those without mutations (OR, 2.90; 95% CI, 1.43 to 5.89; P = .004). pCR was a strong predictor of DFS for patients without BRCA1/2 mutations (hazard ratio, 0.18; 95% CI, 0.11 to 0.31) but not for patients with BRCA1/2 mutations (hazard ratio, 0.74; 95% CI, 0.32 to 1.69). Conclusion The addition of bevacizumab may increase the pCR after standard neoadjuvant chemotherapy for patients with TNBC with BRCA1/2 mutations. In patients treated with anthracycline and taxane-based chemotherapy (with or without bevacizumab), pCR was a weaker predictor of DFS for BRCA1/2 mutation carriers than for patients without mutations.
EVALuna2:56158

BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer - Shimelis, Hermela; Mesman, Romy L. S.; Von Nicolai, Catharina; Ehlen, Asa; Guidugli, Lucia; Martin, Charlotte; Calleja, Fabienne M. G. R.; Meeks, Huong; Hallberg, Emily; Hinton, Jamie; Lilyquist, Jenna; Hu, Chunling; et al. (Cancer Research, 2017)
Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789-99. ©2017 AACR.
EVALuna2:36140

BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers - Meeks, Huong D.; Song, Honglin; Michailidou, Kyriaki; Bolla, Manjeet K.; Dennis, Joe; Wang, Qin; Barrowdale, Daniel; Frost, Debra; Mcguffog, Lesley; Ellis, Steve; Feng, Bingjian; Buys, Saundra S.; et al. (Journal of the National Cancer Institute, 2016)
BACKGROUND: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. METHODS: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. RESULTS: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10(-) (6)) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10(-3)). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10(-5) and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10(-5), respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. CONCLUSIONS: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.
EVALuna2:33125

BRCA mutations and their influence on pathological complete response and prognosis in a clinical cohort of neoadjuvantly treated breast cancer patients - Wunderle, Marius; Gaß, Paul; Häberle, Lothar; Flesch, Vivien M.; Rauh, Claudia; Bani, Mayada; Hack, Carolin; Schrauder, Michael G.; Jud, Sebastian; Emons, Julius; Erber, Ramona; Ekici, Arif Bülent; et al. (Breast Cancer Research and Treatment, 2018)
PURPOSE: BRCA1/2 mutations influence the molecular characteristics and the effects of systemic treatment of breast cancer. This study investigates the impact of germline BRCA1/2 mutations on pathological complete response and prognosis in patients receiving neoadjuvant systemic chemotherapy. METHODS: Breast cancer patients were tested for a BRCA1/2 mutation in clinical routine work and were treated with anthracycline-based or platinum-based neoadjuvant chemotherapy between 1997 and 2015. These patients were identified in the tumor registry of the Breast Center of the University of Erlangen (Germany). Logistic regression and Cox regression analyses were performed to investigate the associations between BRCA1/2 mutation status, pathological complete response, disease-free survival, and overall survival. RESULTS: Among 355 patients, 59 had a mutation in BRCA1 or in BRCA2 (16.6%), 43 in BRCA1 (12.1%), and 16 in BRCA2 (4.5%). Pathological complete response defined as "ypT0; ypN0" was observed in 54.3% of BRCA1/2 mutation carriers, but only in 22.6% of non-carriers. The adjusted odds ratio was 2.48 (95% CI 1.26-4.91) for BRCA1/2 carriers versus non-carriers. Patients who achieved a pathological complete response had better disease-free survival and overall survival rates compared with those who did not achieve a pathological complete response, regardless of BRCA1/2 mutation status. CONCLUSIONS: BRCA1/2 mutation status leads to better responses to neoadjuvant chemotherapy in breast cancer. Pathological complete response is the main predictor of disease-free survival and overall survival, independently of BRCA1/2 mutation status.
EVALuna2:34606

Breakdown of the Endothelial Barrier Function in Tumor Cell Transmigration - Mierke, Claudia; Paranhos Zitterbart, Daniel; Kollmannsberger, Philip; Raupach, Carina; Schlötzer-Schrehardt, Ursula; Goecke, Tamme W.; Behrens, Jürgen; Fabry, Ben (Biophysical Journal, 2007)
UnivIS-Import:2015-04-14:Pub.2007.nat.dphy.IAP.lpmt.breakd
Keywords: transendothelial migration; invasion; metastasis; endothelium; CXCR2; Gro-â; IL-8; cell mechanics

Breast Cancer and Genetic BRCA1/2 Testing in Routine Clinical Practice: Why, When and For Whom? - Lux, Michael P.; Fasching, Peter (Geburtshilfe und Frauenheilkunde, 2023)
Pathogenic variants of the tumor suppressor genes BRCA1 and BRCA2 are responsible for the majority of hereditary breast cancers; they are also becoming increasingly important to identify whether patients are suitable for targeted therapy with poly ADP-ribose polymerase inhibitors (PARPi). Patients with HER2-negative breast cancer and BRCA1/2 germline mutations can benefit significantly from PARPi therapy, and the findings of the OlympiAD and the EMBRACA phase III clinical trials for regulatory approval were recently expanded by the addition of the most recent OlympiA data on the treatment of patients with early disease and a high risk of recurrence. This means that BRCA1/2 germline testing to plan patient therapy is now also relevant for patients with early breast cancer and therefore has a direct impact on survival. Healthcare research data shows, however, that BRCA1/2 testing rates are strongly affected by familial history, cancer subtype (particularly triple-negative subtypes), and patient age at onset of disease (especially with regards to younger patients with breast cancer), despite the existing clear recommendations for BRCA1/2 germline testing to identify whether PARPi therapy is indicated. This article presents the clinical implications of identifying BRCA1/2 germline mutations in patients with breast cancer, the current recommendations on molecular diagnostics, and their implementation in practice. The treatment of patients with breast cancer has progressed greatly in recent years and now offers individual treatment concepts which can only be implemented after the targeted identification of individual parameters. As detection of a BRCA1/2 germline mutation is essential for planning individual therapy, where indicated, testing should be arranged as early as possible. It is the only way of identifying patients suitable for PARPi therapy and ensuring they receive the best possible treatment. This also applies to patients with a negative familial history, HR-positive disease, or who are older at onset of disease.
CRIS-Team Scopus Importer:2023-03-24
Keywords: BRCA1/2 diagnostics; breast cancer; olaparib; PARP inhibitors; talazoparib; therapy planning

Breast cancer in young women: do BRCA1 or BRCA2 mutations matter? - Fasching, Peter (Lancet Oncology, 2018)
EVALuna2:210184

Breast cancer patients' satisfaction with individual therapy goals and treatment in a standardized integrative medicine consultancy service - Hack, Carolin; Antoniadis, Sophia; Hackl, Janina; Langemann, Hanna; Schwitulla, Judith; Fasching, Peter; Beckmann, Matthias; Theuser, Anna-Katharin (Archives of Gynecology and Obstetrics, 2018)
PURPOSE: Complementary medicine services are nowadays usually quite heterogeneous, and little information is available on standards for running an integrative medicine consultancy service. This study aimed to assess patients' satisfaction with a standardized treatment service on integrative medicine. METHODS: Using a cross-sectional design, 75 breast cancer patients from the integrative medicine consultancy service at the University Breast Center for Franconia were evaluated between January 2016 and March 2017. At primary consultation, patients answered a standardized questionnaire on their medical history and treatment goals regarding integrative medicine. In a subsequent interview, patients evaluated their satisfaction with the treatment service and individual treatment goals. RESULTS: 72% of the patients (n = 54) reported high satisfaction with the overall approach of the treatment service. 76% of the patients (n = 57) were very satisfied or satisfied with their individual treatment plans. The most frequently reported goals were to slow tumor progression (n = 64, 85.3%), reducing the side effects of conventional cancer treatments (n = 60, 80%), and a desire to participate actively in the treatment of breast cancer (n = 64, 85.3%). CONCLUSIONS: Using a standardized procedure in integrative medicine allows a high quality level to be offered to patients. Overall, breast cancer patients report very high satisfaction with the integrative medicine consultancy service and state long-term treatment goals. Hence, long-term treatment with integrative medicine methods should be taken into consideration.
EVALuna2:209947

Breast cancer risk assessment in a mammography screening program and participation in the IBIS-II chemoprevention trial - Löhberg, Christian; Jud, Sebastian; Häberle, Lothar; Heusinger, Katharina; Dilbat, Gerhard; Hein, Alexander; Rauh, Claudia; Dall, Peter; Rix, Nadine; Heinrich, Sabrina; Buchholz, Stefan; Lex, Benno; et al. (Breast Cancer Research and Treatment, 2010)
It has been shown in several studies that antihormonal compounds can offer effective prophylactic treatment to prevent breast cancer. In view of the low participation rates in chemoprevention trials, the purpose of this study was to identify the characteristics of women taking part in a population-based mammography screening program who wished to obtain information about the risk of breast cancer and then participate in the the International Breast Cancer Intervention Study II (IBIS-II) trial, a randomized double-blind controlled chemoprevention trial comparing anastrozole with placebo. A paper-based survey was conducted in a population-based mammography screening program in Germany between 2007 and 2009. All women who met the criteria for the mammography screening program were invited to complete a questionnaire. A total of 2,524 women completed the questionnaire, and 17.7% (n = 446) met the eligibility criteria for the IBIS-II trial after risk assessment. The women who wished to receive further information about chemoprevention were significantly younger (P < 0.01) and had significantly more children (P = 0.03) and significantly more relatives with breast cancer (P < 0.001). There were no significant differences between the participants with regard to body mass index or hormone replacement therapy. Normal mammographic findings at screening were the main reason (42%) for declining to participate in the IBIS-II trial or attend risk counseling. The ultimate rate of recruitment to the IBIS-II trial was very low (three women). Offering chemoprevention to women within a mammography screening unit as part of a paper-based survey resulted in low participation rates for both, the survey and the final participation in the IBIS-II trial. More individualized approaches and communication of breast cancer risk at the time of the risk assessment might be helpful to increase the participation and the understanding of chemopreventive approaches. © 2010 Springer Science+Business Media, LLC.
CRIS-Team Scopus Importer:2021-07-19
Keywords: Breast cancer risk; Chemoprevention trial; IBIS-II; Mammography screening; Patient recruitment

Breast Cancer Risk Factors and Survival by Tumor Subtype: Pooled Analyses from the Breast Cancer Association Consortium - Morra, Anna; Jung, Audrey Y.; Behrens, Sabine; Keeman, Renske; Ahearn, Thomas U.; Anton-Culver, Hoda; Arndt, Volker; Augustinsson, Annelie; Auvinen, Päivi K.; Beane Freeman, Laura E.; Becher, Heiko; Beckmann, Matthias; et al. (Cancer Epidemiology Biomarkers & Prevention, 2021)
BACKGROUND: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype. METHODS: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer-specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype. RESULTS: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (Padj > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5-25 kg/m2 [HR (95% confidence interval (CI), 1.19 (1.06-1.34)]; current versus never smoking [1.37 (1.27-1.47)], high versus low physical activity [0.43 (0.21-0.86)], age ≥30 years versus <20 years at first pregnancy [0.79 (0.72-0.86)]; >0-<5 years versus ≥10 years since last full-term birth [1.31 (1.11-1.55)]; ever versus never use of oral contraceptives [0.91 (0.87-0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen-progestin therapy [0.61 (0.54-0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02-1.21) for current versus never smoking. CONCLUSIONS: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype. IMPACT: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.
CRIS-Team Scopus Importer:2021-04-16

Breast cancer risk - From genetics to molecular understanding of pathogenesis - Fasching, Peter; Ekici, Arif Bülent; Wachter, David Lukas; Hein, Alexander; Bayer, Christian M.; Häberle, Lothar; Löhberg, Christian; Schneider, Michael; Jud, Sebastian; Heusinger, K.; Rübner, Matthias; Rauh, Claudia; et al. (Geburtshilfe und Frauenheilkunde, 2013)
Several advancements over the last decade have triggered the developments in the field of breast cancer risk research. One of them is the availability of the human genome sequence along with cheap genotyping possibilities. Another is the globalization of research, which has led to the growth of research collaboration into large international consortia that facilitate the pooling of clinical and genotype data of hundreds of thousands of patients and healthy control individuals. This review concerns with the recent developments in breast cancer risk research and focuses on the discovery of new genetic breast cancer risk factors and their meaning in the context of established non-genetic risk factors. Finally the clinical application is highly dependent on the accuracy of breast cancer risk prediction models, not only for all breast cancer patients, but also for molecular subtypes, preferably for those which are associated with an unfavorable prognosis. Recently risk prediction incorporates all possible risk factors, which include epidemiological risk factors, mammographic density and genetic risk factors. © Georg Thieme Verlag KG Stuttgart• New York•.
CRIS-Team Scopus Importer:2021-07-19
Keywords: BRCA; breast cancer risk; gene-environment interaction; genetic risk factors; prediction models

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women - Dorling, Leila; Carvalho, Sara; Allen, Jamie; Gonzalez-Neira, Anna; Luccarini, Craig; Wahlstrom, Cecilia; Pooley, Karen A.; Parsons, Michael T.; Fortuno, Cristina; Wang, Qin; Bolla, Manjeet K.; Dennis, Joe; et al. (New England Journal of Medicine, 2021)
BACKGROUND
CRIS-Team WoS Importer:2021-03-26

Breast cancer risk - Genes, environment and clinics Mammakarzinomrisiko - Gene, Umwelt und Klinik - Fasching, Peter; Ekici, Arif Bülent; Adamietz, B. R.; Wachter, David Lukas; Hein, Alexander; Bayer, Christian M.; Häberle, Lothar; Löhberg, Christian; Jud, Sebastian; Heusinger, K.; Rübner, Matthias; Rauh, Claudia; et al. (Geburtshilfe und Frauenheilkunde, 2011)
The information available about breast cancer risk factors has increased dramatically during the last 10 years. In particular, studies of low-penetrance genes and mammographic density have improved our understanding of breast cancer risk. In addition, initial steps have been taken in investigating interactions between genes and environmental factors. This review concerns with actual data on this topic. Several genome-wide association studies (GWASs) with a casecontrol design, as well as large-scale validation studies, have identified and validated more than a dozen single nucleotide polymorphisms (SNPs) associated with breast cancer risk. They are located not only in or close to genes known to be involved in cancer pathogenesis, but also in genes not previously associated with breast cancer pathogenesis, or may even not be related to any genes. SNPs have also been identified that alter the lifetime risk in BRCA mutation carriers. With regard to nongenetic risk factors, studies of postmenopausal hormone replacement therapy (HRT) have revealed important information on how to weigh up the risks and benefits of HRT. Mammographic density (MD) has become an accepted and important breast cancer risk factor. Lifestyle and nutritional considerations have become an integral part of most studies of breast cancer risk, and some improvements have been made in this field as well. More than 10 years after the publication of the first breast cancer prevention studies with tamoxifen, other substances such as raloxifene and aromatase inhibitors have been investigated and have also been shown to have preventive potential. Finally, mammographic screening systems have been implemented in most Western countries during the last decade. These may be developed further by including more individualized methods of predicting the patients breast cancer risk. © Georg Thieme Verlag KG Stuttgart - New York.
CRIS-Team Scopus Importer:2021-07-19
Keywords: BRCA (breast cancer antigen); breast; breast feeding; CAM (Complementary and Alternative medicine); cancer registry; estrogen receptor

Breast cancer risks associated with missense variants in breast cancer susceptibility genes - Dorling, Leila; Carvalho, Sara; Allen, Jamie; Parsons, Michael T.; Fortuno, Cristina; Gonzalez-Neira, Anna; Heijl, Stephan M.; Adank, Muriel A.; Ahearn, Thomas U.; Andrulis, Irene L.; Auvinen, Paivi; Becher, Heiko; et al. (Genome Medicine, 2022)
Background Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. Methods We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. Results The most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47-2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set. Conclusions These results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.
CRIS-Team WoS Importer:2022-06-03

Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170 - Dunning, Alison M.; Michailidou, Kyriaki; Kuchenbaecker, Karoline B.; Thompson, Deborah; French, Juliet D.; Beesley, Jonathan; Healey, Catherine S.; Kar, Siddhartha; Pooley, Karen A.; Lopez-Knowles, Elena; Dicks, Ed; Barrowdale, Daniel; et al. (Nature Genetics, 2016)
We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.
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Breast Cancer Update 2014 - Focus on the Patient and the Tumour - Maass, N.; Schuetz, F.; Fasching, Peter; Fehm, T.; Janni, W.; Kuemmel, S.; Kolberg, H. -C.; Lueftner, D.; Wallwiener, M.; Lux, Michael P. (Geburtshilfe und Frauenheilkunde, 2015)
The therapy for patients with breast cancer has developed markedly in the past ten years. Our understanding of the molecular biology of tumours and the characteristics of the patients has shaped the recent advances. In this review we present the latest knowledge about the therapy for breast cancer. There are new tests and options not only in the field of anti-HER2 therapy but also in the management of triple negative and hormone receptor-positive patients. Comprehension of prognosis and therapeutic response to chemotherapies is little by little helping to define patient groups who will not respond to chemotherapy or who do not need treatment because their prognosis is extremely good. In the field of anti-HER2 therapy, work is continuing on the development of drugs suitable for and able to overcome trastuzumab resistance. For hormone receptor-positive cancers, we now have a better understanding of which therapy groups will benefit from which anti-endocrine drugs, and which will be able to overcome a possible resistance (treatment of the PI3K pathways, inhibition of the cell cycle). Molecular tests are still being evaluated with regard to the clinical situations in which they may have the greatest relevance for therapeutic decision-making; however, evidence is also increasing as to the fields in which good predictions for the prognosis can be obtained. On the whole, more work is needed to promote our understanding of the new developments in diagnostics and therapy and to involve both physicians and patients equally in the procedures.
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Breast MRI texture analysis for prediction of BRCA-associated genetic risk - Vasileiou, Georgia; Costa, Maria J.; Long, Christopher; Wetzler, Iris; Hoyer, Juliane; Kraus, Cornelia; Popp, Bernt; Emons, Julius; Wunderle, Marius; Wenkel, Evelyn; Uder, Michael; Beckmann, Matthias; et al. (BMC Medical Imaging, 2020)
BACKGROUND: BRCA1/2 deleterious variants account for most of the hereditary breast and ovarian cancer cases. Prediction models and guidelines for the assessment of genetic risk rely heavily on criteria with high variability such as family cancer history. Here we investigated the efficacy of MRI (magnetic resonance imaging) texture features as a predictor for BRCA mutation status. METHODS: A total of 41 female breast cancer individuals at high genetic risk, sixteen with a BRCA1/2 pathogenic variant and twenty five controls were included. From each MRI 4225 computer-extracted voxels were analyzed. Non-imaging features including clinical, family cancer history variables and triple negative receptor status (TNBC) were complementarily used. Lasso-principal component regression (L-PCR) analysis was implemented to compare the predictive performance, assessed as area under the curve (AUC), when imaging features were used, and lasso logistic regression or conventional logistic regression for the remaining analyses. RESULTS: Lasso-selected imaging principal components showed the highest predictive value (AUC 0.86), surpassing family cancer history. Clinical variables comprising age at disease onset and bilateral breast cancer yielded a relatively poor AUC ( 0.56). Combination of imaging with the non-imaging variables led to an improvement of predictive performance in all analyses, with TNBC along with the imaging components yielding the highest AUC (0.94). Replacing family history variables with imaging components yielded an improvement of classification performance of 4%, suggesting that imaging compensates the predictive information arising from family cancer structure. CONCLUSIONS: The L-PCR model uncovered evidence for the utility of MRI texture features in distinguishing between BRCA1/2 positive and negative high-risk breast cancer individuals, which may suggest value to diagnostic routine. Integration of computer-extracted texture analysis from MRI modalities in prediction models and inclusion criteria might play a role in reducing false positives or missed cases especially when established risk variables such as family history are missing.
CRIS-Team Scopus Importer:2020-08-07
Keywords: BRCA1/2; Breast cancer; HBOC; L-PCR; MRI; Texture analysis

Breast Tumor Analysis Using Shifted-Excitation Raman Difference Spectroscopy (SERDS) - Gebrekidan, Medhanie; Erber, Ramona; Hartmann, Arndt; Fasching, Peter; Emons, Julius; Beckmann, Matthias; Bräuer, Andreas (Technology in Cancer Research & Treatment, 2018)
We used a shifted-excitation Raman difference spectroscopy method for the ex vivo classification of resected and formalin-fixed breast tissue samples as normal (healthy) tissue, fibroadenoma, or invasive carcinoma. We analyzed 8 tissue samples containing invasive carcinoma that were surrounded by normal tissue and 3 tissue samples with fibroadenoma only. We made various measurement sites on various tissue samples, in total 240 measurements for each type of tissue. Although the acquired raw spectra contain enough information to clearly differentiate between normal and tumor (fibroadenoma and invasive carcinoma) tissue, the differentiation between fibroadenoma and invasive carcinoma was possible only after the shifted-excitation Raman difference spectroscopy isolation of pure Raman spectra from the heavily fluorescence interfered raw spectra. We used 784 and 785 nm as excitation wavelengths for the shifted-excitation Raman difference spectroscopy method. The differences in the obtained pure Raman spectra are assigned to the different chemical compositions of normal breast tissue, fibroadenoma, and invasive breast carcinoma. Principal component analysis and linear discriminant analysis showed excellent classification results in the Raman shift range between 1000 and 1800 cm-1. Invasive breast carcinoma was identified with 99.15% sensitivity, and the absence of invasive carcinoma was identified with 90.40% specificity. Tumor tissue in tumor-containing tissue was identified with 100% sensitivity, and the absence of tumor in no-tumor containing tissue was identified with 100% specificity. As gold standard for the determination of the sensitivity and the specificity, we considered the conventional histopathological classification. In summary, shifted-excitation Raman difference spectroscopy could be potentially very useful to support histopathological diagnosis in breast pathology.
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Breast volume assessment with a smart phone device compared to MRI - Behrens, Annika; Wunderle, Marius; Häberle, Lothar; Stamminger, Marc; Zint, Daniel; Emons, Julius; Heindl, Felix; Hack, Caroline; Ohlmeyer, Sabine; Uder, Michael; Beckmann, Matthias; Fasching, Peter (GEBURTSHILFE UND FRAUENHEILKUNDE, 2022)
CRIS-Team WoS Importer:2022-11-04

CA27.29 as a tumour marker for risk evaluation and therapy monitoring in primary breast cancer patients - Rack, Brigitte; Jueckstock, Julia; Trapp, Elisabeth; Weissenbacher, Tobias; Alunni-Fabbroni, Marianna; Schramm, Amelie; Widschwendter, Peter; Lato, Krisztian; Zwingers, Thomas; Lorenz, Ralf; Tesch, Hans; Schneeweiss, Andreas; et al. (Tumor Biology, 2016)
Several trials showed that tumour markers are associated with an impaired prognosis for breast cancer. Whether earlier treatment can improve the course of the disease remains controversial. The SUCCESS Trial compares FEC (500/100/500)-docetaxel (100) vs. FEC (500/100/500)-docetaxel/gemcitabine (75/2000) as well as 2 vs. 5 years of zoledronate in high-risk primary breast cancer patients. In 2669 patients, CA27.29 was measured before and after chemotherapy with the ST AIA-PACK CA27.29 reagent for the AIA-600II automated enzyme immunoassay (Tosoh Bioscience, Belgium). Values above 31 U/ml were considered positive. Of the patients, 7.6 % (n = 202, mean 19, range 3-410) and 19.1 % (n = 511, mean 21, range 3-331) had elevated marker levels before and after chemotherapy, respectively. Of the patients, 4.9 and 78 % showed elevated and low CA27.29, respectively, at both time points. After treatment, 35 % of the pre-therapy positive patients were negative, and 15 % of the initially negative patients became positive. The correlation between both time points was significant (p < 0.0001). No correlations among nodal status, grading, hormonal status, HER2 status and CA27.29 levels were found. However, tumour size (p = 0.02), older age (p < 0.001) and post-menopausal status (p = 0.006) were significantly associated with higher CA27.29 levels. Before treatment, the prevalence of elevated CA27.29 was equally distributed between both treatment arms, whereas after chemotherapy, 13.7 % of the patients in the FEC-doc arm showed an increased level vs. 25.4 % of the patients in the FEC-doc/gemcitabine arm (p < 0.0001). However, we could not show a significant association between the G-CSF application (yes vs. no) and CA27.29 status before/after chemotherapy (p = 0.75). These results indicate a close relationship between CA27.29 levels and tumour mass. Increased values after the completion of chemotherapy might be attributed to treatment effects and should be considered with caution.
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Can a university reproductive medicine centre be financed under the pre-existing general conditions in Germany? - Hildebrandt, Thomas; Oversohl, Nicola; Dittrich, Ralf; Lotz, Laura; Beckmann, Matthias; Lux, Michael P. (Geburtshilfe und Frauenheilkunde, 2019)
Background Reduced resources for financing healthcare services are available to the German health system. For this reason, demographic development represents one of the greatest challenges for the German health system. Reproductive medicine can offer potential solutions and counteract the ageing of the population through an increase in the birth rate. Most reproductive medical treatments take place in private centres. For the development of new, innovative therapeutic approaches, continuing education and scientific advancement, university centres are essential. Materials and Methods Using multistage contribution margin accounting, IVF and ICSI treatments at the University Fertility Centre Franken (UFF) were investigated in 2012. The cost situation from the perspective of the patient couple and the statutory payer were contrasted with the cost and revenue situation of the service provider as a university reproductive medicine centre. Results The costs for the patient couple for an IVF treatment cycle were 538.71 € and for an ICSI cycle, 700.07 €. For the payer, the costs, including the university flat rate (194.80 €) to be paid, amount to 733.51 € for an IVF cycle and 894.87 € for an ICSI cycle. The payments of the patient couple and the payer were added and this yielded total costs of 1272.22 € and 1594.94 €. The University Fertility Centre Franken, as a part of the Department of Gynaecology of the Erlangen University Hospital, incurred costs of 1364.47 € for an IVF treatment cycle and 1423.48 € for an ICSI treatment cycle. In addition, the OB/GYN clinic had to pay the university hospital a flat general expense rate of 14.9% of the income. There was thus a loss for the department of gynaecology of 281.81 € for an IVF cycle and 66.19 € for an ICSI cycle. Discussion From the perspective of a university reproductive medicine centre, IVF and ICSI treatments currently cannot be performed in a cost-covering manner. At the same time, a reproductive medicine treatment cycle represents a significant financial burden on the patient couple due to only partial cost coverage by most statutory health insurance funds. This therefore demonstrates a need for action in health policy to revise and, in the interest of the patient couples, reproductive medicine centres and, not least of all, in the interest of society, to improve existing cost absorption policies and thus also benefit from this as a society over the long term.
CRIS-Team Scopus Importer:2019-05-14
Keywords: Continuing education; Endocrinology; Financial resources; ICSI; IVF; Reproductive medicine

Candidate locus analysis of the TERT-CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk - Carvajal-Carmona, Luis G.; O'Mara, Tracy A.; Painter, Jodie N.; Lose, Felicity A.; Dennis, Joe; Michailidou, Kyriaki; Tyrer, Jonathan P.; Ahmed, Shahana; Ferguson, Kaltin; Healey, Catherine S.; Pooley, Karen; Beesley, Jonathan; et al. (Human genetics, 2015)
Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT-CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 × 10(-6) to P = 7.7 × 10(-5)). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERT P = 1.5 × 10(-18), CLPTM1L P = 1.5 × 10(-19)). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility.
EVALuna2:9280

Can Sonographic Fetal Biometry Predict Adverse Perinatal Outcome? - Pretscher, Jutta; Schwenke, Eva; Baier, Friederike; Kehl, Sven; Schneider, Michael; Stumpfe, Florian Matthias; Schmid, Matthias; Beckmann, Matthias; Mayr, Andreas; Schild, Ralf; Faschingbauer, Florian (Ultraschall in der Medizin, 2019)
Objective To evaluate the association of sonographic fetal biometry (sonographic head circumference (soHC), sonographic abdominal circumference (soAC), estimated fetal weight (EFW)) with mode of delivery and adverse perinatal outcome. Methods Singleton pregnancies with a gestational age ≥ 37 weeks and an ultrasound examination with complete biometric parameters within 7 days before delivery were retrospectively included. The association between soHC, soAC, EFW and fetal (5-min Apgar < 7, pH < 7.1, neonatal intensive care unit (NICU) admission, shoulder dystocia (ShD)) and maternal (obstetric intervention (OI): caesarean or vaginal operative delivery, obstetric anal sphincter injury syndrome (OASIS), postpartum hemorrhage (pph)) adverse outcomes were analyzed using univariate and multivariate logistic regression analyses. Results 12 396 women were included and 3479 (28.07 %) needed an OI. Multivariate analyses demonstrated significant contributions for the prediction of OI by soHC and soAC, whereas EFW did not reach significance. The highest OR was shown for soHC (1087, p < 0.001). ShD occurred in 73 (0.59 %) of the deliveries. Multivariate analyses showed that significant contributions for the prediction of ShD were provided only by soAC (OR 1460, p = 0.007). For the other maternal and neonatal adverse outcome parameters, no significant association with the biometric measurements could be demonstrated in the multivariate analyses. The overall detection rates for the prediction of adverse perinatal outcome by the different biometric parameters and EFW were poor. Conclusion Obstetric management decisions should not be based solely on measurements of biometric parameters or EFW.
CRIS-Team Scopus Importer:2019-05-02
Keywords: adverse perinatal outcome; biometric parameters; fetal weight estimation; mode of delivery; ultrasound

Cardiotoxicity and Cardiovascular Biomarkers in Patients With Breast Cancer: Data From the GeparOcto-GBG 84 Trial - Rüger, Alexandra Maria; Schneeweiss, Andreas; Seiler, Sabine; Tesch, Hans; van Mackelenbergh, Marion; Marmé, Frederik; Lübbe, Kristina; Sinn, Bruno; Karn, Thomas; Stickeler, Elmar; Müller, Volkmar; Schem, Christian; et al. (Journal of the American Heart Association, 2020)
Background Patients with breast cancer can be affected by cardiotoxic reactions through cancer therapies. Cardiac biomarkers, like NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity cardiac troponin T, might have predictive value. Methods and Results Echocardiography, ECG, hemodynamic parameters, NT-proBNP and high-sensitivity cardiac troponin T were assessed in 853 patients with early-stage breast cancer randomized in the German Breast Group GeparOcto-GBG 84 phase III trial. Patients received neo-adjuvant dose-dense, dose-intensified epirubicin, paclitaxel, and cyclophosphamide (iddEPC group, n=424) or paclitaxel, non-pegylated doxorubicin, and in triple negative breast cancer, (paclitaxel, non-pegylated doxorubicin, carboplatin group, n=429) treatment for 18 weeks. Patients positive for human epidermal growth receptor 2 (n=354, 41.5%) received monoclonal antibodies on top of allocated therapy; 119 (12.9%) of all patients showed a cardiotoxic reaction during therapy (15 [1.8%] using a more strict definition). Presence of cardiotoxic reactions was irrespective of treatment allocation (P=0.31). Small but significant increases in NT-proBNP developed early in patients with a cardiotoxic reaction as compared with those without in whom NT-proBNP rose only towards the end of therapy (P=0.04). High-sensitivity cardiac troponin T rose early in both groups. Logistic regression showed that NT-proBNP (odds ratio [OR], 1.03; 95% CI, 1.008-1.055; P=0.01) and hemoglobin (OR, 1.31; 95% CI, 1.05-1.63; P=0.02) measured at 6 weeks after treatment initiation were significantly associated with cardiotoxic reactions. Conclusions NT-proBNP and hemoglobin are significantly associated with cardiotoxic reactions in patients with early-stage breast cancer undergoing dose-dense and dose-intensified chemotherapy, but high-sensitivity cardiac troponin T is not. Registration URL: http://www.clinicaltrials.gov; Unique identifier: NCT02125344.
CRIS-Team Scopus Importer:2020-12-11
Keywords: biomarker; breast cancer; cardiotoxicity; cardio‐oncology; left ventricular ejection fraction

Categorical EHR imputation with generative adversarial nets - Yang, Yinchong; Wu, Zhiliang; Tresp, Volker; Fasching, Peter (2019 IEEE International Conference on Healthcare Informatics, ICHI 2019, 2019)
Electronic Health Records often suffer from missing data, which poses a major problem in clinical practice and clinical studies. A novel approach for dealing with missing data are Generative Adversarial Nets (GANs), which have been generating huge research interest in image generation and transformation. Recently, researchers have attempted to apply GANs to missing data generation and imputation for EHR data: a major challenge here is the categorical nature of the data. State-of-the-art solutions to the GAN-based generation of categorical data involve either reinforcement learning, or learning a bidirectional mapping between the categorical and the a real latent feature space, so that the GANs only need to generate real-valued features. However, these methods are designed to generate complete feature vectors instead of imputing only the subsets of missing features. In this paper we propose a simple and yet effective approach that is based on previous work on GANs for data imputation. We first motivate our solution by discussing the reason why adversarial training often fails in case of categorical features. Then we derive a novel way to re-code the categorical features to stabilize the adversarial training. Based on experiments on two real-world EHR data with multiple settings, we show that our imputation approach largely improves the prediction accuracy, compared to more traditional data imputation approaches.
CRIS-Team Scopus Importer:2021-04-20
Keywords: Data Imputation; Generative Adversarial Nets; Multiple Imputation

Caveolin Gene Expression Predicts Clinical Outcomes for Early-Stage HER2-Negative Breast Cancer Treated with Paclitaxel-Based Chemotherapy in the GeparSepto Trial - Williams, Terence M.; Schneeweiss, Andreas; Jackisch, Christian; Shen, Changxian; Weber, Karsten E.; Fasching, Peter; Denkert, Carsten; Furlanetto, Jenny; Heinmöller, Ernst; Schmatloch, Sabine; Karn, Thomas; Szeto, Christopher W.; et al. (Clinical Cancer Research, 2023)
PURPOSE: Caveolin-1 and -2 (CAV1/2) dysregulation are implicated in driving cancer progression and may predict response to nab-paclitaxel. We explored the prognostic and predictive potential of CAV1/2 expression for patients with early-stage HER2-negative breast cancer receiving neoadjuvant paclitaxel-based chemotherapy regimens, followed by epirubicin and cyclophosphamide. EXPERIMENTAL DESIGN: We correlated tumor CAV1/2 RNA expression with pathologic complete response (pCR), disease-free survival (DFS), and overall survival (OS) in the GeparSepto trial, which randomized patients to neoadjuvant paclitaxel- versus nab-paclitaxel-based chemotherapy. RESULTS: RNA sequencing data were available for 279 patients, of which 74 (26.5%) were hormone receptor (HR)-negative, thus triple-negative breast cancer (TNBC). Patients treated with nab-paclitaxel with high CAV1/2 had higher probability of obtaining a pCR [CAV1 OR, 4.92; 95% confidence interval (CI), 1.70-14.22; P = 0.003; CAV2 OR, 5.39; 95% CI, 1.76-16.47; P = 0.003] as compared with patients with high CAV1/2 treated with solvent-based paclitaxel (CAV1 OR, 0.33; 95% CI, 0.11-0.95; P = 0.040; CAV2 OR, 0.37; 95% CI, 0.12-1.13; P = 0.082). High CAV1 expression was significantly associated with worse DFS and OS in paclitaxel-treated patients (DFS HR, 2.29; 95% CI, 1.08-4.87; P = 0.030; OS HR, 4.97; 95% CI, 1.73-14.31; P = 0.003). High CAV2 was associated with worse DFS and OS in all patients (DFS HR, 2.12; 95% CI, 1.23-3.63; P = 0.006; OS HR, 2.51; 95% CI, 1.22-5.17; P = 0.013), in paclitaxel-treated patients (DFS HR, 2.47; 95% CI, 1.12-5.43; P = 0.025; OS HR, 4.24; 95% CI, 1.48-12.09; P = 0.007) and in patients with TNBC (DFS HR, 4.68; 95% CI, 1.48-14.85; P = 0.009; OS HR, 10.43; 95% CI, 1.22-89.28; P = 0.032). CONCLUSIONS: Our findings indicate high CAV1/2 expression is associated with worse DFS and OS in paclitaxel-treated patients. Conversely, in nab-paclitaxel-treated patients, high CAV1/2 expression is associated with increased pCR and no significant detriment to DFS or OS compared with low CAV1/2 expression.
CRIS-Team Scopus Importer:2023-09-08

CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study - Kang, Eun Young; Weir, Ashley; Meagher, Nicola S.; Farrington, Kyo; Nelson, Gregg S.; Ghatage, Prafull; Lee, Cheng Han; Riggan, Marjorie J.; Bolithon, Adelyn; Popovic, Gordana; Leung, Betty; Tang, Katrina; et al. (Cancer, 2023)
Background: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. Methods: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. Results: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p =.034, and HR, 1.18; 95% CI, 1.05-1.32, p =.015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p =.033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p =.58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. Conclusion: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.
CRIS-Team Scopus Importer:2023-02-17
Keywords: CCNE1 amplification; cyclin E1 expression; high-grade serous carcinoma; ovarian cancer; prognosis

CDK4/6 Inhibitors—Overcoming Endocrine Resistance Is the Standard in Patients with Hormone Receptor-Positive Breast Cancer - Nabieva, Naiba; Fasching, Peter (Cancers, 2023)
Purpose of review: Tamoxifen and aromatase inhibitors can be considered as some of the first targeted therapies. For the past 30 years, they were the endocrine treatment standard in the advanced and early breast cancer setting. CDK4/6 inhibitors, however, are the first substances in almost two decades to broadly improve the therapeutic landscape of hormone receptor-positive breast cancer patients for the upcoming years. This review is designed to discuss the recent history, current role, future directions and opportunities of this substance class. Recent findings: The CDK4/6 inhibitors abemaciclib, dalpiciclib, palbociclib and ribociclib have all demonstrated a statistically significant improvement in progression-free survival in advanced disease. However, to date, abemaciclib and ribociclib are the only CDK4/6 inhibitors to have shown an improvement in overall survival in patients with metastatic breast cancer. Moreover, abemaciclib is the first CDK4/6 inhibitor to also reduce the risk of recurrence in those with early-stage disease. Further CDK inhibitors, treatment combinations with other drugs and different therapy sequences are in development. Summary: Achieving significant improvements in survival rates in the advanced and early breast cancer treatment setting, CDK4/6 inhibitors have set a new standard of care for patients with advanced breast cancer. It remains important to better understand resistance mechanisms to be able to develop novel substances and treatment sequences.
CRIS-Team Scopus Importer:2023-04-14
Keywords: abemaciclib; breast cancer; CDK4/6 inhibitor; dalpiciclib; endocrine treatment; palbociclib; ribociclib

Cell-based endometrial regeneration: current status and future perspectives - Keyhanvar, Neda; Zarghami, Nosratollah; Bleisinger, Nathalie; Hajipour, Hamed; Fattahi, Amir; Nouri, Mohammad; Dittrich, Ralf (Cell and Tissue Research, 2021)
Endometrial-related disorders including Asherman's syndrome, thin endometrium, pelvic organ prolapse, and cesarean scar pregnancies can be accompanied by different symptoms such as amenorrhea, infertility, abnormal placental implantation and recurrent miscarriage. Different methods have been introduced to overcome these problems such as surgery and hormonal therapy but none of them has shown promising outcomes. On the other hand, the development of novel regenerative therapeutic strategies has opened new avenues for the treatment of endometrial-related deficiencies. In this regard, different types of scaffolds, acellular matrices and also cell therapy with adult or stem cells have been investigated for the treatment of endometrial-related deficiencies. In this paper, we review the current status of cell-based endometrium regeneration using scaffold dependent and scaffold-free methods and future perspectives in this field. Moreover, we discuss the endometrial diseases that can be candidates for cell-based treatments. Also, the cells with the potential for endometrial regeneration are explained.
CRIS-Team WoS Importer:2021-03-19

Cell-In-Cell Structures in Early Breast Cancer Are Prognostically Valuable - Bauer, Mareike; Hildebrand, Laura; Rosahl, Marie Charlotte; Erber, Ramona; Schnellhardt, Sören; Büttner-Herold, Maike; Putz, Florian; Ott, Oliver; Hack, Caroline; Fietkau, Rainer; Distel, Luitpold (Cells, 2023)
Cell-in-cell (CIC) structures in breast cancer have so far been studied in a small inhomogeneous patient population, suggesting the prognostic importance of CIC. In the present study, we focused on CIC in early hormone-sensitive breast cancer. With in vitro co-culture experiments, we compared the homotypic phagocytic capacity of two breast cancer cell lines to that of primary human fibroblasts. Afterward, we studied 601 tissue specimens from 147 patients participating in an institutional accelerated partial breast irradiation (APBI) phase II trial. Both breast cancer cell lines performed non-professional phagocytosis at a higher rate than primary human fibroblasts. In this study cohort, 93.2% of the patients had T1 tumours, and 6.8% had T2 tumours. CIC was found in 61.2% of the patients, with a CIC rate ranging from <1/mm2 to 556.5/mm2 with a mean of 30.9/mm2 ± 68.4/mm2. CIC structures were prognostically favourable for local recurrence-free survival and disease-free survival. Regarding metastasis-free survival, CIC-positive patients had an unfavourable prognosis. Subgroup analysis indicated a correlation between a high proliferation index and high CIC rates. CIC had the highest prognostic value in young breast cancer patients (p = 0.004). With this study, we provide further evidence of CIC as a prognostic marker in breast cancer.
CRIS-Team Scopus Importer:2023-01-20
Keywords: accelerated partial breast irradiation; breast cancer; cell-in-cell; ionizing radiation; non-professional phagocytosis; radiotherapy

Cerebroplacental versus Umbilicocerebral Ratio—Analyzing the Predictive Value Regarding Adverse Perinatal Outcomes in Low- and High-Risk Fetuses at Term - Stumpfe, Florian; Mayr, Andreas; Schneider, Michael; Kehl, Sven; Stübs, Frederik; Antoniadis, Sophia; Titzmann, Adriana; Pontones, Constanza; Bayer, Christian M.; Beckmann, Matthias; Faschingbauer, Florian (Medicina, 2023)
Background and Objectives: The aim of this study was to investigate the prediction of adverse perinatal outcomes using the cerebroplacental (CPR) and umbilicocerebral (UCR) ratios in different cohorts of singleton pregnancies. Materials and Methods: In this retrospective cohort study, we established our own Multiple of Median (MoM) for CPR and UCR. The predictive value for both ratios was studied in the following outcome parameters: emergency cesarean delivery, operative intervention (OI), OI due to fetal distress, 5-min Apgar < 7, admission to neonatal intensive care unit, and composite adverse perinatal outcome. The performance of the ratios was assessed in the following cohorts: total cohort (delivery ≥ 37 + 0 weeks gestation, all birth weight centiles), low-risk cohort (delivery ≥ 37 + 0 weeks gestation, birth weight ≥ 10. centile), prolonged pregnancy cohort (delivery ≥ 41 + 0 weeks gestation, birth weight ≥ 10. centile) and small-for-gestational-age fetuses (delivery ≥ 37 + 0 weeks gestation, birth weight < 10. centile). The underlying reference values for MoM were estimated using quantile regression depending on gestational age. Prediction performance was evaluated using logistic regression models assessing the corresponding Brier score, combining discriminatory power and calibration. Results: Overall, 3326 cases were included. Across all cohorts, in the case of a significant association between a studied outcome parameter and CPR, there was an association with UCR, respectively. The Brier score showed only minimal differences for both ratios. Conclusions: Our study provides further evidence regarding predictive values of CPR and UCR. The results of our study suggest that reversal of CPR to UCR does not improve the prediction of adverse perinatal outcomes.
CRIS-Team Scopus Importer:2023-09-08
Keywords: cerebroplacental ratio; CPR; UCR; umbilicocerebral ratio

Cervical cancer Zervixkarzinom - Beckmann, Matthias; Schmidberger, H. (Onkologe, 2020)
CRIS-Team Scopus Importer:2020-06-30

Cervical intraepithelial neoplasia grade 2/3: development during pregnancy and postpartum - Stübs, Frederik; Mergel, F.; Koch, M. C.; Dietl, Anna; Schulmeyer, Carla; Adler, Werner; Geppert, Carol-Immanuel; Hartmann, Arndt; Knöll, Antje; Beckmann, Matthias; Gaß, Paul; Mehlhorn, G. (GEBURTSHILFE UND FRAUENHEILKUNDE, 2022)
CRIS-Team WoS Importer:2022-11-04

Cervical intraepithelial neoplasia grade 3: development during pregnancy and postpartum - Stübs, Frederik; Mergel, Franziska; Koch, Martin; Dietl, Anna; Schulmeyer, Carla; Adler, Werner; Geppert, Carol-Immanuel; Hartmann, Arndt; Knöll, Antje; Beckmann, Matthias; Gaß, Paul; Mehlhorn, Grit (Archives of Gynecology and Obstetrics, 2022)
Purpose: The aims of the present study were to evaluate the development of untreated cervical intraepithelial neoplasia (CIN) 3 during pregnancy and to assess persistence, progression, and regression rates postpartum to identify factors associated with regression. Methods: In a tertiary gynecology and obstetrics department, a total of 154 pregnant women with CIN 3 were treated in the dysplasia unit. The follow-up findings were analyzed retrospectively on the basis of histological, cytological, and human papillomavirus (HPV) testing of 154 pregnant women confirmed as having CIN 3 in colposcopically guided biopsies. Results: The rates of persistence, regression, and progression of CIN 3 in these women were 76.1%, 20% and 3.2%, respectively. Data for the delivery mode was available for 126 women. The rate of regression was almost twice as high with vaginal delivery as with cesarean section, at 27.4 vs. 15.2%, whereas the rate of progression was lower with vaginal delivery, at 2.7 vs. 6.5%. Conclusion: The rate of persistence of CIN observed in this study is comparable to that reported in other studies. The study provides strong evidence for greater regression among women who have vaginal deliveries. Careful work-up is recommended postpartum for this group of women in order to rule out persistent CIN 3 or invasive disease.
CRIS-Team Scopus Importer:2022-11-04
Keywords: Cervical dysplasia; High-grade squamous intraepithelial lesion (HSIL); Mode of delivery; Pregnancy; Treatment

Challenges and Opportunities for Real-World Evidence in Metastatic Luminal Breast Cancer - Lüftner, Diana; Hartkopf, Andreas D.; Lux, Michael P.; Overkamp, Friedrich; Tesch, Hans; Titzmann, Adriana; Pöschke, Patrik; Wallwiener, Markus; Müller, Volkmar; Beckmann, Matthias; Belleville, Erik; Janni, Wolfgang; et al. (Breast Care, 2021)
Background: The therapeutic armamentarium for patients with metastatic breast cancer is becoming more and more specific. Recommendations from clinical trials are not available for all treatment situations and patient subgroups, and it is therefore important to collect real-world data. Summary: To develop recommendations for up-to-date treatments and participation in clinical trials for patients with metastatic breast cancer, the Prospective Academic Translational Research PRAEGNANT Network was established to optimize the quality of oncological care in the advanced therapeutic setting. The main aim of PRAEGNANT is to systematically record medical care for patients with metastatic breast cancer in the real-life setting, including the outcome and side effects of different treatment strategies, to monitor quality-of-life changes during therapy, to identify patients eligible for participation in clinical studies, and to allow targeted therapies based on the molecular structures of breast carcinomas. Key Messages: This article describes the PRAEGNANT network and sheds light on the question of whether the various end points from clinical trials can be transferred to the real-world treatment situation.
CRIS-Team Scopus Importer:2021-04-02
Keywords: Breast cancer; Luminal; Metastasis; PRAEGNANT; Real-world evidence

Changes in serum levels of miR-21, miR-210, and miR-373 in HER2-positive breast cancer patients undergoing neoadjuvant therapy: a translational research project within the Geparquinto trial - Mueller, Volkmar; Gade, Stephan; Steinbach, Bettina; Loibl, Sibylle; Von Minckwitz, Gunter; Untch, Michael; Schwedler, Kathrin; Luebbe, Kristina; Schem, Christian; Fasching, Peter; Mau, Christine; Pantel, Klaus; et al. (Breast Cancer Research and Treatment, 2014)
Trastuzumab and lapatinib are established treatments for patients with HER2 (human epidermal growth factor receptor 2)-positive breast cancer with different mechanisms of action. The focus of this study is to investigate, whether altered expression levels of potentially relevant microRNAs (miRs) in serum are associated with response to trastuzumab or lapatinib. Circulating miR-21, miR-210, and miR-373 were quantified with TaqMan MicroRNA assays in serum of 127 HER2-postive breast cancer patients before and after neoadjuvant therapy and in 19 healthy controls. Patients received chemotherapy combined with either trastuzumab or lapatinib within the prospectively randomized Geparquinto trial. The association between miR levels and pathological response (pCR) to therapy and type of therapy was examined. Serum levels of miR-21 (p = 5.04e-08, p = 1.43e-10), miR-210 (p = 0.00151, p = 1.6e-05), and miR-373 (p = 7.87e-06, p = 1.75e-07) were significantly higher in patients before and after chemotherapy than in healthy women. Concentrations of miR-21 (p = 5.73e-08), miR-210 (p = 0.000724), and miR-373 (p = 0.00209) increased further after chemotherapy. A significant association of higher serum levels of miR-373 with advanced clinical tumor stage could be detected (p < 0.002). An association of miR-21 levels before (p = 0.0091) and after (p = 0.037) chemotherapy with overall survival of the patients could be detected, independent of type of anti-HER2 therapy. No association of circulating miRs with pCR was found. Our findings demonstrate a specific influence of neoadjuvant therapy on the serum levels of miR-21, miR-210, and miR-373 in breast cancer patients together with a prognostic value of miR-21.
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Characteristics and clinical outcome of breast cancer patients with asymptomatic brain metastases - Laakmann, E.; Witzel, I.; Neunhoeffer, T.; Weide, R.; Schmidt, M.; Park-Simon, T. W.; Mobus, V.; Mundhenke, Christoph; Polasik, A.; Lubbe, K.; Hesse, T.; Riecke, K.; et al. (EUROPEAN JOURNAL OF CANCER, 2020)
CRIS-Team WoS Importer:2020-11-13

Characteristics and clinical outcome of breast cancer patients with asymptomatic brain metastases - Laakmann, Elena; Witzel, Isabell; Neunhöffer, Tanja; Weide, Rudolf; Schmidt, Marcus; Park-Simon, Tjoung Won; Möbus, Volker; Mundhenke, Christoph; Polasik, Arkadius; Lübbe, Kristina; Hesse, Tobias; Riecke, Kerstin; et al. (Cancers, 2020)
Background: Brain metastases (BM) have become a major challenge in patients with metastatic breast cancer. Methods: The aim of this analysis was to characterize patients with asymptomatic BM (n = 580) in the overall cohort of 2589 patients with BM from our Brain Metastases in Breast Cancer Network Germany (BMBC) registry. Results: Compared to symptomatic patients, asymptomatic patients were slightly younger at diagnosis (median age: 55.5 vs. 57.0 years, p = 0.01), had a better performance status at diagnosis (Karnofsky index 80–100%: 68.4% vs. 57%, p < 0.001), a lower number of BM (>1 BM: 56% vs. 70%, p = 0.027), and a slightly smaller diameter of BM (median: 1.5 vs. 2.2 cm, p < 0.001). Asymptomatic patients were more likely to have extracranial metastases (86.7% vs. 81.5%, p = 0.003) but were less likely to have leptomeningeal metastasis (6.3% vs. 10.9%, p < 0.001). Asymptomatic patients underwent less intensive BM therapy but had a longer median overall survival (statistically significant for a cohort of HER2-positive patients) compared to symptomatic patients (10.4 vs. 6.9 months, p < 0.001). Conclusions: These analyses show a trend that asymptomatic patients have less severe metastatic brain disease and despite less intensive local BM therapy still have a better outcome (statistically significant for a cohort of HER2-positive patients) than patients who present with symptomatic BM, although a lead time bias of the earlier diagnosis cannot be ruled out. Our analysis is of clinical relevance in the context of potential trials examining the benefit of early detection and treatment of BM.
CRIS-Team Scopus Importer:2020-10-09
Keywords: Asymptomatic; Brain metastases; Breast cancer

Characterization of Hormone Receptor and HER2 Status in Breast Cancer Using Mass Spectrometry Imaging - Gonçalves, Juliana Pereira Lopes; Bollwein, Christine; Noske, Aurelia; Jacob, Anne; Jank, Paul; Loibl, Sibylle; Nekljudova, Valentina; Fasching, Peter; Karn, Thomas; Marmé, Frederik; Müller, Volkmar; Schem, Christian; et al. (International Journal of Molecular Sciences, 2023)
Immunohistochemical evaluation of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 status stratify the different subtypes of breast cancer and define the treatment course. Triple-negative breast cancer (TNBC), which does not register receptor overexpression, is often associated with worse patient prognosis. Mass spectrometry imaging transcribes the molecular content of tissue specimens without requiring additional tags or preliminary analysis of the samples, being therefore an excellent methodology for an unbiased determination of tissue constituents, in particular tumor markers. In this study, the proteomic content of 1191 human breast cancer samples was characterized by mass spectrometry imaging and the epithelial regions were employed to train and test machine-learning models to characterize the individual receptor status and to classify TNBC. The classification models presented yielded high accuracies for estrogen and progesterone receptors and over 95% accuracy for classification of TNBC. Analysis of the molecular features revealed that vimentin overexpression is associated with TNBC, supported by immunohistochemistry validation, revealing a new potential target for diagnosis and treatment.
CRIS-Team Scopus Importer:2023-02-24
Keywords: breast cancer; histopathology; mass spectrometry imaging; proteomics; tissue typing

Characterization of Molecular Subtypes of Paget Disease of the Breast Using Immunohistochemistry and In Situ Hybridization - Wachter, David; wachter, peter wolf; Fasching, Peter; Beckmann, Matthias; Hack, Carolin; Riener, Marc-Oliver; Hartmann, Arndt; Strehl, Johanna D. (Archives of Pathology & Laboratory Medicine, 2018)
CONTEXT: - Paget disease of the breast, in most cases, represents intraepidermal spread of ductal carcinoma in situ. Molecular subtypes of invasive carcinoma of the breast have prognostic and therapeutic significance and show characteristic distribution. Little is known about the distribution of molecular subtypes in Paget disease of the breast. OBJECTIVES: - To examine the distribution of molecular subtypes in Paget disease of the breast and to compare them to concurrent invasive carcinoma of the breast, if present. DESIGN: - We examined 48 cases of Paget disease of the breast with immunohistochemistry and antibodies against estrogen and progesterone receptors, human epidermal growth factor receptor 2 (HER2), and Ki-67, as well as HER2 chromogenic in situ hybridization, to classify the cases into molecular subtypes. Then, we compared the results to the molecular subtypes of associated, invasive carcinoma of the breast, if present. RESULTS: - The HER2 subtype was the most common found in Paget disease of the breast, followed by the luminal B subtype and 2 cases of the triple-negative subtype. The associated, invasive carcinoma cases were most often of the luminal B subtype, followed by the HER2 subtype and the triple-negative subtype. The molecular subtype of Paget disease and invasive carcinoma was congruent in most of the cases. CONCLUSIONS: - Molecular subtypes of invasive carcinoma of the breast can already be detected in Paget disease. The distribution of molecular subtypes of Paget disease and of Paget disease-associated, invasive carcinoma differs from invasive carcinoma without associated Paget disease, with the HER2 subtype overrepresented in Paget disease and associated, invasive carcinoma and the luminal and triple-negative subtypes underrepresented.
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Characterization of the impact of immune checkpoint inhibitors on platelet activation and aggregation - Schlüter, Julian; Cunningham, Sarah; Zimmermann, Robert; Achenbach, Susanne; Kramer, Rafaela; Erdmann, Michael; Beckmann, Matthias; Heinzerling, Lucie; Hackstein, Holger (Immunobiology, 2023)
Immune checkpoint inhibitors (ICIs) are effective oncological drugs which block cellular check-point receptors typically targeted by tumor immune evasion strategies. Despite their benefits, clinicians have reported treatment-associated thromboembolism during ICI therapy in recent years. Though several theories on this ICI-associated pathogenesis exist, the direct effects of ICIs on platelets remains unknown. We therefore investigated the potential direct and indirect effect of PD-1, PD-L1 and CTLA-4-targeting ICIs on platelet functionality in multifaceted in vitro experiments. Interestingly, we could not observe a clear effect of ICI on platelet aggregation and primary hemostasis in whole blood and platelet concentrate-based assays. Furthermore, the presence of ICIs in toll-like receptor stimulation had no significant impact on platelet surface marker expression. In a second approach, we investigated the indirect immunological impact of ICIs on platelet activation by exposing platelets to supernatants from ICI- and Staphylococcal enterotoxin B-exposed PBMCs. Whereas ICIs affected IL-2 levels in supernatants, we could not detect clear differences in the secretion of pro-thrombogenic factors and platelet responses. The obtained data suggest that the direct influence of ICIs on platelet activation or the influence of altered T cell function on platelet activation cannot be considered a major factor in the development of thrombotic events.
CRIS-Team Scopus Importer:2023-01-13
Keywords: Immune checkpoint inhibitors; Platelet activation; Platelet function tests; Platelets; Thrombosis

Characterizing mammographic images by using generic texture features - Häberle, Lothar; Wagner, Florian; Fasching, Peter; Jud, Sebastian; Heusinger, Katharina; Löhberg, Christian; Hein, Alexander; Bayer, Christian M.; Hack, Carolin; Lux, Michael P.; Binder, Katja; Elter, Matthias; et al. (Breast Cancer Research, 2012)
Introduction: Although mammographic density is an established risk factor for breast cancer, its use is limited in clinical practice because of a lack of automated and standardized measurement methods. The aims of this study were to evaluate a variety of automated texture features in mammograms as risk factors for breast cancer and to compare them with the percentage mammographic density (PMD) by using a case-control study design.Methods: A case-control study including 864 cases and 418 controls was analyzed automatically. Four hundred seventy features were explored as possible risk factors for breast cancer. These included statistical features, moment-based features, spectral-energy features, and form-based features. An elaborate variable selection process using logistic regression analyses was performed to identify those features that were associated with case-control status. In addition, PMD was assessed and included in the regression model.Results: Of the 470 image-analysis features explored, 46 remained in the final logistic regression model. An area under the curve of 0.79, with an odds ratio per standard deviation change of 2.88 (95% CI, 2.28 to 3.65), was obtained with validation data. Adding the PMD did not improve the final model.Conclusions: Using texture features to predict the risk of breast cancer appears feasible. PMD did not show any additional value in this study. With regard to the features assessed, most of the analysis tools appeared to reflect mammographic density, although some features did not correlate with PMD. It remains to be investigated in larger case-control studies whether these features can contribute to increased prediction accuracy. © 2012 Fasching et al.; licensee BioMed Central Ltd.
CRIS-Team Scopus Importer:2021-07-19

Chemotherapy (CT)-induced anaemia in patients (pts) treated with dose-dense regimen: Results of the prospectively randomised anaemia substudy from the neoadjuvant GeparOcto study - Tesch, H.; Loibl, S.; Kast, K.; Jackisch, C.; Moebus, V.; Buchen, S.; Untch, M.; Hanusch, C.; Seiler, S.; Weigel, M.; Fasching, Peter; Rhiem, K.; et al. (ANNALS OF ONCOLOGY, 2019)
CRIS-Team WoS Importer:2019-11-08

Chemotherapy-induced ovarian failure in young women with early breast cancer: Prospective analysis of four randomised neoadjuvant/adjuvant breast cancer trials - Furlanetto, Jenny; Marmé, Frederik; Seiler, Sabine; Thode, Christian; Untch, Michael; Schmatloch, Sabine; Schneeweiss, Andreas; Bassy, Martina; Fasching, Peter; Strik, Dominika; Stickeler, Elmar; Schem, Christian; et al. (European Journal of Cancer, 2021)
Background: Young women receiving chemotherapy for early breast cancer (EBC) have a high probability for ovarian failure, defined by chemotherapy-induced amenorrhea (CIA) as a surrogate. CIA is insufficiently reliable and reproducible. We analysed chemotherapy-induced ovarian failure (CIOF) by assessing hormone parameters, CIA, and antral follicle count (AFC). Methods: Blood samples of women aged ≤45 years treated with anthracycline/taxane-based chemotherapy for EBC from four neoadjuvant/adjuvant trials were collected at baseline, at the end of treatment (EOT), and at 6, 12, 18, and 24 months after EOT. Centrally assessed oestradiol (cutoff <52.2 ng/L) and follicle-stimulating hormone (cutoff >12.4IU/L) were used to define CIOF for patients with baseline premenopausal hormone levels, anti-Müllerian hormone (AMH), and AFC to assess ovarian reserve. Further analyses included CIA, regain of premenopausal hormone levels, and disease-free survival (DFS) also in subgroups. Results: Six hundred ninety-six patients aged ≤45 years had premenopausal hormone levels at baseline. Overall, 85.1% (592/696) experienced CIOF at EOT, and 147 of 592 had further hormone measurements after EOT. Of those, 32.7% (48/147) regained premenopausal hormone levels after 6 months, 57.9% (66/114) regained premenopausal hormone levels after 12 months, 83.0% (73/88) regained premenopausal hormone levels after 18 months, and 89.2% (74/83) regained premenopausal hormone levels after 24 months. After 24 months, 72.4% (21/29) of patients without CIOF and 100% (14/14) with CIOF had low AMH levels. Four-year DFS without CIOF versus CIOF was 65.9% versus 84.6% (hazard ratio [HR] = 2.09, 95% confidence interval [CI]: 1.37–3.19; P < 0.001); in hormone receptor positive 61.8% versus 87.5% (HR = 2.69, 95% CI: 1.57–4.60; P < 0.001); in <30 years 68.3% versus 92.6% (HR = 4.87, 95% CI: 1.05–22.63; P = 0.026). Conclusion: Most premenopausal women experienced CIOF after chemotherapy for EBC. After 2 years, nearly all regain premenopausal hormone levels. CIOF was associated with better DFS, especially in patients with hormone receptor–positive EBC or aged <30 years.
CRIS-Team Scopus Importer:2021-06-18
Keywords: Chemotherapy-induced amenorrhea; Chemotherapy-induced ovarian failure; Early breast cancer; Ovarian reserve; Young women

Chylous ascites after lymphadenectomy for gynecological malignancies - Thiel, Falk C.; Parvanta, Parnian; Hein, Alexander; Mehlhorn, Grit; Lux, Michael P.; Renner, Stefan; Preisner, Achim; Beckmann, Matthias; Schrauder, Michael G. (Journal of Surgical Oncology, 2016)
BACKGROUND AND OBJECTIVES: Chylous ascites, an accumulation of milky-white lymph fluid in the peritoneal cavity, is a rare complication following retroperitoneal lymphadenectomy. This study evaluated the appearance and management of chylous ascites following lymphadenectomy for gynecological malignancies. METHODS: A total of 931 patients who underwent lymphadenectomy for gynecological malignancies at Erlangen University Hospital between 2002 and 2013 were reviewed retrospectively. RESULTS: Chylous ascites occurred postoperatively in 28 of the 931 patients (3.0%). All patients with chylous ascites had undergone combined systematic para-aortic and pelvic lymphadenectomy (SAPL). Patients with chylous ascites had a larger mean number of lymph nodes removed (51.9 vs. 40.0, P = 0.002) and the proportion of laparoscopic SAPLs was significantly higher (20/28; 71.4%) in comparison with open surgery (8/28; 28.6%) (P < 0.0001). Additional parameters, such as the number of positive lymph nodes, were not significantly associated with the occurrence of chylous ascites. Conservative management was sufficient to resolve chylous ascites in all observed cases, with a mean time to resolution of 8 days. CONCLUSIONS: Postoperative chylous ascites was more frequently observed in patients with laparoscopic SAPL in comparison with open SAPL and was strongly associated with a larger mean number of removed lymph nodes. J. Surg. Oncol. 2016;114:613-618. © 2016 Wiley Periodicals, Inc.
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