Prevalence of Pathogenic Germline Variants in Women with Non-Familial Unilateral Triple-Negative Breast Cancer

Kerstin Rhiem; Silke Zachariae; Anke Waha; Sabine Grill; Anna Hester; Michael Golatta; Marion van Mackelenbergh; Tanja Fehm; Tanja Schlaiß; Tim Ripperger; Susanne Ledig; Cornelia Meisel; Dorothee Speiser; Kristina Veselinovic; Christopher Schröder; Isabell Witzel; Julia Gallwas; Bernhard H F Weber; Christine Solbach; Bariyhe Aktas; Eric Hahnen; Christoph Engel; Rita Schmutzler

doi:10.1159/000528972

Prevalence of Pathogenic Germline Variants in Women with Non-Familial Unilateral Triple-Negative Breast Cancer

Breast Care (Basel). 2023 May;18(2):106-112. doi: 10.1159/000528972. Epub 2023 Jan 6.

Authors

Kerstin Rhiem¹, Silke Zachariae², Anke Waha¹, Sabine Grill³, Anna Hester⁴, Michael Golatta⁵, Marion van Mackelenbergh⁶, Tanja Fehm⁷, Tanja Schlaiß⁸, Tim Ripperger⁹, Susanne Ledig¹⁰, Cornelia Meisel^{11

12

13

14}, Dorothee Speiser¹⁵, Kristina Veselinovic¹⁶, Christopher Schröder¹⁷, Isabell Witzel¹⁸, Julia Gallwas¹⁹, Bernhard H F Weber^{20

21}, Christine Solbach²², Bariyhe Aktas²³, Eric Hahnen¹, Christoph Engel², Rita Schmutzler¹

Affiliations

¹ Center for Hereditary Breast and Ovarian Cancer and Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany.
² Institute for Medical Informatics, Statistics and Epidemiology, Leipzig University, Leipzig, Germany.
³ Department of Gynecology and Center for Hereditary Breast and Ovarian Cancer, Klinikum Rechts der Isar, Technical University Munich (TUM), Munich, Germany.
⁴ Department of Obstetrics and Gynecology, University Hospital, Ludwig-Maximilians-University, Munich, Germany.
⁵ Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg, Germany.
⁶ Department Gynecology and Obstetrics, University Hospital Schleswig Holstein (UKSH) Campus Kiel, Kiel, Germany.
⁷ Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Düsseldorf, Germany.
⁸ Institute for Gynecology and Obstetrics and Center for Hereditary Breast and Ovarian Can-cer, Medical Faculty, University Hospital Würzburg, Würzburg, Germany.
⁹ Department of Human Genetics, Hannover Medical School, Hannover, Germany.
¹⁰ Institute of Human Genetics, University of Münster, Münster, Germany.
¹¹ Department of Gynecology and Obstetrics, Technische Universität Dresden, Dresden, Germany.
¹² National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹³ Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
¹⁴ Helmholtz-Centre Dresden - Rossendorf (HZDR), Dresden, Germany.
¹⁵ Department of Gynecology and Breast Centre, Centre for Hereditary Breast and Ovarian Cancer Charité, Charité University Hospital, Berlin, Germany.
¹⁶ Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
¹⁷ Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, Tübingen, Germany.
¹⁸ Department of Gynecology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
¹⁹ Department of Gynecology and Obstetrics, University Medicine Göttingen, Göttingen, Germany.
²⁰ Institute of Human Genetics, University of Regensburg, Regensburg, Germany.
²¹ Institute of Clinical Human Genetics, University Hospital Regensburg, Regensburg, Germany.
²² Center for Hereditary Breast and Ovarian Cancer, University Hospital Frankfurt, Frankfurt, Germany.
²³ Department of Gynecology, University of Leipzig Medical Center, Leipzig, Germany.

Abstract

Introduction: International guidelines recommend genetic testing for women with familial breast cancer at an expected prevalence of pathogenic germline variants (PVs) of at least 10%. In a study sample of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC), we have previously shown that women with TNBC diagnosed before the age of 50 years but without a family history of breast or ovarian cancer (sTNBC) meet this criterion. The present study investigates the PV prevalence in BRCA1, BRCA2, and nine additional cancer predisposition genes in an extended sTNBC study sample including a cohort of women with a later age at sTNBC diagnosis.

Patients and methods: In 1,600 women with sTNBC (median age at diagnosis: 41 years, range 19-78 years), we investigated the association between age at diagnosis and PV occurrence in cancer predisposition genes using logistic regression.

Results: 260 sTNBC patients (16.2%) were found to have a PV in cancer predisposition genes (BRCA1: n = 170 [10.6%]; BRCA2: n = 46 [2.9%], other: n = 44 [2.8%]). The PV prevalence in women diagnosed between 50 and 59 years (n = 194) was 11.3% (22/194). Logistic regression showed a significant increase in PV prevalence with decreasing age at diagnosis (OR 1.41 per 10 years younger age at diagnosis; 95% confidence interval: 1.21-1.65; p < 0.001). The PV prevalence predicted by the model was above 10% for diagnoses before the age of 56.8 years.

Conclusion: Based on the data presented, we recommend genetic testing by gene panel analysis for sTNBC patients diagnosed before the age of 60 years. Due to the still uncertain estimate for women with sTNBC diagnosed above the age of 60 years, further studies are needed.

Keywords: BRCA1; BRCA2, triple negative; Breast cancer; Hereditary breast and ovarian cancer.

Grants and funding

The GC-HBOC was supported by the German Cancer Aid (Grant no. 110837 and Grant no. 70114178, coordinator: Rita K. Schmutzler, Cologne) and is currently supported by the Federal Ministry of Education and Research (BMBF), Germany (Grant no. 01GY1901). The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or in the decision to submit the manuscript for publication.