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

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 can-cer predisposition genes in an extended sTNBC study sample including a cohort of women with a later age at sTNBC diagnosis. Patients and methods: In 1600 women with sTNBC (median age at diagnosis 41 years, range 19-78 years) we investigated the association between age at diagnosis and PV occur-rence 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%CI 1.21-1.65; p <0.001). The PV prevalence pre-dicted 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 wide confi-dence interval (7.6-16-6), we recommend the implementation within the framework of a knowledge-generating care concept.

Arbeitsgemeinschaft Gynäkologische Onkologie Recommendations for the Diagnosis and Treatment of Patients with Early Breast Cancer: Update 2024

“…Genetic testing for pathogenic variations includes BRCA1/BRCA2 (LoE 1b/A/AGO++), PALB2 (LoE 3a/B/ AGO+), CDH, PTEN, TP53, STK11 (LoE 3b/B/AGO+), and ATM, BARD1, CHEK, RAD51C/D (LoE3a/B/ AGO+/−) with varying degrees of evidence and impact. Genetic testing of BRCA1/2 germline mutations (gBRCA 1/2mut) is strongly recommended to patients, who are candidates for PARPi therapy in early or metastatic disease [11][12][13] or in those under 60 years of age with triple-negative breast cancer, irrespective of familiar or individual history [14]. Mutations in BRCA1/2 and PALB2 are associated with an increased lifetime risk for breast cancer of approximately 40%, for ATM, BARD1, CHEK2, RAD51C, and RAD51D, 20-30%, respectively [15].…”

Primary Prevention and Early Detection of Hereditary Breast Cancer

“…In a recent study, data from the GC-HBOC showed elevated prevalence rates in patients with triple-negative breast cancer (TNBC). Therefore, the set of criteria has been extended to include patients with TNBC under the age of 60 without further family history of cancer [14, 15]. Since 2023, as a result of the knowledge-generating healthcare research of the GC-HBOC, a further criterion has been added: as the risk of a pathogenic germline variant in male breast cancer patients is increased compared to the general population, especially for BRCA2 and also for BRCA1 , genetic counseling and analysis should start with one single male breast cancer patient [16, 17].…”