Mutations in BRCA1/2 and Other Panel Genes in Patients With Metastatic Breast Cancer —Association With Patient and Disease Characteristics and Effect on Prognosis

Abstract

PURPOSE Among patients with metastatic breast cancer (mBC), the frequency of germline mutations in cancer susceptibility genes and the clinical relevance of these mutations are unclear. In this study, a prospective cohort of patients with mBC was used to determine mutation rates for breast cancer (BC) predisposition genes, to evaluate the clinical characteristics of patients with mutations, and to assess the influence of mutations on patient outcome. PATIENTS AND METHODS Germline DNA from 2,595 patients with mBC enrolled in the prospective PRAEGNANT registry was evaluated for mutations in cancer predisposition genes. The frequencies of mutations in known BC predisposition genes were compared with results from a prospective registry of patients with nonmetastatic BC sequenced using the same QIAseq method and with public reference controls. Associations between mutation status and tumor characteristics, progression-free survival, and overall survival were assessed. RESULTS Germline mutations in 12 established BC predisposition genes (including BRCA1 and BRCA2) were detected in 271 (10.4%) patients. A mutation in BRCA1 or BRCA2 was seen in 129 patients (5.0%). BRCA1 mutation carriers had a higher proportion of brain metastasis (27.1%) compared with nonmutation carriers (12.8%). Mutations were significantly enriched in PRAEGNANT patients with mBC compared with patients with nonmetastatic BC (10.4% v 6.6%, P < .01). Mutations did not significantly modify progression-free survival or overall survival for patients with mBC. CONCLUSION Multigene panel testing may be considered in all patients with mBC because of the high frequency of germline mutations in BRCA1/2 and other BC predisposition genes. Although the prognosis of mutation carriers and nonmutation carriers with mBC was similar, differences observed in tumor characteristics have implications for treatment and for future studies of targeted therapies.

Cyclin-Dependent Kinase 4/6 Inhibitor Outcomes in Patients With Advanced Breast Cancer Carrying Germline Pathogenic Variants in DNA Repair–Related Genes

“…The authors found that BRCA1/2 pathogenic variants were not associated with worse OS and identified an inverse association between ER expression and OS in those with BRCA1 mutations but not with BRCA2 pathogenic variants. 38 In the advanced scenario, a comprehensive publication was recently done by Fasching et al, 39 placebo groups, respectively [HR, 0.3, 0.15 to 0.61]). This led the authors to conclude that BRCA1/2 alterations might be considered a predictive biomarker of greater benefit from ribociclib.…”

Endocrine Treatment for Breast Cancer Patients Revisited—History, Standard of Care, and Possibilities of Improvement

“…Developed on the basis of germline BRCA1/2 mutations and their role in tumor pathology, poly (ADP-ribose) polymerase (PARP) inhibitors are a further therapy option for patients with advanced HER2-negative disease, including both triple-negative and hormone-receptor-positive BC patients, who make up about 50% of all aBC patients [ 95 ]. The OlympiAD trial for olaparib [ 96 ] and the EMBRACA trial for talazoparib [ 97 ] showed an improvement concerning PFS over a chemotherapy of physicians’ choice.…”

Update Breast Cancer 2021 Part 3 – Current Developments in the Treatment of Early Breast Cancer: Review and Assessment of Specialised Treatment Scenarios by an International Expert Panel

“…The SG-EBC Expert Panel did not advocate general testing of all breast cancer patients, despite the fact that almost a quarter of the experts were in favour of either offering panel testing to all breast cancer patients under 65 years of age or to all breast cancer patients regardless of age (Supplementary Table S1 , question 1). Recent research suggests that approximately 5 – 10% of all breast cancer cases involve a mutation in one of the known risk genes 1 , 2 , 3 , 4 , 5 .…”

“…Aktuelle Arbeiten gehen davon aus, dass bei ca. 5 – 10% aller Brustkrebspatientinnen eine Mutation in einem der bekannten Risikogene gefunden werden kann 1 , 2 , 3 , 4 , 5 .…”