# Germline BRCA1/2 Mutations in a Large Clinic-Based Cohort of Patients with Metastatic Breast Cancer in France

## TL;DR

This study finds that a small but significant number of metastatic breast cancer patients in France have BRCA1/2 mutations, many of whom wouldn't qualify for genetic testing under current guidelines.

## Contribution

The study provides new data on the prevalence of BRCA1/2 mutations in metastatic breast cancer patients in France and highlights the limitations of current genetic testing criteria.

## Key findings

- 2.7% of metastatic breast cancer patients carried pathogenic BRCA1/2 mutations.
- 45% of BRCA1/2 mutation carriers would not have met standard criteria for genetic testing.
- Mutation carriers were younger at diagnosis and had higher-grade tumors compared to non-carriers.

## Abstract

Inherited mutations in the BRCA1 and BRCA2 genes are well known in early breast cancer, but much less is known about how often they occur in patients with metastatic breast cancer, especially in routine clinical practice. In this study, we offered genetic testing to a large group of patients with metastatic breast cancer treated in several hospitals in eastern France, regardless of their age or family history. We found that a small but clinically important proportion of patients carried a BRCA1 or BRCA2 mutation, and nearly half of them would not have been identified using standard referral criteria. These results suggest that broader access to genetic testing could help better identify patients who may benefit from targeted treatments, such as PARP inhibitors, and support more equitable implementation of precision medicine in metastatic breast cancer.

Objectives: This study aimed to fill the data gap regarding the prevalence of germline (g) BRCA1/2 mutations in patients with metastatic breast cancer (mBC) in France. Methods: A prospective gBRCA1/BRCA2 mutation analysis was proposed to all patients with mBC treated in seven French centers between 19 February and 30 November 2015. The BRCA TrueTM test (Pathway Genomics®, San Diego, CA, USA) analyzed the coding and flanking regions of BRCA1 and BRCA2 genes using next-generation sequencing, Sanger sequencing, and multiplex ligation-dependent probe amplification. Results: Among 407 included mBC patients, 11 (2.7%) carried pathogenic gBRCA1/2 mutations. Of these, five (45%) would not have met standard criteria for genetic screening. Compared with non-carriers, gBRCA1/2 carriers were significantly younger at mBC diagnosis (47.5 vs. 60.7 years, p = 0.0006), had higher-grade tumor histology (p = 0.044), and had a higher rate of contralateral recurrence (36.4% vs. 11.6%, p = 0.035), with comparable adjusted survival (median overall survival 74.9 vs. 100.1 months, p = 0.97). Variants of uncertain significance were identified in 17 (4.2%) patients. Conclusions: The 2.7% prevalence of gBRCA1/2 mutations in this prospective French mBC cohort was relatively low. Nearly half of the mutation carriers would not have been routinely referred for oncogenetic counseling, underscoring the potential value of broader genetic screening in this population.