Impact of BRCA2 pathogenic variants on outcomes to first-line CDK4/6 inhibitors plus endocrine therapy in HR-positive/HER2-negative metastatic breast cancer.

Germline BRCA2 pathogenic variants (homologous recombination repair deficiency) associated with reduced benefit from first-line CDK4/6 inhibitors.

The impact of homologous recombination repair pathogenic variants on outcomes with first-line CDK4/6 inhibitors plus endocrine therapy in HR-positive/HER2-negative metastatic breast cancer remained uncertain. This multicenter, real-world, case-control study included 233 patients, 116 carrying a homologous recombination repair pathogenic variant and 117 matched controls with negative germline testing, with inverse probability of treatment weighting applied to minimise baseline prognostic differences. After a median follow-up of 44 months, germline BRCA2 carriers (n = 67) had significantly shorter progression-free survival than controls (11 versus 27 months; adjusted HR 2.73; 95% CI 1.65-4.51; P < 0.001), a difference that was even more pronounced in endocrine-sensitive disease (12 versus 39 months; adjusted HR 4.04; 95% CI 1.82-8.98; P < 0.001). Exploratory analyses found RB1 loss of heterozygosity before treatment in most evaluable BRCA2 tumours. The authors suggest that germline BRCA2 carriers may require alternative first-line strategies.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

If this signal holds, germline BRCA2 status becomes a treatment decision parameter from the first metastatic line onwards, not merely a familial screening issue: one more argument for testing early, before treatment selection. The caveats are familiar but real — a retrospective case-control design, only 67 BRCA2 carriers, and statistical weighting that does not substitute for randomisation; the RB1 loss of heterozygosity lead remains exploratory. In practice, it mainly argues against delaying germline testing in HR-positive/HER2-negative metastatic disease.

Analysis by Dr Thibaut Benquey