Impact of BRCA2 pathogenic variants on outcomes to first-line CDK4/6 inhibitors plus endocrine therapy in HR-positive/HER2-negative metastatic breast cancer.
BRCA2 pathogenic variants are associated with shorter progression-free survival in metastatic breast cancer.
Impact of BRCA2 pathogenic variants on outcomes to first-line CDK4/6 inhibitors plus endocrine therapy in HR-positive/HER2-negative metastatic breast cancer.
The impact of homologous recombination repair (homologous recombination repair) pathogenic variants (pathogenic variants) on outcomes with first-line CDK4/6i plus endocrine therapy in HR-positive/HER2-negative metastatic breast cancer remains uncertain.
We conducted a multicenter, real-world, case-control study including 233 patients with HR-positive/HER2-negative metastatic breast cancer treated with first-line CDK4/6i and endocrine therapy.
BRCA2 gene changes meant a higher risk of cancer getting worse or death
Among the included 233 patients, median age at diagnosis was 45 years (interquartile range 39-56) and 33% had de novo metastatic disease.
Primary resistance to adjuvant endocrine therapy was present in 10% and secondary resistance in 27%.
Among patients with endocrine-sensitive disease, germline BRCA2 pathogenic variants carriers had markedly shorter PFS (median PFS 12 versus 39 months; aHR 4.04; 95% CI 1.82-8.98, P < 0.001).
Exploratory analyses revealed RB1 loss of heterozygosity before CDK4/6i-treatment in most evaluable BRCA2 tumors.
BRCA2 PVs were independently associated with poorer outcomes to first-line CDK4/6i plus endocrine therapy in HR-positive/HER2-negative metastatic breast cancer compared with controls, especially relevant among patients with endocrine-sensitive disease.
These findings suggest that patients with a germline pathogenic variants in BRCA2 may require alternative first-line strategies.