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New research · Endocrinology
ESMO open · 23h
Case-controlESMO open · 2026

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

M Cruellas, A Rodriguez-Hernandez, L Carità … J Balmaña
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EndocrinologyCase-control

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.

M Cruellas et al. · ESMO open · 2026
Background

The impact of homologous recombination repair (HRR) pathogenic variants (PV) on outcomes with first-line CDK4/6i plus ET in HR-positive/HER2-negative MBC remains uncertain.

Methods

We conducted a multicenter, real-world, case-control study including 233 patients with HR-positive/HER2-negative MBC treated with first-line CDK4/6i and ET.

n = 233 patients
Results

BRCA2 gene changes meant a higher risk of cancer getting worse or death

AHR 4.04 (95% CI 1.82 to 8.98)
null = 11.828.98
CI excludes the null - significant
More results

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 ET was present in 10% and secondary resistance in 27%.

More results

Among patients with endocrine-sensitive disease, germline BRCA2 PV 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 LOH before CDK4/6i-treatment in most evaluable BRCA2 tumors.

“
Conclusion · 1 of 2

BRCA2 PVs were independently associated with poorer outcomes to first-line CDK4/6i plus ET in HR-positive/HER2-negative MBC compared with controls, especially relevant among patients with endocrine-sensitive disease.

Conclusion · 2 of 2

These findings suggest that patients with a germline PV in BRCA2 may require alternative first-line strategies.

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