Denosumab is associated with longer real-world progression-free survival in BRCA1/2-mutated HR+ /HER2 - breast cancer patients with bone metastases receiving CDK4/6 inhibitors: A multicenter Italian study.

Preclinical evidence suggests that BRCA1/2-mutated tumors may rely on RANKL signaling for survival and proliferation. RANKL inhibition with denosumab could disrupt tumor-bone microenvironment crosstalk and potentially limit metastatic progression. We evaluated the association between denosumab and real-world progression-free survival (rwPFS) in germline BRCA1/2-mutated hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (mBC) with bone metastases. We performed a retrospective, multicenter study across 24 Italian hospitals including HR+/HER2- bone mBC patients treated in first- or second-line with a CDK4/6 inhibitor plus endocrine therapy. rwPFS was estimated by Kaplan-Meier and compared with log-rank tests. Center-stratified multivariable Cox models adjusted for clinically relevant covariates were used to assess the association between denosumab exposure and rwPFS. Effect modification by BRCA status was evaluated using a denosumab×BRCA1/2 mutation status. Among 1399 patients, 46 harbored germline BRCA1/2 mutations (13 BRCA1, 33 BRCA2), and 21 of these patients received denosumab. Among patients not receiving denosumab, BRCA1/2-wild-type/unknown patients had better rwPFS than BRCA1/2-mutated patients (median 28 vs 13 months; hazard ratio (HR) 0.48, 95% CI 0.32-0.73; p = 0.001). Among BRCA1/2-wild-type/unknown patients, denosumab use did not affect rwPFS (HR 0.98, 95% CI 0.85-1.12). Conversely, denosumab use was associated with longer rwPFS among patients with BRCA1/2 mutations (median 35 months, 95% CI 24-NR vs 13 months, 95% CI 9-27; HR 0.34, 95% CI 0.16-0.74; p = 0.006), with no significant difference between BRCA1 and BRCA2-mutated subgroups. Multivariable analysis confirmed the rwPFS benefit of denosumab in BRCA1/2-mutated patients (adjusted HR 0.45, 95% CI 0.21-0.99; p = 0.048). In this real-world cohort, denosumab use was associated with longer rwPFS in germline BRCA1/2-mutated HR+/HER2- mBC with bone metastases.