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

<h2>Abstract</h2><h3>Background</h3> 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. <h3>Methods</h3> 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. <h3>Results</h3> Among 1,399 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). <h3>Conclusions</h3> In this real-world cohort, denosumab use was associated with longer rwPFS in germline BRCA1/2-mutated HR+/HER2− mBC with bone metastases.