Phenotypic Age Acceleration Predicts Survival Outcomes in HR+/HER2-Negative Metastatic Breast Cancer Treated With CDK4/6 Inhibitors: A Real-World Cohort Study.

BACKGROUND: Chronological age alone poorly reflects physiologic vulnerability in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) treated with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). We therefore evaluated phenotypic age acceleration (PhenoAgeAccel), a biomarker of biological aging, as a predictor of survival outcomes. METHODS: This retrospective cohort included 560 patients with HR+/HER2-negative mBC treated with CDK4/6i plus endocrine therapy between 2017 and 2025. PhenoAge was calculated using clinical biomarkers obtained within 1 month prior to treatment initiation, and PhenoAgeAccel was defined as the residual of PhenoAge regressed on chronological age. Patients were categorized as PhenoAgeAccel ≤ 0 or > 0. RESULTS: PhenoAgeAccel was evaluable in 530 patients; 38.3% exhibited PhenoAgeAccel > 0. Median follow-up for the entire cohort was 42.2 months (95% confidence interval [CI], 39.0-45.5). Median progression-free survival (PFS) was 21.1 months (95% CI, 18.6-23.5) and median overall survival (OS) was 49.9 months (95% CI, 41.8-58.0). Patients with PhenoAgeAccel > 0 experienced significantly shorter PFS and OS compared with those without acceleration (median PFS 14.0 vs. 27.6 months, hazard ratio [HR] 1.53, 95% CI, 1.17-2.01; P = .002; median OS 28.9 vs. 68.0 months, HR 1.81, 95% CI, 1.26-2.60; P = .001). The adverse prognostic impact of PhenoAgeAccel was consistent across predefined clinical subgroups. Patients with accelerated biological aging also demonstrated lower objective response (ORR) and disease control rates (DCR) (objective response rate 25.6% vs. 33.9%, P = .043; DCR 72.4% vs. 89.0%, P < .001). CONCLUSIONS: PhenoAgeAccel is an independent prognostic marker associated with inferior survival and reduced treatment response, suggesting that biological age may be more informative than chronological age in HR+/HER2-negative mBC treated with CDK4/6 inhibitors.