Androgen receptor expression, the AR/ER ratio, and progression-free survival in hormone receptor-positive/HER2-negative metastatic breast cancer treated with CDK4/6 inhibitors

Androgen receptor (AR) signaling may influence endocrine responsiveness in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) breast cancer; however, its prognostic relevance in patients receiving CDK4/6 inhibitors remains unclear. This study aimed to evaluate the associations of AR expression and the AR/ER ratio with progression-free survival (PFS) in patients with HR+/HER2 − metastatic breast cancer receiving first-line cyclin-dependent kinase 4/6 (CDK4/6) inhibitor-based therapy. This retrospective cohort study included 127 patients with HR+/HER2 − metastatic breast cancer treated with first-line CDK4/6 inhibitor plus endocrine therapy. AR expression was assessed by immunohistochemistry and analyzed as both continuous and categorical variables. The AR/ER ratio was analyzed primarily as a continuous variable, while a cohort-derived cut-off of 0.425 was used for exploratory categorical analyses. PFS was analyzed using the Kaplan–Meier method and Cox proportional hazards regression. The discriminatory performance of the AR/ER ratio was also assessed using time-dependent ROC analysis. AR positivity was observed in 65 patients (51.2%) and was associated with significantly longer median PFS compared with AR-negative tumors (30.5 vs. 16.3 months, p = 0.040). Similarly, higher continuous AR expression and a higher AR/ER ratio were associated with prolonged PFS in univariable analyses. Using the exploratory cohort-derived cut-off of 0.425, patients with AR/ER ratios above this threshold experienced significantly longer median PFS than those with lower ratios (32.6 vs. 17.5 months, p = 0.002). However, after adjustment for established clinicopathological factors, neither continuous AR expression nor the AR/ER ratio remained independently associated with PFS. Instead, higher Ki-67 expression, visceral metastasis, and central nervous system metastasis emerged as independent predictors of shorter PFS. The AR/ER ratio showed modest discriminatory performance in time-dependent ROC analyses. Higher AR expression and a higher AR/ER ratio were associated with longer PFS in univariable analyses, but neither remained independently associated with PFS after adjustment for established clinicopathological factors. The AR/ER ratio also showed only modest discriminatory performance in time-dependent ROC analyses, indicating limited prognostic value beyond routinely available clinical and pathological features. These findings do not support the AR/ER ratio as a stand-alone prognostic biomarker in this setting. Further validation in larger, independent cohorts is warranted.