Intrinsic Subtype and Overall Survival of Patients with Advanced HR+/HER2_ Breast Cancer Treated with Ribociclib and ET: Correlative Analysis of MONALEESA-2, -3, -7

Purpose: The MONALEESA-2, -3, -7 trials demonstrated statistically significant and clinically meaningful progression-free survival and overall survival (OS) benefits with ribociclib plus endocrine therapy (ET) versus ET alone in hormone receptor-positive, HER2- negative (HR+/HER2_) advanced breast cancer (ABC). Understanding the association of intrinsic subtypes with survival outcomes could potentially guide treatment decisions. Here, we evaluated the association of intrinsic subtypes with OS in MONALEESA-2, -3, -7. Experimental Design:Tumor samples fromMONALEESA-2, -3, -7 underwent PAM50-based subtyping. The relationship between subtypes and OS was assessed using univariable and multivariable Cox proportional hazardsmodels.Multivariablemodels were adjusted for clinical prognostic factors. Results: Overall, 990 tumors (among 2,066 patients) from ribociclib (n = 580) and placebo (n = 410) arms were profiled. Subtype distribution was luminal A, 54.5%; luminal B, 28.0%; HER2-enriched (HER2E) 14.6%; and basal-like, 2.8%; and was consistent across treatment arms. The luminal A subtype had the best OS outcomes in both arms, while basal-like had the worst. Patients with HER2E (HR, 0.60; P = 0.018), luminal B (HR, 0.69; P = 0.023), and luminal A (HR, 0.75; P = 0.021) subtypes derived OS benefit with ribociclib. Patients with basal-like subtype did not derive benefit from ribociclib (HR, 1.92; P = 0.137); however, patient numbers were small (n = 28). Conclusions:The prognostic value of intrinsic subtypes for OS was confirmed in this pooled analysis of the MONALEESA trials (largest dataset in HR+/HER2_ ABC). While basal-like subtype did not benefit, a consistent OS benefit was observed with ribociclib added to ET across luminal and HER2E subtypes.