Baseline cell cycle and immune profiles indicate CDK4/6 inhibitor response in metastatic HR + /HER2- breast cancer.

While CDK4/6 inhibitors (CDK4/6i) and endocrine therapy are standard-of-care for metastatic HR + /HER2- breast cancer, patient selection for durable efficacy remains undefined. Here, we assessed baseline cell cycle and immune profiles in a CDK4/6i-treated patient cohort with differential progression-free survival (PFS < 6 months vs. >23 months) using transcriptomic and protein-based imaging approaches. Cell cycle, polo-like kinase signaling and transcription gene sets are largely enriched among pre-treatment tissue of patients with short PFS. Pre-treatment tumors express cyclin A or E significantly higher in patients with short PFS and correlate with macrophage accumulation. Patients with long PFS display gene set enrichment for growth factor and immune signaling pre-treatment, while gene set enrichment for immune activation emerges during CDK4/6i therapy. Our data highlight baseline tumor-intrinsic and tumor microenvironments-associated indicators of CDK4/6i response in the "real-world" setting and offer implications for precision-based therapeutic combinations to enhance CDK4/6i efficacy. Clinical trial registration number: NCT04526587.