An early resistance genomic state (ERGS) as an identifier of primary CDK4/6 inhibitor failure in HR+/HER2− metastatic breast cancer.

1086 Background: CDK4/6 inhibitors combined with endocrine therapy are the standard first-line treatment for patients with hormone receptor-positive (HR+), HER2-negative metastatic breast cancer (mBC). However, a substantial subset of patients experience early disease progression, and there are currently no clinically practical tools available at treatment initiation to identify patients unlikely to derive lasting benefit. In this study, we attempt to define a clinically actionable genomic resistance phenotype using routine tumor sequencing. Methods: We conducted a retrospective real-world analysis using the MSK CHORD 2024 cohort, including 1,690 patients with HR+/HER2− mBC treated with first-line CDK4/6 inhibitors (palbociclib, ribociclib, or abemaciclib). An Early Resistance Genomic State (ERGS) was pre-specified based on alterations in five genes with established roles in endocrine and cell-cycle resistance: TP53, ESR1, RB1, PTEN, and NF1. The primary endpoint was time to first documented progression following CDK4/6 initiation, with early progression defined as progression within 6 months. Multivariable Cox proportional hazards models were adjusted for age, visceral disease, and central nervous system (CNS) involvement. Model performance was assessed using internal validation with resampling. Results: ERGS alterations were present in 41% of patients. ERGS demonstrated a graded, dose-dependent association with progression risk. Compared with ERGS-negative patients, those with one ERGS alteration had a 29% higher risk of progression (Hazard Ratio (HR) = 1.29, 95% CI: 1.15-1.45), those with two alterations had a 58% higher risk (HR = 1.58, 95% CI: 1.30-1.91), and those with three or more alterations had more than double the risk (HR = 2.19, 95% CI: 1.24-3.87; global log-rank p<0.0001). Twelve-month progression rates were 48%, 62%, 71%, and 85% across ERGS 0, 1, 2, and ≥3 groups, respectively. The prognostic impact of ERGS remained consistent across endocrine partner (aromatase inhibitor vs fulvestrant) and metastatic pattern subgroups. Incorporation of ERGS significantly improved model discrimination beyond clinical covariates alone, increasing the concordance index from 0.61 to 0.85 in internal validation analysis. Conclusions: ERGS defines a systems-level intrinsic CDK4/6 resistance phenotype identifiable using routine tumor sequencing at treatment initiation. This parsimonious genomic state provides clinically meaningful risk stratification beyond standard clinicopathologic features and identifies patients unlikely to derive lasting benefit from CDK4/6-based therapy. Therefore, ERGS may serve as a practical biomarker to prioritize enrollment on escalated first-line trials or alternative therapeutic strategies in HR+/HER2− metastatic breast cancer.