Association of an Early Resistance Genomic State With Early Progression Following CDK4/6 Inhibitor Therapy in HR+/HER2− Metastatic Breast Cancer

ABSTRACT

CDK4/6 inhibitors combined with endocrine therapy are the standard first‐line treatment for hormone receptor‐positive (HR+) HER2‐negative metastatic breast cancer. However, a substantial proportion of patients experience early disease progression in routine practice. Clinicians currently lack practical tools at treatment initiation to identify patients at high risk of poor outcomes. In this study, we analyzed a real‐world cohort of 1690 patients treated with first‐line CDK4/6 inhibitors from the MSK CHORD 2024 dataset and defined an Early Resistance Genomic State (ERGS) based on alterations in five routinely sequenced genes: TP53, ESR1, RB1, PTEN, and NF1. ERGS was common, present in 41% of patients, and demonstrated a clear stepwise association with progression risk. Compared with ERGS‐negative patients, those with one, two, and three or more ERGS alterations had progressively higher risk of progression (hazard risk [HR] 1.29, 1.58, and 2.19, respectively; p  < 0.0001). ERGS remained independently associated with outcomes after adjustment for key clinical factors, including visceral and CNS disease, and significantly improved risk stratification, increasing the concordance index from 0.61 to 0.85. Clinically, ERGS identified a subgroup with very high absolute risk of early progression, with over 80% progressing within 12 months in the highest ERGS group. These findings indicate that a small set of routinely available genomic features can identify patients at high risk of early progression and support risk‐adapted first‐line treatment strategies in HR++/HER2− metastatic breast cancer. Because all patients received CDK4/6 inhibitor–based therapy, these findings should be interpreted as prognostic within a treated population rather than predictive of treatment‐specific resistance.