Real-world cell-free circulating tumor DNA (ctDNA) analysis identifies CDK4/6 inhibitor resistance and tumor evolution in HR+ advanced breast cancer

A large clinical-genomic database was used to assess circulating tumor DNA (ctDNA) pre- and post-CDK4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) treatment in a cohort of patients with HR+/HER2− metastatic breast cancer (mBC). A panel of putative resistance alterations to CDK4/6i + ET (CDK4/6i+ET-R) was developed based upon previous studies. Patients with ≥1 baseline CDK4/6i + ET-R were compared to patients without CDK4/6i + ET-R, and univariate and multivariate analyses were performed to assess differences in real-world time to treatment discontinuation (rwTTD), real-world time to next treatment (rwTTNT), and overall survival (OS). ESR1 and RB1 alterations were significantly more frequent post-CDK4/6i. Patients with CDK4/6i + ET-R mutations prior to CDK4/6i treatment had significantly worse outcomes in terms of time on CDK4/6i and OS, suggesting that this resistance signature could prove useful in better refining personalized treatment selection in future clinical practice, though further exploration is needed.