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BACKGROUND: In estrogen receptor-positive metastatic breast cancer, mutations (ESR1) are a common mechanism of acquired resistance to aromatase inhibitors (ArIh). However, the impact alterations have on CDK4/6 inhibitor (CDK4/6i) sensitivity has not been established. Analyses of CDK4/6i trials suggest that the endocrine therapy partner and specific allele may affect susceptibility. We analyzed a real-world data set to investigate CDK4/6i efficacy in ESR1 metastatic breast cancer and associated clinical factors.METHODS: ESR1 were identified by analysis of circulating-tumor deoxyribonucleic acid. The GuardantINFORM database contains genomic information from tumors linked with claims data. Patients who started a CDK4/6i within 30 days of sequencing were categorized as having ESR1 or non--mutant (non-ESR1) breast cancer. Data were analyzed to determine the real-world time-to-next-treatment, defined as the start of a breast cancer treatment to initiation of the subsequent treatment.RESULTS: One hundred forty-five patients with ESR1 and 612 with non-ESR1 metastatic breast cancer were analyzed. ESR1 and non-ESR1 tumors had similar real-world time-to-next-treatment on CDK4/6i regimens (hazard ratio, 1.02; 95% confidence interval, 0.82 to 1.23). Duration on therapy in the first-line and second-line plus treatment settings were comparable regardless of status. We stratified treatment duration by concurrent endocrine therapy, and patients with ESR1 had worse outcomes on ArIh but comparable real-world time-to-next-treatment on fulvestrant.CONCLUSIONS: These data suggest variants are not associated with pan-CDK4/6i resistance and are consistent with the hypothesis that CDK4/6 blockade combined with a selective estrogen receptor degrader is potentially an effective option for ESR1 metastatic breast cancer.