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AbstractPurpose: We explored the clinical and genomic characteristics of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) after progression on cyclin-dependent kinase 4 and 6 inhibitors (CDK4 14% and 45% of patients had prior chemotherapy/ET and 35% and 26% had de novo stage IV MBC, respectively. The most common biopsy site was liver (CohortPre, 23%; CohortPost, 56%). CohortPost had significantly higher tumor mutational burden (TMB), (median 3.16 vs 1.67 Mut/Mb, PESR1 alteration frequency (mutations: 37% vs 10%, FDRMDM2, FRS2, and YEATS4 versus CohortPre patients. Additionally, CDK4 copy number gain on chr12q13 was significantly higher in CohortPost vs. CohortPre (27% vs. 11%, P=0.0005). Conclusions: Distinct mechanisms potentially associated with resistance to CDK4 & 6i +/- ET, including alterations in ESR1 and amplification of chr12q15 and CDK4 copy number gain, were identified.
Rao et al. (Mon,) studied this question.