Clinical and Genomic Characteristics of Patients with HR+, HER2- Metastatic Breast Cancer Following Progression on a CDK4 and 6 Inhibitor

Abstract Purpose: 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 & 6i) +/- endocrine therapy (ET) to understand potential resistance mechanisms that may aid in identifying treatment options. Experimental Design: US patients with HR+, HER2- MBC had tumor biopsies collected from metastatic site during routine care following progression on a CDK4 & 6i +/- ET (CohortPost) or prior to initiating CDK4 & 6i treatment (CohortPre) and analyzed using a targeted mutation panel and RNA-seq. Clinical and genomic characteristics were described. Results: The mean age at MBC diagnosis was 59 years in CohortPre (n=133) and 56 years in CohortPost (n=223); 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, P<0.0001), ESR1 alteration frequency (mutations: 37% vs 10%, FDR<0.0001; fusions: 9% vs 2%, P=0.0176), and higher copy number amplification of genes on chr12q15, including MDM2, 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.