Genomic accesssment of patients with HR+/HER2- metastatic breast cancer treated with palbociclib (PROMISE study) paired

Biomarker studies for cyclin-dependent 4/6 kinase inhibitors (CDK4/6i) are often limited by tissue availability and narrow genomic assessments. We conducted a multicenter prospective study to obtain an unbiased 'omics’ assessment of tumors derived from women commencing 1st line (1L) palbociclib plus letrozole for HR+ HER2- MBC. We generated RNA and DNA data from baseline and a subset of progression samples. Patient-derived xenograft models were established from 10 samples. Genome-wide analyses and semi-supervised assessments of RB1-genes were conducted using whole exome and RNA sequencing data from baseline and progression tumors. Genes (FAT1, MYC, CDK2, and AMBRA1) known to drive CDK4/6i response, were confirmed to be associated with progression free survival (PFS). Novel CDK4/6i response genes including TIMELESS, SAE1, CENPU, SPAG5, and EXO1, as well as copy alterations in cytobands 12q21.2; 11q24.2; 1p22.3; 11p15.1, and 4q22.2 were observed to be associated with PFS. Paired baseline/progression samples demonstrated enrichment of genes involved in lipid metabolic processes, particularly beta oxidation as well as frequent intrinsic subtype switching. An RB1 signature, associated with shorter PFS (HR=2.72, p=0.006) and lack of cell cycle arrest in the NeoPalana study, may identify a subgroup of patients with de novo endocrine resistance.