Genomic characterization of ER-positive primary tumors and corresponding relapses identifies potentially targetable alterations

The majority of breast cancer patients have tumors expressing estrogen receptor α (ER) and receive endocrine therapy. However, around one-third relapse in their disease, predominantly with retained ER expression. Molecular alterations are proposed to be contributors to the resistance mechanisms. Patients with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative primary breast cancer with an ER-positive relapse < 5 years of ongoing endocrine therapy were retrospectively assessed. Extracted DNA was analyzed through panel sequencing, and RNA by microarray, from patients’ primary ( n = 58), and paired relapse tumors ( n = 54), and tumor-free lymph nodes (DNA germline controls, n = 62). Several single-nucleotide variations and copy number variations showed nominal exploratory associations with worse overall survival. Copy number correlations with intrinsic subtypes and individual gene expression supported the findings. These results identify hypothesis-generating genomic and transcriptomic features, including potentially targetable alterations, in a clinically defined cohort of endocrine-resistant breast cancer patients.