Genomics of <i>ERBB2</i>-Positive Breast Cancer in Young Women Before and After Exposure to Chemotherapy Plus Trastuzumab.

Abstract

Erb-B2 receptor tyrosine kinase 2 (<i>ERBB2</i>)-positive breast cancer (BC) is particularly common in young women. Genomic features of <i>ERBB2</i>-positive tumors before and after chemotherapy and trastuzumab (chemo + H) have not been described in young women and are important for guiding study of therapeutic resistance in this population. From a large prospective cohort of women age 40 years or younger with BC, we identified patients with <i>ERBB2</i>-positive BC and tumor tissue available before and after chemo + H. Whole-exome sequencing (WES) was performed on each tumor and on germline DNA from blood. Tumor-normal pairs were analyzed for mutations and copy number (CN) changes. Twenty-two women had successful WES on samples from at least one time point; 12 of these had paired sequencing results from before and after chemo + H and 10 had successful sequencing from either time point. <i>TP53</i> was the only significantly recurrently mutated gene in both pre- and post-treatment samples. <i>MYC</i> gene amplification was observed in four post-treatment tumors. Seven of 12 patients with paired samples showed acquired and/or clonally enriched alterations in cancer-related genes. One patient had an increased clonality putative activating mutation in <i>ERBB2.</i> Another patient acquired a clonal hotspot mutation in <i>TP53</i>. Other genomic changes acquired in post-treatment specimens included alterations in <i>NOTCH2</i>, <i>STIL</i>, <i>PIK3CA</i>, and <i>GATA3</i>. There was no significant change in median <i>ERBB2</i> CN (20.3 <i>v</i> 22.6; Wilcoxon <i>P</i> = .79) between paired samples. <i>ERBB2</i>-positive BCs in young women displayed substantial genomic evolution after treatment with chemo + H. Approximately half of patients with paired samples demonstrated acquired and/or clonally enriched genomic changes in cancer genes. <i>ERBB2</i> CN changes were uncommon. We identified several genes warranting exploration as potential mechanisms of resistance to therapy in this population.