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PURPOSE: Erb-B2 receptor tyrosine kinase 2 ()-positive breast cancer (BC) is particularly common in young women. Genomic features of -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.METHODS: From a large prospective cohort of women age 40 years or younger with BC, we identified patients with -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.RESULTS: 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. was the only significantly recurrently mutated gene in both pre- and post-treatment samples. 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 Another patient acquired a clonal hotspot mutation in . Other genomic changes acquired in post-treatment specimens included alterations in , , , and . There was no significant change in median CN (20.3 22.6; Wilcoxon = .79) between paired samples.CONCLUSION: -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. CN changes were uncommon. We identified several genes warranting exploration as potential mechanisms of resistance to therapy in this population.