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

Abstract

PURPOSE:

Erb-B2 receptor tyrosine kinase 2 (ERBB2)-positive breast cancer (BC) is particularly common in young women. Genomic features of ERBB2-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 ERBB2-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. TP53 was the only significantly recurrently mutated gene in both pre- and post-treatment samples. MYC 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 ERBB2. Another patient acquired a clonal hotspot mutation in TP53. Other genomic changes acquired in post-treatment specimens included alterations in NOTCH2, STIL, PIK3CA, and GATA3. There was no significant change in median ERBB2 CN (20.3 v 22.6; Wilcoxon P = .79) between paired samples.

CONCLUSION:

ERBB2-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. ERBB2 CN changes were uncommon. We identified several genes warranting exploration as potential mechanisms of resistance to therapy in this population.

• Authors: Marla Lipsyc-Sharf, Esha Jain, Laura C Collins, Shoshana M Rosenberg, Kathryn J Ruddy, Rulla M Tamimi, Lidia Schapira, Steven E Come, Jeffrey M Peppercorn, Virginia F Borges, Ellen Warner, Craig Snow, Ian E Krop, Dewey Kim, Jakob Weiss, Jorge Gomez Tejeda Zanudo, Ann H Partridge, Nikhil Wagle, Adrienne G Waks
• Journal: JCO precision oncology (JCO Precis Oncol) Vol. 7 Pg. e2300076 (06 2023) ISSN: 2473-4284 [Electronic] United States
• PMID: 37364233 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ERBB2 protein, human
• Receptor, ErbB-2
• Trastuzumab

Topics

• Adult
• Female
• Humans
• Breast Neoplasms (drug therapy, genetics, pathology)
• Genomics (methods)
• Mutation
• Prospective Studies
• Receptor, ErbB-2 (genetics)
• Trastuzumab (therapeutic use)