Genomics of HER2+ breast cancer in young women before and after exposure to chemotherapy (chemo) plus trastuzumab (H).

person Adrienne Gropper Waks Dana-Farber Cancer Institute, Boston, MA info_outline Adrienne Gropper Waks, Esha Jain, Laura C. Collins, Shoshana M. Rosenberg, Kathryn Jean Ruddy, Rulla M Tamimi, Lidia Schapira, Steven E. Come, Jeffrey M. Peppercorn, Virginia F. Borges, Ellen Warner, Craig Snow, Ann H. Partridge, Nikhil Wagle

Authors person Adrienne Gropper Waks Dana-Farber Cancer Institute, Boston, MA info_outline Adrienne Gropper Waks, Esha Jain, Laura C. Collins, Shoshana M. Rosenberg, Kathryn Jean Ruddy, Rulla M Tamimi, Lidia Schapira, Steven E. Come, Jeffrey M. Peppercorn, Virginia F. Borges, Ellen Warner, Craig Snow, Ann H. Partridge, Nikhil Wagle Organizations Dana-Farber Cancer Institute, Boston, MA, Broad Institute of MIT and Harvard, Cambridge, MA, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, Mayo Clinic, Department of Oncology, Rochester, MN, Brigham and Women's Hospital, Boston, MA, Stanford Cancer Center, Palo Alto, CA, Beth Israel Deaconess Medical Center, Boston, MA, Massachusetts General Hospital, Boston, MA, University of Colorado Comprehensive Cancer Center, Aurora, CO, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada Abstract Disclosures Research Funding Other Foundation Background: HER2+ breast cancer (BC) is particularly common in young women. Genomic features of HER2+ tumors before and after H-based therapy have not been described in a population of young women and may point to clinically targetable mechanisms of resistance. Methods: From a large prospective cohort of women diagnosed with BC age ≤40 years, we identified those with HER2+ BC and tumor tissue available for sequencing 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. Evolutionary analysis was performed for patients with both pre- and post-treatment (tx) samples. Results: 22 women had successful WES samples from at least one timepoint; 13 of these had paired sequencing results both before and after chemo+H. For the majority of women, post-tx sample was following neoadjuvant chemo + H, though post-tx timepoint for other women represented locoregional or distant metastasis (Table). TP53 was the only gene that was significantly recurrently mutated in both pre- and post-tx samples. Comparison of matched pre-tx and post-tx samples demonstrated that large changes in HER2 CN over the course of tx were uncommon, only 2/13 pts had > 2-fold change in HER2 CN. Other clonal and subclonal genomic alterations were found to be acquired in the post-tx sample compared to the pre-tx sample. One patient acquired a putative activating mutation in ERBB2. Another patient acquired a clonal hotpsot mutation in TP53 . MYC gene amplification was observed in 4 post-tx tumors. NOTCH2 alterations were found in post-tx biopsies from 2 different patients, and mutations in STIL were also found in post-tx biopsies from 2 patients, though the function of these mutations is not known. Conclusions: HER2+ breast tumors in young women display genomic evolution following tx with chemo+H. HER2 CN changes are uncommon, but we identified several genes that warrant exploration as potential mechanisms of resistance to therapy in this population. Parameter # (%) Age at dx Median 36 yo (range 27-39) Stage at dx I 1 (5%) II 10 (45%) III 9 (41%) IV 2 (9%) Receptor status at dx ER+ and/or PR+ 17 (77%) ER- and PR- 5 (23%) Disease status after chemo+H Surgery post-neoadjuvant tx 13 (59%) Locoregional recurrence 2 (9%) Metastatic 7 (32%)