Abstract 2024: Circulating tumor DNA detectability and targetability in patients undergoing neoadjuvant therapy for localized breast cancer

Background: Circulating tumor DNA (ctDNA) detection can identify patients (pts) at higher risk for cancer recurrence. Hormone receptor positive (HR+)/HER2- breast cancer (BC) is typically less responsive to chemotherapy, and standard indicators of tumor response to neoadjuvant therapy (NAT) are less informative of prognosis. In this study, we analyzed banked plasma samples for ctDNA in pts receiving neoadjuvant BC treatment to determine the associations between ctDNA detectability and post-NAT surgical pathology and overall outcomes. Methods: Plasma samples from pts with high-risk localized HR+/HER2- BC treated with NAT were retrospectively analyzed for ctDNA using the Invitae Personalized Cancer Monitoring™ assay. Primary tumors underwent whole exome sequencing (WES), and personalized primer sets were designed for up to 50 tumor-specific variants. High throughput next generation sequencing was then used to evaluate plasma samples for ctDNA at up to 3 timepoints: prior to, during, and after NAT. Levels of residual disease were determined by residual cancer burden index (RCB). WES data was interrogated for variants with approved matched targeted therapies. Results: Retrospective plasma samples from twelve patients with high-risk early BC (9 stage II, 3 stage III) underwent ctDNA analysis. Five pts had +ctDNA pre-NAT; 3 experienced ctDNA clearance on NAT (all chemotherapy), and 2 of these pts showed sustained post-NAT ctDNA clearance. One of these pts had RCB-0 and the other RCB-2 disease. To date, these 2 pts have not had recurrence of their disease (f/u 45.7 & 47.1 months). Among the 2 pts with +ctDNA on NAT, 1 was receiving chemotherapy and 1 endocrine therapy. The other 3 pts with pre-NAT +ctDNA who did not have documented post-NAT ctDNA clearance experienced recurrences: 14.4, 68.4, & 72 months after surgery. The 7 pts with -ctDNA pre-NAT have not experienced recurrence to date (median f/u 62.7 months). Overall, 7/12 pts (58%) had targetable variants detected on tissue WES: 4 PIK3CA (N345K x2, Q546K, H1047R) and 3 AKT1E17K. Three of these pts had +ctDNA, and all had activating PIK3CA mutations. One pt with PIK3CAN345K experienced sustained ctDNA clearance. Conclusions: Persistence of ctDNA despite NAT appears to be associated with disease recurrence, though the number of patients in this retrospective analysis was small. These hypothesis generating findings require validation in larger datasets. If validated, results could guide development of interception clinical trials with PI3K inhibitors for pts with ctDNA+ PIK3CA-mutant breast cancer. Citation Format: Arielle J. Medford, Elyssa Denault, Veerle Bossuyt, Michelle Hutchinson, Emily Westheimer, Jianhua Zhao, Bob Daber, Steven J. Isakoff, Beverly Moy, Dejan Juric, Laura M. Spring, Ryan Corcoran, Aditya Bardia. Circulating tumor DNA detectability and targetability in patients undergoing neoadjuvant therapy for localized breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2024.