Abstract 1975: The use of circulating tumor DNA (ctDNA) in HER2+ metastatic breast cancer (MBC) for prognostication and management

Abstract Background: HER2+ breast cancers account for 20% of all breast cancers, and survival rates in the metastatic setting remain low. There have been advances in treatment with HER2 targeted therapies, but progression free survival (PFS) decreases after each subsequent line of therapy. Understanding patients’ mutational profile with the use of ctDNA may identify resistance to HER2 targeted therapies, aid in prognostication, and guide the addition of further targeted therapies to improve outcomes. Methods: Patients with HER2+ MBC were enrolled from 2016-2024 under an IRB approved clinical trial (NU16B06) at Northwestern University were retrospectively analyzed. Plasma ctDNA was analyzed by Guardant 360 and tissue NGS was performed using commercially available tests such as FoundationOne or TempusX. Mutations that developed as well as additional clinical, pathologic, treatment, and response data were collected for analysis. Results: There were 67 patients with HER2+ MBC included in the analysis. The mean initial PFS following HER2 targeted therapy was 29.8 months, the mean second PFS was 12 months, and the overall mortality was 63%. The overall second PFS was significantly shorter than the initial PFS (HR 4.00, p <0.001). ESR1+ patients had a significantly shorter initial PFS compared to ESR1 wildtype (wt) patients (14 vs 22 months, p=0.038). There was no significant difference between second PFS for ESR1+ patients compared to ESR1wt patients (5.5 vs 6.8 months, p=0.28). There was a significant difference in initial PFS for patients FGFR+ patients and FGFRwt patients (12 vs 22 months, p=0.002) but not for second PFS (6 vs 8 months, p=0.07). The initial PFS for PIK3CA+ patients was shorter compared to PIK3CAwt (12 vs 22 months, p=0.087) but was similar for the second PFS (6 vs 6 months, p=0.52). Conclusion: The use of ctDNA in HER2+ MBC can aid in understanding a patient’s genomic landscape and prognosis. There is overall shorter PFS in patients with identified mutations and that significantly worsens with progression of disease. The initial PFS in patients with ESR1, FGFR, and PIK3CA mutations is significantly less than in respective wildtype patients. While targeted therapies for these mutations currently exist in the hormone positive breast cancer setting, our findings demonstrate that HER2+ patients may also benefit from additional targeted therapy in adjunct to HER2 directed therapy in the early metastatic setting. This therapeutic benefit should be prospectively studied in a larger cohort to understand if there exists a clinically significant improvement in outcomes. Citation Format: Surbhi Warrior, Diana Jaber, Natalie Heater, Sarah Marini, Yangruijue Ma, Zequn Sun, Lisa Flaum, Patricia Robinson, Regina Stein, Regina Stein, Massimo Cristofanilli, William Gradishar, Janice Lu. The use of circulating tumor DNA (ctDNA) in HER2+ metastatic breast cancer (MBC) for prognostication and management [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 1975.