The use of circulating tumor DNA (ctDNA) to evaluate need for additional targeted therapies in HER2 positive metastatic breast cancer (MBC).

e13003 Background: HER2+ MBC is an aggressive form of breast cancer. There have been significant advances in HER2 targeted therapies, but progression free survival (PFS) remains low and mortality remains high after 2nd and 3rd line therapies. Liquid biopsies with use of ctDNA can show development of ESR1 and PIK3CA mutations, among others, in HER2+ patients. Development of selective estrogen receptor degraders and PIK3CA targeted therapies have shown survival benefit in hormone receptor positive, HER2 negative breast cancers. There are currently no guidelines or data about the use of these targeted therapies in HER2+ breast cancers. Methods: Patients were prospectively enrolled from 2016-2024 under an IRB approved clinical trial (NU16B06) 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 clinical, pathologic, treatment, and response data were collected. Results: There were 67 patients with HER2+ MBC with mean overall PFS of 29 months and 62.7% mortality. There were 8 patients with ESR1 mutations with a significantly shorter PFS compared to ESR1 wildtype (wt) (14.5 vs 20.9 months, p = 0.009). The OS of ESR1+ patients was significantly less than ESR1wt patients (109 vs 178 months, p = 0.029). The mortality for ESR1+ patients was significantly higher than ESR1wt (75% vs 34%, p = 0.028). There were 20 patients with PIK3CA mutations. The OS of PIK3CA+ patients was significantly lower than PIK3CAwt (94 vs 163 months, p = 0.036). The mortality for PIK3CA+ patients was significantly higher compared to PIK3CAwt (90% vs 52%, p = 0.004). There were other mutations found such as TP53 (50), FGFR (15), MYC (14), EGFR (8), and PTEN (5). Conclusions: Changes in molecular profiles found on ctDNA in HER2+ MBC can help identify patients who are more likely to have therapy resistance and may benefit from further targeted therapies. This retrospective analysis showed that HER2+ MBC patients who are ESR1+ or PIK3CA+ had significantly higher mortality and lower OS. The addition of targeted therapies, potentially in combination with HER2 targeted therapy, may improve prognosis. Further research to use these targeted agents in a larger HER2+ cohort needs to be done to investigate benefit and response.