Abstract 4708: FGFR gene amplification and response to HER2-directed therapy in patients with HER2+ metastatic breast cancer (MBC)

Introduction: Amplification of fibroblast growth factor receptor (FGFR) signaling has been implicated in driving resistance to endocrine therapies and, more recently, HER2-directed therapies in vitro. While FGFR pathway dysregulation is well-established as a poor prognostic marker in hormone-positive BC, its impact in HER2+ BC is less clear. This study aims to investigate the association between FGFR amplification and clinical response to HER2-directed therapy in patients with HER2+ MBC. Methods: This study retrospectively analyzed 73 patients with HER2+ MBC by IHC/FISH and/or HER2+ CTCs who received HER2-directed therapy between 2016-2024 under an IRB-approved trial (NU16B06) at Northwestern University Robert H. Lurie Cancer Center. CTC enumerations were performed via CELLTRACKS (Menarini). All patients completed NGS testing. FGFR1 and FGFR2 amplifications were identified via plasma ctDNA (Guardant 360) and tissue NGS (TempusX or FoundationOne®). FGFR gene amplification was considered positive for copy number values > 3 copies per cell. Results: FGFR amplification was detected in 21 (28.8%) patients with HER2+ MBC. The most common co-mutations included TP53 (52.4%), MYC (33.3%), PIK3CA (28.6%), and ESR1 (28.6%). Prior to FGFR detection, 17 (80.9%) FGFR+ patients had received endocrine therapy, 13 (61.9%) had received CDK4/6 inhibitors, and 10 (47.6%) had received HER2-directed therapy. Median progression-free survival (PFS) after detection of FGFR amplification was 3.4 months (range 0.5-19.2). FGFR+ and wild-type (WT) patients did not differ in age at metastatic diagnosis (median age 50 vs 56; p = 0.8), de-novo MBC presentation (28.6% vs 25.0%; p = 0.8), or having received endocrine therapy (85.7% vs 67.3%; p = 0.2). FGFR+ patients were more likely to have ER-positive MBC (85.0% vs 50.0%, p = 0.012) and to have received a CDK4/6 inhibitor (61.9% vs 28.8%; p = 0.009). FGFR+ patients demonstrated significantly shorter median PFS in all HER2-directed therapy lines compared to WT patients, as follows: first- or second-line therapy (4.53 vs 8.25 months; p = 0.0053), third- or fourth-line therapy (3.03 vs 8.17 months; p = 0.0023), and in fifth-line or later therapies (2.20 vs 9.57 months; p < 0.0001). FGFR+ patients had significantly worse median overall survival compared to WT patients (HR: 2.13, 95% CI: 1.19-3.83; 4.47 vs 6.19 years, p = 0.011). Conclusion: FGFR amplification in HER2+ MBC is associated with shorter PFS in all lines of HER2-directed therapies, as well as worse overall survival. These findings suggest that FGFR amplification may drive poor outcomes in patients with advanced HER2+ MBC and highlight its potential as a therapeutic target. Future studies are needed to confirm these findings and evaluate the efficacy of combining HER2 and FGFR directed therapies in this population. Citation Format: Diana Jaber, Natalie K. Heater, Sarah Marini, Surbhi Warrior, Yangruijue Ma, Patricia Robinson, Lisa Flaum, Regina Stein, Claudia Tellez, Huiping Liu, Qiang Zhang, Youbin Zhang, Massimo Cristofanilli, William Gradishar, Janice Lu. FGFR gene amplification and response to HER2-directed therapy in patients with HER2+ metastatic breast cancer (MBC) [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 4708.