FGFR gene amplification and response to HER2-targeted therapy in patients with HER2-expressing metastatic breast cancer

Purpose Resistance to HER2-targeted therapies remains a major clinical challenge in metastatic breast cancer (MBC), with limited biomarkers to guide treatment. This study sought to evaluate the prognostic and therapeutic significance of FGFR amplification in patients with HER2-expressing MBC treated with HER2-targeted therapies. Methods We retrospectively analyzed 73 patients with HER2-expressing MBC who underwent genomic profiling and received HER2-targeted therapy. FGFR1 and FGFR2 amplifications were identified using plasma ctDNA or tissue-based NGS. Multivariate Cox models were used to compare progression-free (PFS) and overall survival (OS) between FGFR-amplified and wild-type patients. Results FGFR amplification was detected in 21 (28.8%) patients. FGFR + patients were more likely to have ER-positive disease (85.0% vs. 50.0%, p  = 0.012) and prior CDK4/6 inhibitor use (61.9% vs. 28.8%, p  = 0.009). FGFR amplification was associated with shorter OS (median 4.47 vs. 6.19 years, p  = 0.009; adjusted hazard ratio [aHR] 3.00, 95% CI 1.48–6.09, p  = 0.002). FGFR + patients had shorter PFS on HER2-targeted therapy across all lines, with the strongest effect observed in later-line settings (aHR up to 13.38, p  < 0.001). Reduced PFS on HER2 therapy was observed prior to FGFR detection, suggesting early resistance (aHR = 4.03, p  = 0.025). Conclusion ​​Our findings support FGFR amplification as an independent biomarker of poor prognosis and resistance to HER2-targeted therapies in HER2-expressing MBC, highlighting its therapeutic relevance and the need for prospective studies to guide biomarker-driven strategies in this high-risk subset.