High FGFR1-4 mRNA Expression Levels Correlate with Response to Selective FGFR Inhibitors in Breast Cancer

Purpose: FGFR1 amplification (FGFR1amp) is recurrent in metastatic breast cancer (MBC) and is associated with resistance to endocrine therapy and CDK4/6 inhibitors (CDK4/6is). Multityrosine kinase inhibitors (MTKIs) and selective pan-FGFR inhibitors (FGFRis) are being developed for FGFR1 amp breast cancer. High-level FGFR amplification and protein expression by IHC have identified breast cancer responders to FGFRis or MTKIs, respectively. Experimental Design: Here, we used preclinical models and patient samples to identify predictive biomarkers to these drugs. We evaluated the antitumor activity of an FGFRi and an MTKI in a collection of 17 breast cancer patient-derived xenografts (PDXs) harboring amplification in FGFR1/2/3/4 and in 10 patients receiving either an FGFRi/MTKI. mRNA levels were measured on FFPE tumor samples using two commercial strategies. Proliferation and angiogenesis were evaluated by detecting Ki-67 and CD31 in viable areas by immunofluorescence. angiogenesis were evaluated by detecting Ki-67 and CD31 in viable areas by immunofluorescence. Results: High FGFR1-4 mRNA levels but not copy-number alteration (CNA) is associated with FGFRi response. Treatment with MTK1s showed higher response rates than with FGFRis (86% vs. 53%), regardless of the FGFR1-4 mRNA levels. FGFR-addicted PDXs exhibited an antiproliferative response to either FGFRis or MTKIs, and PDXs exclusively sensitive to MTI\1 exhibited an additional antiangiogenic response. Consistently, the clinical benefit of MTKIs was not associated with high FGFR1-4 mRNA levels and was observed in patients previously treated with antiangiogenic drugs. Conclusions: Tailored therapy with FGFRis in molecularly selected MBC based on high FGFR1-4 mRNA levels warrants prospective validation in patients with CDK4/6i-resistant luminal breast cancer and in patients with TNBC without targeted therapeutic options.

Automated summary

FGFR1 amplification is common in breast cancer and is associated with resistance to endocrine therapy and CDK4/6 inhibitors. High levels of FGFR1-4 mRNA expression are predictive of response to FGFRis, while MTKIs show higher response rates. These findings suggest that tailored therapy based on high mRNA levels may be effective in treating breast cancer patients.