INVESTIGATION OF BIOMARKER POTENTIAL OF FGF RECEPTOR IN BREAST CANCER MODELS

Abstract

Breast cancer is a molecularly heterogeneous disease in which prognosis can be significantly improved through biomarker-driven targeted therapies. The aberration of fibroblast growth factor receptor (FGFR) signaling has been shown to be a key player in breast carcinogenesis. We aimed to investigate the efficacy of the novel FGFR inhibitor, futibatinib, in breast cancer and analyze different FGFR alterations for their suitability as predictive biomarkers for therapeutic outcomes. We utilized previously well-defined nine different patient-derived xenograft (PDX) models coming from diverse FGFR1-4 amplification, expression, and mutation backgrounds and assessed the monotherapy efficacy of futibatinib. Tumor volume change and event-free survival (EFS, characterized by time to tumor doubling) measurements were employed in this assessment. Futibatinib showed a significant anti-tumor effect in 3 of 9 PDX models tested. These three PDX models showed statistically significant EFS prolongation, with EFS treatment/control ratios being 1.9, >2.6, and >12.9. Notably, two of the sensitive models were FGFR2 amplified, and among them, PDX.007, which also harbors the FGFR2 Y375C mutation, showed a durable response over 110 days. We showed for the first time that the FGFR2 Y375C mutation suggests drastic change in sensitivity to futibatinib in vivo. In conclusion, the outcomes of this thesis indicate that FGFR2-activating mutations are promising targets for therapy in breast cancer and possibly several other cancers and emphasize the necessity for further investigation of FGFR2 amplification and FGFR2-activating mutations as predictive biomarkers for novel FGFR inhibitors.