Hormonal Receptor Status Determines Prognostic Significance of FGFR2 in Invasive Breast Carcinoma

Simple Summary FGFR2-ER-PR crosstalk leads to hormone-independent progression of breast cancer. In vitro, FGFR2 stimulates PR transcriptional activity and mediates resistance to anti-ER therapies. The postulated poor prognostic effect of FGFR2 overexpression has not been confirmed at clinical level. Our clinical data show that, counterintuitively, low expression of FGFR is linked to poor prognosis in breast cancer and its prognostic value is dependent on the hormonal receptor status, but not PR transcriptional activity. This shows, that the role of FGFR in breast cancer is more complex, which may explain unsatisfactory results of the clinical trials with FGFR inhibitors. Interaction between fibroblast growth factor receptor 2 (FGFR2) and estrogen/progesterone receptors (ER/PR) affects resistance to anti-ER therapies, however the prognostic value of FGFR2 in breast cancer (BCa) remains largely unexplored. We have recently showed in vitro that FGFR2-mediated signaling alters PR activity and response to anti-ER treatment. Herein, prognostic significance of FGFR2 in BCa was evaluated in relation to both ER/PR protein status and a molecular signature designed to reflect PR transcriptional activity. FGFR2 was examined in 353 BCa cases using immunohistochemistry and Nanostring-based RNA quantification. FGFR2 expression was higher in ER+PR+ and ER+PR- compared to ER-PR- cases (p< 0.001). Low FGFR2 was associated with higher grade (p< 0.001), higher Ki67 proliferation index (p< 0.001), and worse overall and disease-free survival (HR = 2.34 (95% CI: 1.26-4.34),p= 0.007 and HR = 2.22 (95% CI: 1.25-3.93),p= 0.006, respectively). The poor prognostic value of low FGFR2 was apparent in ER+PR+, but not in ER+PR- patients, and it did not depend on the expression level of PR-dependent genes. Despite the functional link between FGFR2 and ER/PR revealed by preclinical studies, the data showed a link between FGFR2 expression and poor prognosis in BCa patients.