<i>FGFR1</i> Amplification Mediates Endocrine Resistance but Retains TORC Sensitivity in Metastatic Hormone Receptor-Positive (HR⁺) Breast Cancer.

Abstract

While <i>FGFR1</i> amplification has been described in breast cancer, the optimal treatment approach for <i>FGFR1</i>-amplified (FGFR1⁺) metastatic breast cancer (MBC) remains undefined.<b>Experimental Design:</b> We evaluated clinical response to endocrine and targeted therapies in a cohort of patients with hormone receptor-positive (HR⁺)/HER2^- MBC and validated the functional role of <i>FGFR1</i>-amplification in mediating response/resistance to hormone therapy <i>in vitro</i>. In the clinical cohort (<i>N</i> = 110), we identified that patients with FGFR1⁺ tumors were more likely to have progesterone receptor (PR)-negative disease (47% vs. 20%; <i>P</i> = 0.005), coexisting <i>TP53</i> mutations (41% vs. 21%; <i>P</i> = 0.05), and exhibited shorter time to progression with endocrine therapy alone and in combination with CDK4/6 inhibitor, but not with a mTOR inhibitor (everolimus), adjusting for key prognostic variables in multivariate analysis. Furthermore, mTOR-based therapy resulted in a sustained radiological and molecular response in an index case of FGFR1⁺ HR⁺/HER2^- MBC. In preclinical models, estrogen receptor-positive (ER⁺)/<i>FGFR1</i>-amplified CAMA1 human breast cancer cells were only partially sensitive to fulvestrant, palbociclib, and alpelisib, but highly sensitive to everolimus. In addition, transduction of an FGFR1 expression vector into ER⁺ T47D cells induced resistance to fulvestrant that could be overcome by added TORC1 inhibition, but not PI3K or CDK4/6 inhibition. Collectively, these findings suggest that while <i>FGFR1</i> amplification confers broad resistance to ER, PI3K, and CDK4/6 inhibitors, mTOR inhibitors might have a unique therapeutic role in the treatment of patients with ER⁺/FGFR1⁺ MBC.