Amplification Mediates Endocrine Resistance but Retains TORC Sensitivity in Metastatic Hormone Receptor-Positive (HR) Breast Cancer

Purpose: While amplification has been described in breast cancer, the optimal treatment approach for -amplified (FGFR1) metastatic breast cancer (MBC) remains undefined. 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 -amplification in mediating response/resistance to hormone therapy .

Results: In the clinical cohort ( = 110), we identified that patients with FGFR1 tumors were more likely to have progesterone receptor (PR)-negative disease (47% vs. 20%; = 0.005), coexisting mutations (41% vs. 21%; = 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)/-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.

Conclusions: Collectively, these findings suggest that while 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.