Abstract 3119: Identification of genetic drivers in HER2enriched/HER2negative breast cancer
Authors: Susana Garcia Recio, Cheng Fan, Marni Siegel, Joel S. Parker, Gina N. Duronio, Aleix Prat, Charles M. Perou
Journal: Cancer Research (2017)

Abstract Background: The non-basal triple negative breast cancer (Non Basal-TNBC) tumors, also called the luminal androgen receptor (LAR) subtype, make up ~20% of all new TNBC cases and is limited to multi-agent chemotherapy. TNBC is considered one of the leading causes of cancer-associated mortality amongst women in the USA with a high number of patients dying of metastatic disease. Some metastases that arise from luminal primary tumors lose their luminal features and become a HER2-enriched (HER2E) subtype, but remain clinically HER2 negative (HER2E/HER2-). The molecular features that drive these HER2E/HER2- tumors may also represent key checkpoints of metastatic progression. Within this HER2E/HER2- subtype, besides the androgen receptor (AR), FGFR4 has been shown to be expressed, but its functional role remains unknown. FGFR4 is a tyrosine kinase receptor involved in proliferation, survival and migration during embryonic development and cancer. We hypothesize that in addition to AR, that FGFR4 may be a driver of HER2E/HER2- tumors and that the therapeutic targeting of this gene/protein might improve patient outcomes. Objective: Our objective is to identify the mechanism of action of FGFR4 in HER2E/HER2- tumors as well as additional genetic drivers of HER2E TNBC subtype. Methods: We performed computational analysis of databases (TCGA, METABRIC) and the analysis of matched breast cancer primary tumors and metastases to detect genetic drivers. We ran microarrays on two FGFR4 stably transfected luminal HER2-/ER+ cell lines (MCF7 and T47D) and also treated a Luminal B cell line (MDA-MB-453; HER2high/AR+/ER-) and HER2E cell line (CAMA-1; HER2low/ARmed/ER+/low) with a FGFR4 inhibitor using a time course strategy. Results: Through the analysis of microarrays using all 4 cell lines, we identified a gene expression signature of FGFR4-activity enriched in genes involved in proliferation, cell junctions and cell differentiation. The FGFR4-associated signature of upregulated genes was enriched in HER2E and Basal-like subtypes and the downregulated genes enriched in the Luminal subtypes. To identify predictors of chemotherapy response, we evaluated FGFR4-associated gene signatures in the diagnostic (pre-treatment) samples of MDACC neoadjuvant dataset of 500 tumors. The high expression of the FGFR4- induced gene signature predicted pathological complete response (T.test P &amp;lt;0.001). Conclusions: FGFR4 may play an important role in the progression of Luminal disease and has been identified as a new genetic driver of HER2E/HER2- subtype making it an attractive option as a therapeutic target. We are further testing these genetic predictions using Patient Derived Xenograft (PDX) mouse models. Citation Format: Susana Garcia Recio, Cheng Fan, Marni Siegel, Joel S. Parker, Gina N. Duronio, Aleix Prat, Charles M. Perou. Identification of genetic drivers in HER2enriched/HER2negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3119. doi:10.1158/1538-7445.AM2017-3119