Abstract PD9-04: FGFR4 as a key regulator of HER2E subtype in the primary and metastatic setting
Authors: Garcia Recio S , Parker JS , Fan C , Mott K , He X , Cejalvo JM , Brasó Maristany F , Galván P , Lluch A , Albanell J , Rojo F , Martinez de Dueñas E , Prat A , Perou CM 
Published: May 2019

Abstract
Background: Therapeutic targets in TNBC remain a challenge. We have observed that some Luminal A primary breast tumors give rise to HER2-enriched (HER2E) subtype metastases but remain clinically HER2 negative (HER2E/cHER2-). Molecular features that drive these HER2E/cHER2- tumors may represent key targets of metastatic progression.
Methods: A comparative genetic and transcriptomic analysis in TCGA (1100 patients) related to the FGFR family was performed. We focused on FGFR4, in part, due to its unique association with the HER2E expression subtype and we developed a robust FGFR4-signature based upon a supervised analysis of a HER2E/cHER2- PDX (WHIM11) treated with a FGFR4 inhibitor (BLU9931). We also constructed a new Luminal Tumor Score (LTS) to identify the optimal axis of separation between Luminal A versus HER2E tumors (higher scores represent greater Luminal A phenotype). Univariate and multivariate analyses were performed using TCGA and METABRIC (1971 samples). Finally, we performed RNA-seq on a cohort of 77 matched primary breast cancer and metastatic tissues pairs from the GEICAM/2009-03 and Hospital Clinic of Barcelona study, and did multiple analyses on these cohorts using our FGFR4-signatures.
Results: FGFR4 was significantly higher in HER2E subtype (P&lt;0.0001), independent of HER2 clinical status. FGFR4 amplification/deletions and mutations were rare and did not correlate with FGFR4 high expression. In vivo, BLU9931 treatment of WHIM11 showed a significant tumor growth inhibition (P=0.01), prolonged survival, and a significant higher LTS (P=0.016). We also identified 745 up-regulated genes called FGFR4-repressed (FGFR4-rep) and 427 down regulated genes called FGFR4-induced (FGFR4-ind), after BLU9931 treatment. Gene set enrichment analysis revealed that FGFR4-ind genes were enriched for STAT3, PI3K/AKT/mTOR pathway and KRAS activation, proliferation, hypoxia, glycolysis and metastasis. FGFR4-rep genes were involved with KRAS inhibition, cell polarity, p53 pathway and upregulation of IFNγ response. In the METABRIC cohort, FGFR4-ind and FGFR4-rep each predicted OS (HR=6.30, P&lt;0.0001; HR=0.33; P&lt;0.0001, respectively). Multivariate analysis showed FGFR4-ind (HR=2.34, P=0.014) as a significant independent prognostic factor beyond subtype for OS. Supervised analysis of the 77 primary-met cohort revealed that the FGFR4-ind was significantly higher in luminal metastases compared with their primaries counterparts (P&lt;0.001), along with proliferation, angiogenesis, and a M2 macrophage signature (with most other immune features being unchanged). Finally, univariate and multivariate analysis demonstrated that the FGFR4-related signatures predicted site-specific metastasis for lung, liver and brain, but not for bone and lymph nodes.
Conclusion: FGFR4 is one of the drivers of HER2-enriched subtype tumors, including those that are clinically HER2-. The FGFR4-ind signature was predictive of worse survival, progression in the metastatic setting, and site-specific metastasis. Treatment options in HER2-enriched TNBC, and for HER2E/cHER2+ patients, may benefit from targeting FGFR4, whose high expression is not based upon genomic or genetic features.
Citation Format: Garcia Recio S, Parker JS, Fan C, Mott K, He X, Cejalvo JM, Brasó Maristany F, Galván P, Lluch A, Albanell J, Rojo F, Martinez de Dueñas E, Prat A, Perou CM. FGFR4 as a key regulator of HER2E subtype in the primary and metastatic setting [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD9-04.