Abstract 419: Integrative analysis of multi-omics tumor profiles identifies pathways associated with resistance to anti-HER2 therapy in early stage breast cancer
Authors: Singh Salendra , Gilmore Hannah , Abu-Khalaf Maysa , Somlo George , Sikov William , Harris Lyndsay , Varadan Vinay 
Published: July 2017

Abstract
Background: HER2 positive breast cancers are heterogeneous at both the clinical and molecular levels, with the HER2-enriched subtype exhibiting increased levels of immune infiltration signatures and the highest rate of pathologic complete response (pCR), while the HER2-Basal subtype is resistant to anti-HER2 therapy (Varadan et al, CCR 2016). Here we aim to characterize the molecular underpinnings of response and their interaction with increased immune infiltration across these HER2-subtypes using integrative analyses of genomic and transcriptomic data from two multicenter trials (DFCI 03-311 and BrUOG 211B).
Methods: Fresh tumor core biopsies were taken at baseline and a 2-week time point after a single dose of trastuzumab. 80 HER2+ early breast cancer (EBC) patients were enrolled in the 03-311 trial, and 60 patients in the 211B trial. Biopsy samples were profiled for gene expression (Microrrays:03-311; RNAseq:211B), somatic mutations (Whole-exome sequencing: 211B; Targeted Sequencing: 03-311) and somatic copy-number aberrations (SNP-arrays: 03-311; Whole-exome Sequencing: 211B). Subtyping was performed using gene expression data and tumors were classified into HER2-Enriched, HER2-Luminal and HER2-Basal subtypes. Integrative analysis of gene expression and copy-number data to infer signaling network activities per sample, was performed using the recently developed InFlo framework (Dimitrova et al, Oncogene 2016).
Results: HER2-Basal tumors exhibited lower average copy number for HER2 and were less likely to have high-level amplifications of co-amplicons (e.g. 11q13, 20q13). In the 211B and 03-311 trials, respectively, 62% and 63% of somatic mutations persisted after one dose of therapy, while 21% and 19% of mutations were undetectable after one dose of therapy. Tumors harboring amplifications in the 8p11 (FGFR1) genomic locus exhibited higher indices immune signatures associated with macrophages (P=0.0073) and T-cells (P = 0.0493) in 211B, but this association did not achieve significance in the 03-311 trial. Integrative InFlo-based analysis of tumor gene expression and copy-number profiles after one dose of trastuzumab in the 211B trial revealed significantly higher activity of signaling pathways associated with CD4+ T-cells in the responders (P=0.008), while higher activity of mTOR pathway was observed in non-responders (P=0.0014).
Conclusions: Changes in mutational profiles over time may either be related to therapy-induced alterations of clonal architecture or the consequence of intra-tumor heterogeneity, thus warranting further exploration. Integrative analysis of gene expression and copy-number profiles reveal signaling pathways associated with response and resistance, enabling the discovery of biomarkers of response to anti-HER2 therapy.
Citation Format: Salendra Singh, Hannah Gilmore, Maysa Abu-Khalaf, George Somlo, William Sikov, Lyndsay Harris, Vinay Varadan. Integrative analysis of multi-omics tumor profiles identifies pathways associated with resistance to anti-HER2 therapy in early stage 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 419. doi:10.1158/1538-7445.AM2017-419