Differential gene expression analysis and correlation with outcome in HER2-positive metastatic breast cancer treated with HER2-targeted therapy.

Abstract

1036 Background: Improvement in progression-free (PFS: HR: 0.73; p=0.008) and overall survival (OS: HR: 0.74; p=0.026) was demonstrated with the combination of lapatinib (L) plus trastuzumab (T) in comparison with L alone in a randomized, phase III study of 296 women (198 per arm) with HER2-positive metastatic breast cancer (MBC) that progressed on a median of 3 prior T-based therapies. Gene expression analysis was conducted on tumor tissue from this study to identify genes correlating with efficacy outcome parameters. Methods: Tumor tissue from primary breast tumor or metastatic sites was obtained in the form of formalin-fixed, paraffin-embedded (FFPE) material. Manual microdissection was performed on 10μ m sections to isolate tumor tissue. RNA was extracted using the High Pure RNA Paraffin kit (Roche). Using 200ng of total RNA, cDNA-mediated annealing, selection, and ligation (DASL) assay (Illumina Corp) was performed to determine the expression of 502 cancer associated genes. PFS and OS were analyzed using proportional hazards regression models that included covariates found to significantly impact PFS and OS. Results: Of the 156 patients with adequate tumor tissue remaining, 133 had material suitable for DASL profiling and were representative of the entire study population (68 received L; 65 received L+T). When treatment arms were combined, higher expression of genes mapping to extracellular matrix and adhesion pathways associated with worse PFS whereas higher expression of HER2 correlated with improved PFS. Genes that mapped to pathways involved in cell cycle regulation and cytoskeletal remodeling were among the genes that associated with OS. Differential expression of HER2 was not associated with OS (p=0.16). Additional analyses will be reported. Conclusions: The determination of HER2 status, which subsequently directs treatment with HER2-targeted agents, may be feasible using RNA based assays. Gene expression analysis may be a valid approach in identifying transcriptional features that correlate with improved outcome following treatment with anti-cancer therapy thus individualizing treatment for patients with breast cancer. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline, Roche GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline