Outliers: A study of factors influencing progression free and overall survival among women with metastatic HER2 positive breast cancer treated with trastuzumab (Herceptin)
Kathleen Pritchard

This study has promise to greatly improve our understanding of HER2 positive breast cancer biology and drug resistance.  Our current ability to predict response to trastuzumab and other anti-HER2 based therapies is limited. Therefore, we propose a large clinical translational research study to investigate novel molecular predictors and gene signatures of survival following treatment with trastuzumab.  This will also increase our understanding of trastuzumab drug resistance. The goal of our research is to develop new predictive biomarkers to optimize patient selection, improve patient safety, and help ensure we achieve the greatest value when employing our available anti-cancer therapies.  This type of research is needed in order to personalize cancer therapy as numerous agents are now emerging for clinical use.

Human epidermal growth factor receptor 2 (HER2) positive breast cancer is particularly aggressive, but with the introduction of the anti-HER2 therapy trastuzumab (T), survival with HER2 positive metastatic breast cancer has improved. However, responses vary greatly for individuals. The only clearly recognized predictor of T response is HER2 overexpression or amplification.

An “outlier” is defined as an extreme result falling on the outer edge of statistical probability. We propose an outlier study to investigate standard clinical, pathologic and newer molecular factors associated with response to T-based therapy in a cohort of patients with HER2 positive metastatic breast cancer treated at Sunnybrook Odette Cancer Centre (SOCC) from 1999 through 2013. These patients will undergo integrated genomic and transcriptomic analyses of: 1) molecular features identifying pathways linked to T response/resistance; 2) amplification of downstream HER2 cell signaling pathways; 3) measures of acquired immune moderated response; and 4) more specific measures of HER2 expression/amplification. The study will be exploratory but with validation may increase our ability to personalize therapy for these patients and may identify new “druggable” targets.