Genome-wide analysis of therapeutic response uncovers molecular pathways governing tamoxifen resistance in ER+ breast cancer.

Abstract

BackgroundPrioritization of breast cancer patients based on the risk of resistance to tamoxifen plays a significant role in personalized therapeutic planning and improving disease course and outcomes.MethodsIn this work, we demonstrate that a genome-wide pathway-centric computational framework elucidates molecular pathways as markers of tamoxifen resistance in ER+ breast cancer patients. In particular, we associated activity levels of molecular pathways with a wide spectrum of response to tamoxifen, which defined markers of tamoxifen resistance in patients with ER+ breast cancer.FindingsWe identified five biological pathways as markers of tamoxifen failure and demonstrated their ability to predict the risk of tamoxifen resistance in two independent patient cohorts (Test cohort1: log-rank p-value = 0.02, adjusted HR = 3.11; Test cohort2: log-rank p-value = 0.01, adjusted HR = 4.24). We have shown that these pathways are not markers of aggressiveness and outperform known markers of tamoxifen response. Furthermore, for adoption into clinic, we derived a list of pathway read-out genes and their associated scoring system, which assigns a risk of tamoxifen resistance for new incoming patients.InterpretationWe propose that the identified pathways and their read-out genes can be utilized to prioritize patients who would benefit from tamoxifen treatment and patients at risk of tamoxifen resistance that should be offered alternative regimens.FundingThis work was supported by the Rutgers SHP Dean's research grant, Rutgers start-up funds, Libyan Ministry of Higher Education and Scientific Research, and Katrina Kehlet Graduate Award from The NJ Chapter of the Healthcare Information Management Systems Society.