Genetic variants in tamoxifen metabolism and early treatment discontinuation among premenopausal breast cancer patients

Abstract

Purpose: Premenopausal, estrogen receptor (ER)-positive breast cancer patients should receive tamoxifen for at least 5 years, but many prematurely discontinue. Activation, transport, and deactivation of tamoxifen and its metabolites are controlled by proteins encoded by genes with functional variations. We examined the impact of genetic polymorphisms in the tamoxifen pathway on early treatment discontinuation. Methods: We included premenopausal women diagnosed with ER-positive breast cancer (2002–2011) in Denmark who initiated tamoxifen. We genotyped 26 genetic variants in 15 enzymes involved in tamoxifen metabolism. Early discontinuation was defined as tamoxifen use for < 5 years. We estimated individual and combined effects of genetic variants using a Bayesian pathway approach. We report Bayes Factors (BF), wherein values > 1 indicate support of an effect of the genetic pathway on discontinuation (compared with no effect). Results: Among 3,729 patients, 536 (14%) discontinued tamoxifen within 5 years. Genetic variants involved in tamoxifen activation impacted early discontinuation (BF = 7.5), in a manner driven almost entirely by CYP2D6 activity (BF = 22.6). Several variants in CYP2D6 and transporter genes synergistically increased the hazard of early discontinuation (e.g., CYP2D6*2 and ABCC2; BF = 138). Conclusions: Variants in enzymes responsible for activating tamoxifen metabolites—particularly within CYP2D6—influence early tamoxifen discontinuation. CYP2D6 variants synergistically interact with transporter gene variants, namely ABCC2, to further raise the risk of discontinuation.