(031) The relation between tamoxifen metabolism and time to discontinuation: A Bayesian pathway analysis in premenopausal breast cancer patients

Background: Most premenopausal breast cancer patients should use tamoxifen for at least 5 years, but many discontinue early. Phase I activation, transport, and phase II deactivation of tamoxifen are controlled by proteins subject to functional variation in encoding genes. Gene variants may affect recurrence risk and may also influence early discontinuation, possibly mediating the recurrence hazard.

Objectives: To evaluate the influence of genetic polymorphisms in the tamoxifen metabolic pathway on early discontinuation of tamoxifen.

Methods: We included premenopausal women diagnosed with stage I-III breast cancer in Denmark, registered in the Danish Breast Cancer Group database, and who initiated tamoxifen during 2002–2011. We genotyped 26 gene variants in 15 enzymes involved in tamoxifen metabolism and codified the established metabolic pathway as a prior topology for Bayesian pathway analysis. We defined early discontinuation as use of tamoxifen for < 5 years after diagnosis, operationalized as time between initiation and the last day of a six-month consecutive period with no prescribed tamoxifen. We used the Algorithm for Learning Pathway Structure (ALPS) to estimate the individual and combined effects of metabolic enzyme and transporter gene variants on discontinuation, with Bayes Factors (BF) >1 indicating that the data support an effect of the pathway on discontinuation (compared with no effect).

Results: Among 3,729 patients, there was evidence for effects of CYP2D6 genes (BF=25), all phase I metabolism genes (BF=6.9), and transporter genes (BF=3.3) on early discontinuation of tamoxifen. There was strong evidence of an interaction between a variant in CYP2D6 (rs16947)–a contributor to Phase I metabolism–and a variant in the transporter ABCC2 (rs3740065; BF=97). Similar findings were seen for other Phase I metabolic genes interacting with transporters or Phase II genes, such as CYP2D6 (rs1065852) and ABCB1 (rs1128503) (BF=64), and CYP2D6 (rs1065852) and SULT1A1 (rs9282861) (BF=32).

Conclusions: Our previous research showed a moderately increased recurrence hazard among patients with genomic variants relevant to Phase I metabolism. This may be related to early discontinuation of treatment. Some of the genes involved in these pathways have previously been identified as increasing postoperative and chemotherapy-induced nausea and may also play a role in increasing early tamoxifen discontinuation. We are currently estimating discontinuation effects for specific genotype combinations in the gene interactions discovered by ALPS.