CYP2C19 Polymorphisms and Breast Cancer Recurrence in a Heterogeneous Population of Tamoxifen-Treated Women 公开

Abstract

Though tamoxifen is a standard treatment to prevent recurrences in women suffering from breast cancer, the drug is still not effective for 20 to 30% of patients receiving it. The important role of cytochrome P450 (CYP) proteins in the metabolism of tamoxifen has led to speculation that polymorphisms in CYP2C19, among other P450s, may contribute to the observed variations in treatment efficacy. This study utilized the publicly available data of the International Tamoxifen Pharmacogenomics Consortium to assess whether the CYP2C19*2 loss-of-function and CYP2C19*17 gain-of-function variants are associated with disease-free survival time in 2,102 female breast cancer patients prescribed 2 or 5 years of adjuvant tamoxifen therapy. Kaplan-Meier curves and Cox proportional hazards analyses showed that observed associations between CYP2C19*2 or CYP2C19*17 genotypes and disease-free survival were not substantial and were imprecise. Carriers of one or two CYP2C19*2 alleles had adjusted hazard ratios of 1.05 (95% CI: 0.78, 1.42) and 0.79 (95% CI: 0.32, 1.94) compared to non-carriers, respectively. Carriers of one or two CYP2C19*17 alleles had adjusted hazard ratios of 1.02 (95% CI: 0.71, 1.46) and 0.57 (95% CI: 0.26, 1.24) compared to non-carriers, respectively. The lack of a noteworthy association was robust to stratification by CYP2D6 genotype or by menopausal status, and the null results were further confirmed by imputation of missing data. This study contains one of the largest sample sizes of any examining the association between CYP2C19 genotype and tamoxifen efficacy, and addresses the conflicting prior findings regarding this topic. The results of this study indicate that CYP2C19 genotype is not a useful predictor of the risk of recurrence with tamoxifen therapy, and future research should focus on alternative methods to improve the outlook for breast cancer patients.

Table of Contents

Introduction ----------------------------------Pg. 1

Methods -------------------------------------- Pg. 5

Results ----------------------------------------Pg. 10

Discussion ------------------------------------Pg. 13

References ------------------------------------Pg. 17

Tables -----------------------------------------Pg. 26

Figures ----------------------------------------Pg. 32

About this Master's Thesis

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School	Rollins School of Public Health
Department	Epidemiology
Degree	MPH
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Epidemiology
关键词	CYP2C19 breast cancer tamoxifen
Committee Chair / Thesis Advisor	Lash, Timothy L, Emory University

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