Evaluation of CYP2D6 and Efficacy of Tamoxifen and Raloxifene in Women Treated for Breast Cancer Chemoprevention: Results from the NSABP P-1 and P-2 Clinical Trials by Goetz Matthew P, Schaid Daniel J, Wickerham D Lawrence, Sagfren Stephanie, Mushiroda Taisei, Kubo Michiaki, Batzler Anthony, Costantino Joseph P, Vogel Victor G, Paik Soonmyung, Carlson Erin E, Flockhart David A, Wolmark Norman, Nakamura Yusuke, Weinshilboum Richard M, Ingle James N, Ames Matthew in Clinical cancer research : an official journal of the American Association for Cancer Research (2011). PubMed

Abstract

Background: Controversy exists regarding the association between CYP2D6 enzyme activity and tamoxifen effectiveness in the adjuvant treatment of invasive breast cancer; however this association in the primary prevention of breast cancer is unknown.Methods: We performed a nested case-control study in the context of the NSABP P-1 and P-2 prevention trials to determine the impact of CYP2D6 genotype, CYP2D6 inhibitor use, as well as metabolizer status (CYP2D6 genotype combined with CYP2D6 inhibitor use), on breast cancer events. Women who developed breast cancer (both non-invasive and invasive) while on five years of SERM therapy (cases) were matched to controls free of breast cancer. Comprehensive CYP2D6 genotyping was performed for alleles associated with absent (*3, *4, *5, *6), reduced (*10, *17, *41), and increased (*1XN and *2XN) enzyme activity. Information regarding the use of CYP2D6 inhibitors was recorded.RESULTS: 591 cases were matched to 1126 controls and DNA was genotyped in {greater than}97%.In patients treated with tamoxifen, there was no association of CYP2D6 genotype [OR(extensive/poor metabolizer): 0.90; 95% CI 0.46-1.74, p=0.74), use of a potent CYP2D6 inhibitor (OR 0.92; 95% CI 0.575-1.486), or CYP2D6 metabolizer status (OR 1.03; 95% CI 0.669-1.607) with breast cancer occurrence. Likewise, there was no association between any CYP2D6 metabolism parameter with breast cancer events in raloxifene treated patients.CONCLUSIONS: In the NSABP P1 and P2 clinical trials, alterations in CYP2D6 metabolism are not associated with either tamoxifen or raloxifene efficacy.

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