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CYP2D6 Metabolism and Patient Outcome in the Austrian Breast and Colorectal Cancer Study Group Trial (ABCSG) 8.


Clin Cancer Res. 2012 Dec 4;


Authors: Goetz MP, Suman V, Hoskin TL, Gnant M, Filipits M, Safgren S, Kuffel MJ, Jakesz R, Rudas M, Greil R, Dietze O, Lang A, Offner F, Reynolds CA, Weinshilboum RM, Ames M, Ingle JN


Abstract

Background: Controversy exists regarding CYP2D6 genotype and tamoxifen efficacy. Methods: A matched case-control study was conducted utilizing the Austrian Breast and Colorectal Cancer Study Group Trial 8 that randomized post-menopausal women with estrogen receptor positive breast cancer to tamoxifen for 5 years (Arm A) or tamoxifen for 2 years followed by anastrozole for 3 years (Arm B). Cases had disease recurrence, contralateral breast cancer, second non-breast cancer, or died. For each case, controls were identified from the same treatment arm of similar age, surgery/radiation, and TNM stage. Genotyping was performed for alleles associated with no (PM; *3, *4, *6); reduced (IM; *10, and *41); and extensive (EM: absence of these alleles) CYP2D6 metabolism. Findings: The common CYP2D6 *4 allele was in Hardy Weinberg Equilibrium. In Arm A during the first 5 years of therapy, women with 2 poor alleles (PM/PM: OR=2.45, 95% CI: 1.05-5.73, p=0.04) and women with one poor allele (PM/IM or PM/EM: OR=1.67, 95% CI: 0.95-2.93, p=0.07) had a higher likelihood of an event than women with two extensive alleles (EM/EM). In years 3-5 when patients remained on tamoxifen (Arm A) or switched to anastrozole (Arm B), PM/PM tended towards a higher likelihood of a disease event relative to EM/EM (OR= 2.40, 95% CI: 0.86-6.66, p=0.09) among women on Arm A but not among women on Arm B (OR= 0.28; 95% CI: 0.03-2.30). CONCLUSION: In ABCSG8, the negative effects of reduced CYP2D6 metabolism were observed only during the period of tamoxifen administration, and not after switching to anastrozole.

PMID: 23213055 [PubMed - as supplied by publisher]