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Variation of CYP2D6 Affects Clinical Outcomes In Women With Breast Cancer Receiving Tamoxifen CHICAGO -- October 6, 2009 -- Among women with early stage breast cancer, genetic variation of a certain enzyme appears to be associated with clinical outcomes for women treated with tamoxifen, according to a study published in the October 7 issue of JAMA. “Approximately 100 polymorphic cytochrome P450 2D6 (CYP2D6) genetic variants have been identified, which manifest in the population in 4 distinct phenotypes, extensive (normal activity), intermediate (reduced activity), poor (no activity), and ultrarapid (high activity) metabolism, and a gene-dose effect with respect to endoxifen plasma concentrations has been demonstrated. Thus, it can be speculated that genotype-related differences in the formation of active metabolites influence therapeutic response to tamoxifen.” Werner Schroth, Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany, and colleagues conducted a study to determine whether CYP2D6 variation is associated with clinical outcomes in women receiving tamoxifen as a supplemental treatment. The study included 1,325 patients who had diagnoses of stage I through III breast cancer between 1986 and 2005 and who were mainly postmenopausal (95.4%). Last follow-up was in December 2008, and the median follow-up time was 6.3 years. DNA from tumour tissue or blood was genotyped for CYP2D6 variants associated with reduced or absent enzyme activity. Women were classified as having an extensive (n = 609), heterozygous extensive/intermediate (n = 637), or poor (n = 79) CYP2D6 metabolism. The researchers found higher breast cancer event rates in patients with reduced or absent CYP2D6 function versus extensive metabolism patients. “At 9 years of follow-up, the recurrence rates were 14.9% for extensive metabolisers, 20.9% for heterozygous extensive/intermediate metabolisers, and 29.0% for poor metabolisers, and all-cause mortality rates were 16.7%, 18.0%, and 22.8%, respectively,” the authors wrote. Compared with extensive metabolisers, heterozygous extensive/intermediate metabolisers had a 40% increased risk of recurrence; poor metabolisers had nearly twice the risk. “Compared with extensive metabolisers, those with decreased CYP2D6 activity had worse event-free survival and disease-free survival, but there was no significant difference in overall survival.” “Genotyping has the potential for identification of women who have the CYP2D6 poor metabolism phenotype and for whom the use of tamoxifen is associated with poor outcomes, thus indicating consideration of alternative forms of adjuvant endocrine therapy,” the authors concluded. SOURCE: JAMA E-mail this page to a friend or colleague! To print, use this version