Cytochrome P-450 2D6 ( CYP2D6 ) Genotype and Breast Cancer Recurrence in Tamoxifen-Treated Patients: Evaluating the Importance of Loss of Heterozygosity

<span class="paragraphSection"><div class="boxTitle">Abstract</div>Tamoxifen therapy for estrogen receptor–positive breast cancer reduces the risk of recurrence by approximately one-half. Cytochrome P-450 2D6, encoded by the polymorphic cytochrome P-450 2D6 gene (<span style="font-style:italic;">CYP2D6</span>), oxidizes tamoxifen to its most active metabolites. Steady-state concentrations of endoxifen (4-hydroxy-<span style="font-style:italic;">N</span>-desmethyltamoxifen), the most potent antiestrogenic metabolite, are reduced in women whose <span style="font-style:italic;">CYP2D6</span> genotypes confer poor enzyme function. Thirty-one studies of the association of <span style="font-style:italic;">CYP2D6</span> genotype with breast cancer survival have yielded heterogeneous results. Some influential studies genotyped DNA from tumor-infiltrated tissues, and their results may have been susceptible to germline genotype misclassification from loss of heterozygosity at the <span style="font-style:italic;">CYP2D6</span> locus. We systematically reviewed 6 studies of concordance between genotypes obtained from paired nonneoplastic and breast tumor–infiltrated tissues, all of which showed excellent <span style="font-style:italic;">CYP2D6</span> genotype agreement. We applied these concordance data to a quantitative bias analysis of the subset of the 31 studies that were based on genotypes from tumor-infiltrated tissue to examine whether genotyping errors substantially biased estimates of association. The bias analysis showed negligible bias by discordant genotypes. Summary estimates of association, with or without bias adjustment, indicated no clinically important association between <span style="font-style:italic;">CYP2D6</span> genotype and breast cancer survival in tamoxifen-treated women.</span>

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