Abstract P4-02-01: Correlations between Genetic Variants in CYP2D6 and UGT2B7 and Survival in Breast Cancer Patients Treated with or without Tamoxifen: Results from a Large Cohort Study
Authors: S Oesterreich, SH Hilsenbeck, T Skaar, RJ Hartmaier, DA Flockhart, MJ Sikora, CK Osborne, JM. Rae
Journal: Cancer Research (2010)

Abstract Background. A large number of studies testing the hypothesis that genetic variants in drug metabolizing enzymes can influence breast cancer patient response to the selective estrogen receptor modulator tamoxifen have provided equivocal and conflicting data. Possible confounding factors in all studies to date include the relatively small number of patients, lack of comprehensive genotyping analysis (in particular regarding the cytochrome P450 2D6 (CYP2D6) enzyme), use of selective serotonin reuptake inhibitors (SSRIs) (antidepressant medication), and lack of untreated (i.e. no tamoxifen treatment) control groups. Currently, it is not clear whether genotype determinations can predict which patients will likely benefit from tamoxifen therapy. Methods: We conducted a large community-based cohort study to test for associations between clinical outcomes and variants in CYP2D6, one of the key enzymes responsible for the conversion of tamoxifen to its potent anti-estrogenic metabolite endoxifen, as well as variants in UDP-glucuronosyltransferase 2B7 (UGT2B7), an enzyme responsible for the elimination of endoxifen. The majority of patients in this cohort began their tamoxifen treatment more than twenty ago, at a time when SSRIs (a possible confounding factor in CYP2D6 studies) were not widely used. Five hundred patients with ER+ early breast cancer treated adjuvantly with tamoxifen monotherapy and 500 who did not receive any adjuvant therapy were genotyped and assigned a CYP2D6 “score” based on known specific allele activities from 0 (no activity) to 2 (high activity) and also grouped as either low, intermediate and high UGT2B7 activity based on the *2 allele. Results: Univariately, Kaplan-Meier estimates in conjunction with the log-rank test did not reveal any significant associations between either CYP2D6 or UGT2B7 score and time to relapse (TTR). In tamoxifen treated cases, after adjustment for tumor size, nodal status and PgR, Cox regression found increased CYP2D6 score, reflecting increased conversion of tamoxifen to endoxifen, was significantly associated with worse time to relapse (HR=1.53, p=0.02). This was not seen in the patients without endocrine treatment (HR=0.73, p=0.10). Patients with high UGT2B7 activity, reflecting increased elimination of endoxifen had better survival rates (HR= 0.75, p = 0.04) in the tamoxifen treated group, while again no effect of UGT2B7 was seen in the untreated group (HR=1.0, p=0.78). Finally, CYP2D6 and UGT2B7 genotypes were not associated with any special tumor characteristics in either patient group. Conclusion: In our study, CYP2D6 and UGT2B7 genotypes associated with increased endoxifen levels were associated with worse outcome in tamoxifen treated (but not untreated) breast cancer patients. Thus, the data from this cohort study do not support the hypothesis that breast cancer patients with low CYP2D6 are resistant to tamoxifen. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-02-01.