Association Of CYP2D6*10, OATP1B1 Polymorphisms And Therapeutic Effects Of Breast Cancer Patients After Tamoxifen Therapy

Purpose: To evaluate the association of CYP2D6*10(c.100C>T and c.1039C>T), OATP1B1 A388 G, OATP1B1 T521 C polymorphisms with adjuvant tamoxifen therapy of invasive breast cancer survival with hormone receptor(estrogen receptor or progesterone receptor)-positive tumors(ER+/PR+).Methods: 296 invasive breast cancer patients with hormone receptor positive tumors during 2002.1-2009.12 were included in the study. We collected patient data including clinical features, tamoxifen therapy, survival status etc. Archived paraffin blocks from surgery were the source of tissue for genotyping. CYP2D6*10, OATP1B1 A388 G, T521 C polymorphisms were detected by direct sequencing of genomic DNA. Overall survivals(OS) were assessed with Kaplan-Meier analysis, while using the Cox proportional hazards model to implement multivariate tests for the prognostic significance. Association of gene expression with overall survival was estimated with Cox proportional hazards regression coefficients, the single factor and multiple factor were analyzed by the Cox proportional hazard models, in order to find gene polymorphism as independent prognostic factors and clinical factors on prognosis whether it was meaningful.Results: In the death group, these genotyping(OATP1B1 A388 G, T521 C, CYP2D6*10) and clinicopathological parameters were of no statistical significance. Overall, baseline characteristics of the patients were comparable(P>0.05), including menopausal status, tumor size, and lymph node metastasis. The frequencies of OATP1B1 521 wild type was 43.1% and the C carrier was 56.9%, the T and C allele frequencies was 70% and 30%, respectively. While in the survival group, wild type was 56.7% and 43.3%, the T and C allele frequencies was 75.5% and 24.5%. The frequencies of OATP1B1 388 wild type was 10.8% and the G carrier was 89.2% in the death group, the A and G allele frequencies was 39.2% and 60.9%, respectively. While in the survival group, wild type was 6.5% and 93.5%, the A and G allele frequencies was 32.9% and 77.1%. The frequencies of CYP2D6*10 wild type was 10.8% and the *10 carrier was 89.2% in the death group, the C and T allele frequencies was 47.7% and 52.3%, respectively. While in the survival group, wild type was 20.8% and 79.2%, the C and T allele frequencies was 42.6% and 57.4%. All of this were testing for Hardy Weinberg equilibrium. After Kaplan-Meier and Log-rank test, the OS of T521 C wild-type patients was significantly higher than that of T521 C mutant patients; this difference was statistically significant(P=0.034).However, OS of patients with wild type OATP1B1 A388 G was lower than that of OATP1B1 A388 G mutant patients, and the difference was not statistically significant(P = 0.388). OS of patients with wild type CYP2D6*10 was higher than that of CYP2D6*10 mutant patients, and the difference was not statistically significant(P = 0.096). The investigators’ stratified analysis showed that the OS of patients with wild type OATP1B1 T521 was higher than that of the mutant patients, and the difference was statistically significant(P=0.040). the single factor and multiple factor were analyzed by the Cox proportional hazard models showed that the OATP1B1 T521 C was still an independent impact factor(P=0.038, HR=0.593, 95%CI=0.363-0.971), but not the OATP1B1 A388G(P=0.396) and CYP2D6*10(P=0.102).Conclusion: These results suggest that OATP1B1 T521 C mutation may be an independent prognostic marker for the invasive breast cancer patients using tamoxifen therapy.