Abstract P2-09-21: Effect of MDR1 Gene Polymorphisms and Haplotypes on Taxanes-Based Chemotherapy Responses in Chinese Han Patients with Breast Cancer

Background: In recent years, taxanes play an important role in chemotherapy of breast cancer patients, and its response rate is about 50%. Taxanes is primarily metabolized by CYP450 in liver microsome, and it also is a substrate for P-glycoprotein (the coded product of MDR1 gene). The interindividual heterogeneity in drug-metabolizing enzymes and transporters has contributed to the variability on anti-cancer efficacy of taxanes in breast cancer patients. Several studies showed that the pharmacokinetics of taxanes was influenced by the MDR1 polymorphisms. The aim of this study is to investigate the relationship between MDR1 gene polymorphisms and taxanes-based chemotherapy responses, and provides useful information for clinical personalized medicine and prognostic judgment. Material and Methods: Genotyping of MDR1 variants was determined in the blood samples from 142 Chinese Han patients with breast cancer, by PCR-RFLP. The association of the gene polymorphisms of MDR1 C1236T at exon 12, G2677T/A at exon 21 and C3435T at exon 26 with chemotherapy responses was analyzed on the 63 patients, who received taxanes-based neoadjuvant chemotherapy [56 cases with TA (taxanes and anthracycline), 7 cases with TAC (C: cyclophosphamide)] and had the intact treatment follow-up information. Results: In the 142 breast cancer patients, the frequencies of C1236T, G2677T, G2677A and C3435T variant alleles was 70.7%,52.1%,2.5% and 46.5%, respectively, and the frequency of 3435T allele was significantly higher in comparison with that in healthy subjects (34.7%). In the 63 patients with neoadjuvant chemotherapy, the overall clinical response rate (CR+PR) to chemotherapy was 66.7%. 3435TT genotype was showed to be related to taxanes-based chemotherapy, and its efficient rate was 23.1%, significantly lower than that of patients carrying C allele (73.5%; x2 = 9.125, P=0.003). The 3 SNPs were in linkage disequilibrium, and the 4 haplotypes TTT, TGC, CGC and TTC were 90.6 % of all. The patients who carrying 2677G-3435C haplotype showed better response to chemotherapy compared with those with the other haplotypes combined (72.1% vs 40.0%;x 2 =9.125, P=0.003). The response rate of the patients with 2677T-3435T haplotype or 1236T-3435T haplotype (54.3% or 54.9%) were lower than that of the patients harboring the other haplotypes (82.4% or 91.7%;x 2 =4.128 and x 2 =4.118, P =0.042 for both) respectively, and the efficient rate of the patients with 1236T-2677T-3435T (54.3%) were also lower than that of the patients with other haplotypes combined (82.4%;x 2 =4.128, P=0.042). Conclusion: C1236T, G2677T/A and C3435T of MDR1 gene were polymorphic with different frequency in breast cancer patients. The analyses of MDR1 C3435T genotype and its haplotypes with C1236T or G2677T/A are valuable for predicting the taxanes-based chemotherapy responses in breast cancer patients, which deserve the further study. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-21.