Abstract Background Anthracycline is one of the most effective drugs in the treatment of breast cancer and many of our most effective treatment regimens include anthracycline. Its efficacy can be influenced by cellular detoxification mechanisms involving drug metabolism and transport pathways. This study aimed to assess whether the functional polymorphisms in drug-metabolizing enzymes (MnSOD, CAT and GSTs) and transporter MDR1 may predict anthracycline treatment-related outcomes in Chinese Han breast cancer patients. Material and methods: Genotyping was performed by allele-specific oligonucleotide ligation reaction (MnSOD T47C, CAT C-262T, GSTP1 A313G), multiplex PCR (GSTM1 null, GSTT1 null), and PCR-RFLP (MDR1 C3435T, G2677T/A and C1236T). Based on 153 evaluable patients received anthracycline-based neoadjuvant chemotherapy for breast cancer, the associations of these genotypes or their haplotypes with clinical response and recurrence-free survival (RFS) were analyzed. Results: Of the 153 cases, the patients with GSTP1 313AA genotype had inferior response rates relative to those with AG or GG genotype (58.4% vs 77.8% or 100.0%; χ2=4.922, P=0.027). Moreover, the response rate of the combination of GSTP1 AA with both GSTT1 present and GSTM1 present was 44%, which was also lower comparing with the other groups (70.3%; χ2=6.454, P=0.011). A similar result was noticed for MDR1 3435 TT genotype, which had a significantly worse chemotherapy response compared with wild-type C allele carrier (33.3% vs 71.2%; χ2=11.586, P=0.001). Further, the response rate of the patients with 3435T-2677T, 3435T-1236T or 3435T-2677T-1236T haplotypes was lower than that of the patients with the other corresponding haplotypes (P=0.018, 0.011 and 0.019, respectively), too. Of note, the patients with both the adverse genotypes of GSTP1 314AA and MDR 3435TT shown the worst treatment efficacy in all (14.3%;χ2=26.33, P=0.000). Mean follow-up time of the 149 patients (4 patients lost) was 51 months. The recurrence rate in the patients with GSTP1 313AA or/and MDR 3435TT in the first three years was 39.0% (41/105), higher significantly than those with no adverse genotype [15.9% (7/44); OR=0.725, 95%Cl: 0.594−0.885, P=0.006]. Kaplan-Meier survival analysis showed that the patients with no adverse genotype were associated with reduced hazard of relapse (long-rank test, P<0.01), compared to those with 1 or 2 adverse genotypes. Conclusion: Polymorphisms in GSTs and MDR1 genes may help to predict clinical response and RFS of anthracycline-based chemotherapy in breast cancer, but further validation is required. These results provide support for a polygenic pathway approach for assessing the predictive potential of polymorphisms in treatment outcomes. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-13-14.