Polymorphisms in genes involved in drug detoxification and clinical outcomes of anthracycline-based neoadjuvant chemotherapy in Chinese Han breast cancer patients

Abstract

Background: The large individual variability for anticancer drugs in both outcome and toxicity risk makes the identification of pharmacogenetic markers that can be used to screen patients before therapy selection an attractive prospect.

Aims: This work aimed to evaluate the importance of genetic polymorphisms involved in drug detoxification to predict clinical outcomes of anthracycline-based neoadjuvant chemotherapy for breast cancer.

Results: GSTP1 313 AA genotype was associated with a poor clinical response relative to G allele carrier (58.4% vs 80.8%; p = 0.006), and MDR1 3435 TT genotype had a worse response compared with C allele carrier (33.3% vs 71.2% p = 0.001). Patients with both the adverse genotypes of GSTP1 314AA and MDR 3435TT showed the worst therapy efficacy in all (14.3%; p = 0.000). Kaplan-Meier survival analysis showed that the patients with no adverse genotype were associated with decreased hazard of relapse (p = 0.002), compared with those with 1 or 2 adverse genotypes. Multivariate analysis demonstrated that clinical response and no adverse genotype was independent predictors of disease-free survival (DFS).

Methods: Genotyping was performed by allele-specific oligonucleotide ligation reaction (MnSOD, CAT, GSTP1), multiplex PCR (GSTM1, GSTT1) or PCR-RFLP (MDR1). Based on 153 patients received anthracycline-based neoadjuvant chemotherapy, these genotypes or their combinations in relation to treatment-related response, hematologic toxicity and DFS were investigated.

Conclusions: These results suggest that polymorphisms in GSTP1 and MDR1 may help to predict clinical response and DFS of anthracycline-based chemotherapy, and a polygenic pathway approach should provide more useful information. The findings required independent prospective confirmation.

Key words:

• anthracycline
• breast cancer
• chemotherapy
• clinical response
• disease-free survival (DFS)
• individualizing treatment
• polymorphism

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

This study was supported by the National Natural Science Foundation of China (30840093) and Social Development Project of Science Technology of Jiangsu Province (BS2007077).

Figures and Tables

Figure 1 Comparison of patients' disease-free survival between GSTP1 313 AA and GA + GG genotypes (A), and between MDR1 3435 TT and CT + CC genotypes (B), between 0 adverse genotype and 1 or 2 adverse genotypes (C).

Table 1 Comparison of clinical response rate according to patient characteristics (n = 153)

Table 2 Clinical responses and hematologic toxicity to anthracycline-based chemotherapy according to MnSOD and CAT Genotypes

Table 3 Clinical responses and hematologic toxicity to anthracycline-based chemotherapy according to GSTP1, GSTM1 and GSTT1 Genotypes

Table 4 Clinical responses and hematologic toxicity to anthracycline-based chemotherapy according to genotypes and haplotypes in MDR1

Table 5 The combined adverse genotypes in GSTP1 A313G and MDR1 C3435T and clinical response to anthracycline-based chemotherapy

Table 6 Cox regression analysis for DFS in 149 neoadjuvant chemotherapy patients