SLCO1B1 and SLC19A1 gene variants and irinotecan-induced rapid response and survival: a prospective multicenter pharmacogenetics study of metastatic colorectal cancer

Liu Huang, Tao Zhang, Conghua Xie, Xin Liao, Qianqian Yu, Jueping Feng, Hong Ma, Jing Dai, Min Li, Jigui Chen, Aihua Zang, Qian Wang, Shuwang Ge, Kai Qin, Juan Cai, Xianglin Yuan, Liu Huang, Tao Zhang, Conghua Xie, Xin Liao, Qianqian Yu, Jueping Feng, Hong Ma, Jing Dai, Min Li, Jigui Chen, Aihua Zang, Qian Wang, Shuwang Ge, Kai Qin, Juan Cai, Xianglin Yuan

Abstract

Background: Rapid response to chemotherapy in metastatic colorectal cancer (mCRC) patients (response within 12 weeks of chemotherapy) may increase the chance of complete resection and improved survival. Few molecular markers predict irinotecan-induced rapid response and survival. Single-nucleotide polymorphisms (SNPs) in solute carrier genes are reported to correlate with the variable pharmacokinetics of irinotecan and folate in cancer patients. This study aims to evaluate the predictive role of 3 SNPs in mCRC patients treated with irinotecan and fluoropyrimidine-containing regimens.

Materials and methods: Three SNPs were selected and genotyped in 137 mCRC patients from a Chinese prospective multicenter trial (NCT01282658). The chi-squared test, univariate and multivariable logistic regression model, and receiver operating characteristic analysis were used to evaluate correlations between the genotypes and rapid response. Kaplan-Meier survival analysis and Cox proportional hazard models were used to evaluate the associations between genotypes and survival outcomes. Benjamini and Hochberg False Discovery Rate correction was used in multiple testing.

Results: Genotype GA/AA of SNP rs2306283 of the gene SLCO1B1 and genotype GG of SNP rs1051266 of the gene SLC19A1 were associated with a higher rapid response rate (odds ratio [OR] =3.583 and 3.521, 95%CI =1.301-9.871 and 1.271-9.804, p=0.011 and p=0.013, respectively). The response rate was 70% in patients with both genotypes, compared with only 19.7% in the remaining patients (OR = 9.489, 95%CI = 2.191-41.093, Fisher's exact test p=0.002). Their significances were all maintained even after multiple testing (all p c < 0.05). The rs2306283 GA/AA genotype was also an independent prognostic factor of longer progression-free survival (PFS) (hazard ratio = 0.402, 95%CI = 0.171-0.945, p=0.037). None of the SNPs predicted overall survival.

Conclusions: Polymorphisms of solute carriers' may be useful to predict rapid response to irinotecan plus fluoropyrimidine and PFS in mCRC patients.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Flow chart.
Figure 1. Flow chart.
Figure 2. Receiver operating characteristic (ROC) analysis…
Figure 2. Receiver operating characteristic (ROC) analysis of OCF, Age and AGene in predicting RRR.
OCF (other clinical factors) includes sex, surface area, performance status and smoking status. Agene includes age, rs2306283 and rs1051266. SE, standard error.
Figure 3. PFS (A, D, G), IR-TTF…
Figure 3. PFS (A, D, G), IR-TTF (B, E, H) and OS (C, F, I) in patients according to rs2306283, rs1051266 and rs4149056 genotypes (log-rank test).

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