A pharmacogenetic study for clinical outcomes of high-risk stage II and stage III colon cancer patients Treated with oxaliplatin and fluoropyrimidines adjuvant chemotherapy

Background:  single nucleotide polymorphisms (SNPs) can predict treatment dose and safety of chemotherapeutic agentsi n different subgroups of cancer patients. We investigated 17 SNPs in 11 genes involved in the DNA repair, drug metabolism and as drug targets :TS, MTHFR, ERCC1, XRCC1, XRCC3, XPD, GSTT, GSTP, GSTM, ABCC1, ABCC2.    Material and methods:  TOSCA was a non-profit, Italian, multicentre, randomized, non-inferiority phase III study conducted in high-risk stage II and stage III colorectal cancer patients treated with 6 or 3 months of FOLFOX-4 or XELOX adjuvant chemoterapy. Patients who signed the informed consent were prospectively accrued in this ancillary study. Patients were genotyped by classical methods. The primary and secondary endpoints were relapse free survival (RFS) and overall survival (OS), respectively. Univariate and multivariate Cox proportional hazard models were used. Results:  524 patients were enrolled in this study (from July 2007 to October 2011), Eight patients were excluded from analysis due to major violation and 4 never started treatment. . 185 and 188 patients were treated with FOLFOX-4, 68 and 71 with XELOX in 6-month and in 3-month arm, respectively. Allele frequencies of all SNPs were consistent with Hardy-Weinberg equilibrium.  82(16%) progression and 71(14%) deaths were observed. Progression or deaths occurred in 106(21%) patients. The XRCC1 rs25487 G>A shortened significantly RFS (adjusted HR [AA vs GG] 2.02; 95%CI 1.15-3.56; p=0.015) and OS (adjusted HR[AA vs GG] 3.07; 95%CI 1.57-5.99; p=0.001). Interactions between SNPs and treatment duration were detected. In detail, 3-month treatment was correlated with a shorter RFS for patients with G allele in XPD rs13181 T>G and for patients with CC genotype (vs TC+TT) in ERCC1 rs11675 T>C. A better RFS and OS were identified in patients treated for 3 months with GG genotype for ABCC2 rs4148386 A>G. Finally, the GG genotype in ABCC2 rs1885301G>A increased OS in patients treated with 3 months treatment. Conclusions:  XRCC1 rs25487 G>A produced remarkable differences in RFS and OS in the studied population. Additional functional SNPs involved in the DNA repair pathways may engage a clinical impact according to the duration of the adjuvant chemotherapy program. These findings may impact on the overall chemotherapy treatment strategy of colon cancer patients. Additional prospective studies are warranted for confirming this associations and after adjustment for tumor-related prognostic factors.