Germline variants and clinical outcomes of high-risk stage II and stage III colon cancer patients treated with oxaliplatin and fluoropyrimidines adjuvant chemotherapy: a pharmacogenetic ancillary study to TOSCA trial

Background: Functional germline variants (SNPs) may characterize sub-populations of cancer patients who gain different benefits from chemotherapy. We investigated 17 SNPs in 11 genes with putative impact on sensitivity to fluoropyrimidines and oxaliplatin (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. 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: From July 2007 to October 2011, 524 patients were enrolled in this study. 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 germline variants 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.