A prospective validation pharmacogenomic study in the adjuvant setting of colorectal cancer patients treated with the 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX4) regimen

Abstract

The discovery of pharmacogenomic markers in colorectal cancer (CRC) could be setting-specific. FOLFOX4 is employed in the adjuvant and metastatic setting in CRC. This prospective study is aimed to validate in the adjuvant setting the pharmacogenomic markers of toxicity reported in the metastatic setting (that is, GSTP1-rs947894, and -rs1138272; GSTM1-null genotype; AGXT-rs4426527, -rs34116584 and del-74 bp), and to discover additional markers. CRC patients (n=144) treated with adjuvant FOLFOX4 were genotyped for 57 polymorphisms in 29 genes. Grade ≥ 2 neurotoxicity was associated (false discovery rate-adjusted q-value <0.1) with single-nucleotide polymorphisms in ABCC1 (rs2074087: odds ratio=0.43(0.22-0.86)), and ABCC2 (rs3740066: 2.99(1.16-7.70); rs1885301: 3.06(1.35-6.92); rs4148396: 4.69(1.60-13.74); rs717620: 14.39(1.63-127.02)). hMSH6-rs3136228 was associated with grade 3-4 neutropenia (3.23(1.38-7.57), q-value=0.0937). XRCC3-rs1799794 was associated with grade 3-4 non-hematological toxicity (8.90(2.48-31.97), q-value=0.0150). The markers previously identified in metastatic CRC were not validated. We have identified new markers of toxicity in genes of transport and DNA repair. If validated in other studies, they could help to identify patients at risk of toxicity.

Figures

Figure 1

Pairwise linkage disequilibrium analysis among ABCC2 polymorphisms associated to neurotoxicity grade ≥2. The value within each diamond represents the pairwise correlation between polymorphims (measured as D’ (a) or r2 (b)). The black to white gradient reflects higher to lower values. The plots were generated by HaploView 3.32.