Determination of ERCC2 Lys751 Gln and GSTP1 Ile105Val gene polymorphisms in colorectal cancer patients:: relationships with treatment outcome

Introduction: Glutathione S-transferase P1 (GSTP1) and excision-repair cross-complementing repair deficiency group 2 protein (ERCC2 or XPD) may modulate the activity of platinum derivatives. The SNPs, IIe105Val for GSTP1 and Lys751Gln for ERCC2, may affect the efficiency of oxaliplatin in patients treated with an oxaliplatin-based regimen for metastatic colorectal carcinoma. Patients & Methods: A total of 107 patients treated with first-line chemotherapy, 59 with an oxaliplatin-based regimen and 48 with an irinotecan-based regimen, were included retrospectively. GSTP1 and ERCC2 genotypes were identified on DNA samples extracted from paraffin blocks containing either normal tissue (nodes) or tumor tissue. We analyzed treatment response, event-free and overall survival. Results: GSTP1 genotype distribution was Ile/Ile 58%, Ile/Val 35% and Val/Val 7%. ERCC2 genotype distribution was Lys/Lys 49%, Lys/Gln 44%, Gln/Gln 7%. Event-free and overall survivals were not significantly different as a function of the GSTP1 genotype, whatever the treatment received. Event-free survival was significantly different as a function of the ERCC2 genotype only in patients receiving oxaliplatin: patients having at least one variant allele had a shorter median event-free survival (6 months) than those having no variant allele (11.6 months, p = 0.008). This difference was maintained for median overall survival (15.6 vs 25.3 months, p = 0.016). Using univariate analysis, ERCC2 genotype, hemoglobinemia and carbohydrate antigen 19.9 plasma levels were significantly related to overall and event-free survival in patients receiving oxaliplatin. Conclusion: The ERCC2 genotype appears as an important predictive factor of the survival of patients treated with oxaliplatin in first-line therapy for metastatic colorectal cancer.