R ESEARCH R EPORT 10.2217/14622416.8.12.1693 © 2007 Future Medicine Ltd ISSN 1462-2416 Pharmacogenomics (2007) 8(12), 1693–1703 1693 part of Determination of ERCC2 Lys751Gln and GSTP1 Ile105Val gene polymorphisms in colorectal cancer patients: relationships with treatment outcome Valérie Le Morvan 1 *, Denis Smith 2 * Armelle Laurand 1 , Véronique Brouste 3 , Ricardo Bellott 1 , Isabelle Soubeyran 4 , Simone Mathoulin- Pelissier 3 & Jacques Robert 1† † Author for correspondence 1 Université Victor Segalen, Institut Bergonié, Laboratoire de Pharmacologie des Agents Anticancéreux, 229 cours de l’Argonne, 33076 Bordeaux-cedex, France Tel.: +33 556 333 327; Fax: +33 556 330 438; robert@bergonie.org 2 Hôpital Saint-André, Centre Hospitalier Régional, Bordeaux, France 3 Unité de recherche clinique, Institut Bergonié, Bordeaux, France 4 Département de Pathologie, Institut Bergonié, Bordeaux, France *These authors contributed equally to this article Keywords: chemotherapy, colorectal cancer, excision- repair cross-complementing repair deficiency group 2 protein, gene polymorphisms, glutathione S-transferase P1 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, Ile105Val 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. Colorectal adenocarcinoma is a leading cause of cancer in developed countries and is responsible for 16,000 deaths every year in France [1] and 200,000 in Europe [2]. New drug development and combination therapy have recently trans- formed the outcome of metastatic patients [3,4] thanks to the use of oxaliplatin and irinotecan [5,6] and the introduction of therapeu- tic antibodies directed against the EGF receptor or VEGF [7,8]. Palliative treatment of metastatic colorectal cancer is now based upon the combi- nation of folinic acid–modulated fluorouracil (5-FU) with oxaliplatin or irinotecan, giving response rates of 30–50% and an overall survival (OS) of more than 20 months [9]. This has encouraged the use of such combinations in the adjuvant setting; the 5-FU–oxaliplatin combina- tion has been recently approved in this indica- tion, and the 5-FU–irinotecan combination is still under evaluation in the adjuvant setting. The choice of the chemotherapy regimen appears critical: in view of the impressive sur- vival advantage that can be expected in the palli- ative setting, and in view of the possible curability, it is crucial to offer to every patient the maximum likelihood of drug efficacy. We currently have no rational way to choose one combination over the other(s), in particular no predictive test allowing the selection of either oxaliplatin or irinotecan to be combined with 5-FU. If drugs are selective, it would be neces- sary to identify the parameters that determine this selectivity in order to prescribe the drug or drug combination most likely to provide a response and a survival advantage to a given patient. In addition, it would also be important to predict for drug-associated toxicity in order to avoid the prescription of a drug with a high risk of neutropenia or mucosal damage. There again, we need to identify individual parameters that are predictive of drug-induced toxicity. The expression of several genes has been shown to influence drug response in the clinical setting: for instance, thymidylate synthase (TS) and dihy- dropyrimidine dehydrogenase (DPD) mRNA or protein levels have been shown to predict for 5-FU efficacy and toxicity [10]. For irinotecan and oxaliplatin, several gene-expression profiling studies have been performed on in vitro models. They have provided tracks that have not yet been For reprint orders, please contact: reprints@futuremedicine.com