Abstract 2610: TYMS and XRCC1 gene polymorphisms as possible predictors for the addition of oxaliplatin to 5FU in the adjuvant treatment of stage II and III colorectal cancer
Authors: Martinez-Balibrea Eva , Abad Albert , Martinez-Cardús Anna , Ginés Alba , Manzano José Luis , Layos Laura , Salazar Ramón , Macarulla Teresa , Rivera Fernando , Benavides Manuel , Grávalos Cristina , Sastre Javier , Gallego Javier , Aranda Enrique , Marcuello Eugenio , Antón Antonio ,   Spanish group for the treatment of digestive tumors (TTD).
Published: February 2011

Abstract
Background: The MOSAIC trial demonstrated that adding oxaliplatin to LV5FU2 significantly improved 5-year disease free survival (DFS) and 6-year overall survival (OS) in the adjuvant treatment of stage II/III colorectal cancer (CRC). However, oxaliplatin-related toxicities represent a problem when managing these patients. Genetic variants in TYMS and XRCC1 have shown to influence patients' outcomes in the metastatic setting. The purpose of the present study was to evaluate the influence of these polymorphisms on DFS and OS of stage II/III CRC patients treated with LV5FU2 +/- oxaliplatin in an adjuvant setting. Methods: We genotyped 216 patients (53.7% LV5FU2 and 46.3% FOLFOX4) from the MOSAIC trial. TYMS polymorphisms (5′TRP and 5′UTR SNP) and XRCC1-Arg399Gln were analyzed through PCR, RFLP and allelic discrimination respectively. According to TYMS 5′UTR SNP, genotypes were grouped as low expression (2R/2R, 2R/3RC, 3RC/3RC) or high expression (2R/3RG, 3RC/3RG, 3RG/3RG). Association of genetic variants with DFS and OS was investigated through Kaplan Meyer curves, log rank test and Cox regression models. Results: In our cohort 57.5% of patients were males; median age was 61 years (33-79); stage II/III tumors were equally distributed (50.2% and 49.8%). After 6 years of follow-up, 20.4% (38.6% FOLFOX4, 61.4% LV5FU2) of patients had relapsed and 15.4% (42.4% FOLFOX4, 57.6% LV5FU2) were dead. There were no statistical significant differences in DFS or OS according to individual genetic variants either in the whole group or by treatment. Therefore, they were analyzed jointly. TYMS high expression genotypes were considered as non-favorable for 5FU and XRCC1-399 Gln/Gln or Arg/Gln genotypes were considered as non-favorable for oxaliplatin. Patients in the FOLFOX4 group with non-favorable genotypes were more likely to relapse (28% vs. 11% for some favorable genotype; HR=2.7, 95% CI 1.00-7.34; Log rank p=0.04) or dying (17% vs. 5% for some favorable genotype; HR=2.7, 95% CI 0.92-8.17; Log rank p=0.06). Interestingly, these phenomena didn't occur in the LV5FU2 group of patients. Taken together, patients with some favorable genotype had better outcomes when receiving FOLFOX4 (87% vs. 78% for DFS, HR=0.63, 95% CI 0.28-1.43; p=0.07 and 95% vs. 89% for OS, HR=0.56, 95% CI 0.27-1.15; p=ns) after 6 years of follow-up. Inversely, FOLFOX4 was detrimental for those patients with non-favorable genotypes as compared with patients receiving LV5FU2 (68% vs. 78% for DFS, HR=2.5, 95% CI 0.60-11.1; p=ns and 83% vs. 89% for OS, HR=1.27, 95% CI 0.41-4; p=ns). Conclusion: TYMS 5′UTR SNP and XRCC1 Arg399Gln genotyping could help in the decision of adding or not oxaliplatin to LV5FU2 as adjuvant treatment in patients with stage II/III CRC and thus avoid undesirable oxaliplatin-related toxicities to these patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2610.