Pharmacogenetic Assessment of Toxicity and Outcome in Patients With Metastatic Colorectal Cancer Treated With LV5FU2, FOLFOX, and FOLFIRI: FFCD 2000-05
- 20 May 2010
- journal article
- research article
- Published by American Society of Clinical Oncology (ASCO) in Journal of Clinical Oncology
- Vol. 28 (15), 2556-2564
- https://doi.org/10.1200/jco.2009.25.2106
Abstract
The aim was to investigate whether germline polymorphisms within candidate genes known or suspected to be involved in fluorouracil (FU), oxaliplatin, and irinotecan pathways were associated with toxicity and clinical outcome in patients with metastatic colorectal cancer (mCRC). Blood samples from 349 patients included in the Fédération Francophone de Cancérologie Digestive 2000-05 randomized trial, which compared FU plus leucovorin (LV5FU2) followed by FU, leucovorin, and oxaliplatin (FOLFOX) followed by FU, leucovorin, and irinotecan (FOLFIRI; sequential arm) with FOLFOX followed by FOLFIRI (combination arm) in terms of progression-free survival (PFS) and overall survival, were collected. Twenty polymorphisms within the DPD, TS, MTHFR, ERCC1, ERCC2, GSTP1, GSTM1, GSTT1, and UGT1A1 genes were genotyped. The ERCC2-K751QC allele was independently associated with an increased risk of FOLFOX-induced grade 3 or 4 hematologic toxicity (P = .01). In the sequential arm, TS-5′UTR3RG and GSTT1 alleles were independently associated with response to LV5FU2 (P = .009) and FOLFOX (P = .01), respectively. The effect of oxaliplatin on tumor response increased with the number of MTHFR-1298C alleles (test for trend, P = .008). The PFS benefit from first-line FOLFOX was restricted to patients with 2R/2R (hazard ratio [HR] = 0.39; 95% CI, 0.23 to 0.68) or 2R/3R (HR = 0.59; 95% CI, 0.42 to 0.82) TS-5′UTR genotypes, respectively. Conversely, patients with the TS-5′UTR 3R/3R genotype did not seem to benefit from the adjunction of oxaliplatin (HR = 0.96; 95% CI, 0.66 to 1.40; trend between the three HRs, P = .006). A pharmacogenetic approach may be a useful strategy for personalizing and optimizing chemotherapy in mCRC patients and deserves confirmation in additional prospective studies.Keywords
This publication has 47 references indexed in Scilit:
- Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and FOLFOX response in colorectal cancer patientsBritish Journal of Clinical Pharmacology, 2009
- Pharmacogenetic Analyses of a Phase III Trial in Metastatic Gastroesophageal Adenocarcinoma With Fluorouracil and Leucovorin Plus Either Oxaliplatin or Cisplatin: A Study of the Arbeitsgemeinschaft Internistische OnkologieJournal of Clinical Oncology, 2009
- Liver-only metastatic colorectal cancer patients and thymidylate synthase polymorphisms for predicting response to 5-fluorouracil-based chemotherapyBritish Journal of Cancer, 2008
- K-Ras Mutations and Treatment Outcome in Colorectal Cancer Patients Receiving Exclusive Fluoropyrimidine TherapyClinical Cancer Research, 2008
- Cost of Cancer Care: Issues and ImplicationsJournal of Clinical Oncology, 2007
- Relationships between promoter polymorphisms in the thymidylate synthase gene and mRNA levels in colorectal cancersEuropean Journal of Cancer, 2005
- ERCC1 Codon 118 Polymorphism Is a Predictive Factor for the Tumor Response to Oxaliplatin/5-Fluorouracil Combination Chemotherapy in Patients with Advanced Colorectal CancerClinical Cancer Research, 2005
- Cellular processing of platinum anticancer drugsNature Reviews Drug Discovery, 2005
- Negative prognostic value of glutathione S-transferase(GSTM1 and GSTT1) deletions in adult acute myeloid leukemiaBlood, 2002
- A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductaseNature Genetics, 1995