Pharmacogenetic Assessment of Toxicity and Outcome in Patients With Metastatic Colorectal Cancer Treated With LV5FU2, FOLFOX, and FOLFIRI: FFCD 2000-05

Author:

Boige Valérie1,Mendiboure Jean1,Pignon Jean-Pierre1,Loriot Marie-Anne1,Castaing Marine1,Barrois Michel1,Malka David1,Trégouët David-Alexandre1,Bouché Olivier1,Le Corre Delphine1,Miran Isabelle1,Mulot Claire1,Ducreux Michel1,Beaune Philippe1,Laurent-Puig Pierre1

Affiliation:

1. From the Departments of Medicine, Biostatistics and Epidemiology, and Oncogenetics and Institut National de la Santé et de la Recherche Médicale (INSERM) U981, Institut Gustave-Roussy, Villejuif; Université Paris Descartes, INSERM UMR-S775; INSERM UMR-S 937, Pierre et Marie Curie University and Medical School, Paris; and Department of Hepatogastroenterology, Centre Hospitalier Universitaire de Reims, Reims, France.

Abstract

PurposeThe 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).Patients and MethodsBlood 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.ResultsThe 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).ConclusionA pharmacogenetic approach may be a useful strategy for personalizing and optimizing chemotherapy in mCRC patients and deserves confirmation in additional prospective studies.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

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