[Skip to Content]
[Skip to Content Landing]
Original Investigation
May 2016

DPYD Genotyping to Predict Adverse Events Following Treatment With Fluorouracil-Based Adjuvant Chemotherapy in Patients With Stage III Colon CancerA Secondary Analysis of the PETACC-8 Randomized Clinical Trial

Author Affiliations
  • 1Department of Oncologic Medicine, Gustave-Roussy, Villejuif, France
  • 2Université Paris Descartes, Paris Sorbonne Cité INSERM UMR-S775, Paris, France
  • 3Digestive Oncology Unit, University Hospital Gasthiusberg, Leuven, Belgium
  • 4Department of Oncology, Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
  • 5Barcelona Department of Pathology, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain
  • 6Department of Statistics, Fédération Francophone de Cancérologie Digestive, Dijon, France
  • 7Department of Oncology, Salzburger Landesklinik, Salzburg, Austria
  • 8Department of Gastroenterology, Imelda General Hospital, Bonheiden, Belgium
  • 9Department of Oncology, Aalborg Hospital, Aalborg, Denmark
  • 10Department of Gastroenterology, Hospital La Roche-sur-Yon, La Roche-sur-Yon, France
  • 11Department of Internal Medicine II, Asklepios Clinic Uckermark, Gastroenterology, Nephrology, Hematology and Oncology, Schwedt, Germany
  • 12Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, L’Hospitalet de Llobregat, Barcelona, Spain
  • 13Department of Hepato-Gastroenterology, Dijon University Hospital and INSERM U 866, Dijon, France
  • 14Assistance Publique–Hopitaux de Paris Department of Hepatogastroenterology and Gastrointestinal Oncology, Georges Pompidou Hospital, Descartes University, Paris, France
JAMA Oncol. 2016;2(5):655-662. doi:10.1001/jamaoncol.2015.5392

Importance  Previous pharmacogenetic studies have shown the prognostic impact of several rare dihydropyrimidine dehydrogenase gene (DPYD) variants on fluorouracil-related adverse events (fluorouracil AEs). However, conflicting results highlight the need for prospective validation in large, homogeneous patient populations uniformly treated with current standard combination therapies used in colon cancer (CC).

Objective  To determine the impact of DPYD variants on fluorouracil AEs in patients with stage III CC treated with a fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) regimen.

Design, Setting, and Participants  Pharmacogenetic substudy of 1545 patients who participated from December 2005 to November 2009 in the European Pan-European Trials in Alimentary Tract Cancer (PETACC)-8 randomized phase 3 clinical trial.

Interventions  Patients with resected stage III CC were randomized to receive standard adjuvant FOLFOX4 alone or FOLFOX4 combined with cetuximab for 6 months.

Main Outcomes and Measures  Patients were genotyped on 25 DPYD variants. We tested the individual associations between each DPYD variant and grade 3 or greater fluorouracil AEs.

Results  A total of 1545 patients (57.6% male; median [range] age, 60 [19-75] years) were included in the analysis. The incidence of grade 3 or greater fluorouracil AEs in D949V and V732I (DPYD*6) carriers was 18 in 21 (85.7%) and 121 in 199 (60.8%), respectively. After adjusting for multiple variables, statistically significant associations were identified between grade 3 or greater fluorouracil AEs and both D949V (odds ratio [OR], 6.3 [95% CI, 2.0-27.0]; P < .001) and V732I variants (OR, 1.7 [95% CI, 1.3-2.4]; P < .001). Grade 3 or greater overall hematologic adverse events were associated with V732I (OR, 1.9 [95% CI, 1.4-2.6]) and D949V (OR, 5.2 [95% CI, 2.0-16.0]), and V732I was associated with grade 3 or greater neutropenia (OR, 1.8 [95% CI, 1.3-2.4]). The association of V732I with the occurrence of grade 3 or greater fluorouracil AEs and overall hematologic adverse events was validated in an independent cohort of 339 patients with metastatic colorectal cancer receiving FOLFOX4 in the Fédération Francophone de Cancérologie Digestive 2000-05 phase 3 trial.

Conclusions and Relevance  In this large phase 3 study, statistically significant associations were found between DPYD variants (D949V and V732I) and increased incidence of grade 3 or greater fluorouracil AEs in patients treated with adjuvant fluorouracil-based combination chemotherapy. Further studies are warranted to confirm and quantitate these associations.

Trial Registration  eudract Identifier 2005-003463-23