title: DPYD Genotyping to Predict Adverse Events Following Treatment With Fluorouracil-Based Adjuvant Chemotherapy in Patients With Stage III Colon Cancer: A Secondary Analysis of the PETACC-8 Randomized Clinical Trial.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  Patients with resected stage III CC were randomized to receive standard adjuvant FOLFOX4 alone or FOLFOX4 combined with cetuximab for 6 months.
  
  
  METHODS
  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
  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.
  
  
  BACKGROUND
  eudract Identifier 2005-003463-23.
authors.affiliation: Department of Oncologic Medicine, Gustave-Roussy, Villejuif, France2Université Paris Descartes, Paris Sorbonne Cité INSERM UMR-S775, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Boige
authors.affiliation: Université Paris Descartes, Paris Sorbonne Cité INSERM UMR-S775, Paris, France.
authors.forename: Marc
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authors.lastname: Vincent
authors.affiliation: Université Paris Descartes, Paris Sorbonne Cité INSERM UMR-S775, Paris, France.
authors.forename: Philippe
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authors.lastname: Alexandre
authors.affiliation: Digestive Oncology Unit, University Hospital Gasthiusberg, Leuven, Belgium.
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
authors.affiliation: Department of Oncology, Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain5Barcelona Department of Pathology, Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Ba.
authors.forename: Stefania
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authors.lastname: Landolfi
authors.affiliation: Department of Statistics, Fédération Francophone de Cancérologie Digestive, Dijon, France.
authors.forename: Karine
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authors.affiliation: Department of Oncology, Salzburger Landesklinik, Salzburg, Austria.
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authors.affiliation: Department of Gastroenterology, Imelda General Hospital, Bonheiden, Belgium.
authors.forename: Pieter Jan
authors.initials: PJ
authors.lastname: Cuyle
authors.affiliation: Department of Oncology, Aalborg Hospital, Aalborg, Denmark.
authors.forename: Mette
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authors.lastname: Yilmaz
authors.affiliation: Department of Gastroenterology, Hospital La Roche-sur-Yon, La Roche-sur-Yon, France.
authors.forename: Roger
authors.initials: R
authors.lastname: Faroux
authors.affiliation: Department of Internal Medicine II, Asklepios Clinic Uckermark, Gastroenterology, Nephrology, Hematology and Oncology, Schwedt, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Matzdorff
authors.affiliation: Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Salazar
authors.affiliation: Department of Hepato-Gastroenterology, Dijon University Hospital and INSERM U 866, Dijon, France.
authors.forename: Côme
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authors.lastname: Lepage
authors.affiliation: Assistance Publique-Hopitaux de Paris Department of Hepatogastroenterology and Gastrointestinal Oncology, Georges Pompidou Hospital, Descartes University, Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Taieb
authors.affiliation: Université Paris Descartes, Paris Sorbonne Cité INSERM UMR-S775, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig