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JAMA Oncol. 2016 Jan 21. doi: 10.1001/jamaoncol.2015.5392. [Epub ahead of print]

DPYD Genotyping to Predict Adverse Events Following Treatment With Flourouracil-Based Adjuvant Chemotherapy in Patients With Stage III Colon Cancer: A Secondary Analysis of the PETACC-8 Randomized Clinical Trial.

Author information

1
Department of Oncologic Medicine, Gustave-Roussy, Villejuif, France2Université Paris Descartes, Paris Sorbonne Cité INSERM UMR-S775, Paris, France.
2
Université Paris Descartes, Paris Sorbonne Cité INSERM UMR-S775, Paris, France.
3
Digestive Oncology Unit, University Hospital Gasthiusberg, Leuven, Belgium.
4
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.
5
Department of Statistics, Fédération Francophone de Cancérologie Digestive, Dijon, France.
6
Department of Oncology, Salzburger Landesklinik, Salzburg, Austria.
7
Department of Gastroenterology, Imelda General Hospital, Bonheiden, Belgium.
8
Department of Oncology, Aalborg Hospital, Aalborg, Denmark.
9
Department of Gastroenterology, Hospital La Roche-sur-Yon, La Roche-sur-Yon, France.
10
Department of Internal Medicine II, Asklepios Clinic Uckermark, Gastroenterology, Nephrology, Hematology and Oncology, Schwedt, Germany.
11
Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain.
12
Department of Hepato-Gastroenterology, Dijon University Hospital and INSERM U 866, Dijon, France.
13
Assistance Publique-Hopitaux de Paris Department of Hepatogastroenterology and Gastrointestinal Oncology, Georges Pompidou Hospital, Descartes University, Paris, France.

Abstract

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.

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