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

Valérie Boige, Marc Vincent, Philippe Alexandre, Sabine Tejpar, Stefania Landolfi, Karine Le Malicot, Richard Greil, Pieter Jan Cuyle, Mette Yilmaz, Roger Faroux, Axel Matzdorff, Ramon Salazar, Côme Lepage, Julien Taieb, Pierre Laurent-Puig, Evaristo Maiello

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalJAMA oncology
DOIs
Publication statusE-pub ahead of print - Jan 21 2016

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Dihydrouracil Dehydrogenase (NADP)
Adjuvant Chemotherapy
Fluorouracil
Colonic Neoplasms
Randomized Controlled Trials
Genes
Neoplasms
Odds Ratio
oxaliplatin
Therapeutics
Phase III Clinical Trials
Leucovorin
Pharmacogenetics
Incidence
Combination Drug Therapy
Neutropenia
Colorectal Neoplasms
Outcome Assessment (Health Care)

Keywords

  • Journal Article

Cite this

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. / Boige, Valérie; Vincent, Marc; Alexandre, Philippe; Tejpar, Sabine; Landolfi, Stefania; Le Malicot, Karine; Greil, Richard; Cuyle, Pieter Jan; Yilmaz, Mette; Faroux, Roger; Matzdorff, Axel; Salazar, Ramon; Lepage, Côme; Taieb, Julien; Laurent-Puig, Pierre; Maiello, Evaristo.

In: JAMA oncology, 21.01.2016.

Research output: Contribution to journalArticle

Boige, V, Vincent, M, Alexandre, P, Tejpar, S, Landolfi, S, Le Malicot, K, Greil, R, Cuyle, PJ, Yilmaz, M, Faroux, R, Matzdorff, A, Salazar, R, Lepage, C, Taieb, J, Laurent-Puig, P & Maiello, E 2016, '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', JAMA oncology. https://doi.org/10.1001/jamaoncol.2015.5392
Boige, Valérie ; Vincent, Marc ; Alexandre, Philippe ; Tejpar, Sabine ; Landolfi, Stefania ; Le Malicot, Karine ; Greil, Richard ; Cuyle, Pieter Jan ; Yilmaz, Mette ; Faroux, Roger ; Matzdorff, Axel ; Salazar, Ramon ; Lepage, Côme ; Taieb, Julien ; Laurent-Puig, Pierre ; Maiello, Evaristo. / 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. In: JAMA oncology. 2016.
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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 F{\'e}d{\'e}ration Francophone de Canc{\'e}rologie 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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TY - JOUR

T1 - DPYD Genotyping to Predict Adverse Events Following Treatment With Flourouracil-Based Adjuvant Chemotherapy in Patients With Stage III Colon Cancer

T2 - A Secondary Analysis of the PETACC-8 Randomized Clinical Trial

AU - Boige, Valérie

AU - Vincent, Marc

AU - Alexandre, Philippe

AU - Tejpar, Sabine

AU - Landolfi, Stefania

AU - Le Malicot, Karine

AU - Greil, Richard

AU - Cuyle, Pieter Jan

AU - Yilmaz, Mette

AU - Faroux, Roger

AU - Matzdorff, Axel

AU - Salazar, Ramon

AU - Lepage, Côme

AU - Taieb, Julien

AU - Laurent-Puig, Pierre

AU - Maiello, Evaristo

PY - 2016/1/21

Y1 - 2016/1/21

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1001/jamaoncol.2015.5392

DO - 10.1001/jamaoncol.2015.5392

M3 - Article

JO - JAMA oncology

JF - JAMA oncology

SN - 2374-2437

ER -