Dihydropyrimidine dehydrogenase pharmacogenetics for predicting fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients

A. Ruzzo, F. Graziano, Fabio Galli, Francesca Galli, E. Rulli, S. Lonardi, M. Ronzoni, B. Massidda, V. Zagonel, N. Pella, C. Mucciarini, R. Labianca, M. T. Ionta, I. Bagaloni, E. Veltri, P. Sozzi, S. Barni, V. Ricci, L. Foltran, M. NicoliniE. Biondi, A. Bramati, D. Turci, S. Lazzarelli, C. Verusio, F. Bergamo, A. Sobrero, L. Frontini, M. Menghi, M. Magnani

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Abstract

METHODS: The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg's False Discovery Rate (FDR) procedure was used.

RESULTS: FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR<0.0001), *2A rs3918290 A allele carriers (FDR<0.0001), and rs2297595 GG genotype carriers (FDR=0.0014). Neutropenia was the most common FAEs (28.5%). *6 rs1801160 (FDR<0.0001), and *2A rs3918290 (FDR=0.0004) variant alleles were significantly associated with time to neutropenia.

CONCLUSIONS: This study adds evidence on the role of DPYD pharmacogenetics for safety of patients undergoing fluoropyrimidine-based chemotherapy.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% of the administered dose of fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients' risk of fluoropyrimidine-related severe toxicity.

Original languageEnglish
Pages (from-to)1269-1277
Number of pages9
JournalBritish Journal of Cancer
Volume117
Issue number9
DOIs
Publication statusPublished - Oct 24 2017

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Dihydrouracil Dehydrogenase (NADP)
Pharmacogenetics
Colonic Neoplasms
Alleles
Neutropenia
Adjuvant Chemotherapy
Patient Safety
Genotype
Drug Therapy
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Dihydropyrimidine dehydrogenase pharmacogenetics for predicting fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients. / Ruzzo, A.; Graziano, F.; Galli, Fabio; Galli, Francesca; Rulli, E.; Lonardi, S.; Ronzoni, M.; Massidda, B.; Zagonel, V.; Pella, N.; Mucciarini, C.; Labianca, R.; Ionta, M. T.; Bagaloni, I.; Veltri, E.; Sozzi, P.; Barni, S.; Ricci, V.; Foltran, L.; Nicolini, M.; Biondi, E.; Bramati, A.; Turci, D.; Lazzarelli, S.; Verusio, C.; Bergamo, F.; Sobrero, A.; Frontini, L.; Menghi, M.; Magnani, M.

In: British Journal of Cancer, Vol. 117, No. 9, 24.10.2017, p. 1269-1277.

Research output: Contribution to journalArticle

Ruzzo, A, Graziano, F, Galli, F, Galli, F, Rulli, E, Lonardi, S, Ronzoni, M, Massidda, B, Zagonel, V, Pella, N, Mucciarini, C, Labianca, R, Ionta, MT, Bagaloni, I, Veltri, E, Sozzi, P, Barni, S, Ricci, V, Foltran, L, Nicolini, M, Biondi, E, Bramati, A, Turci, D, Lazzarelli, S, Verusio, C, Bergamo, F, Sobrero, A, Frontini, L, Menghi, M & Magnani, M 2017, 'Dihydropyrimidine dehydrogenase pharmacogenetics for predicting fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients', British Journal of Cancer, vol. 117, no. 9, pp. 1269-1277. https://doi.org/10.1038/bjc.2017.289
Ruzzo, A. ; Graziano, F. ; Galli, Fabio ; Galli, Francesca ; Rulli, E. ; Lonardi, S. ; Ronzoni, M. ; Massidda, B. ; Zagonel, V. ; Pella, N. ; Mucciarini, C. ; Labianca, R. ; Ionta, M. T. ; Bagaloni, I. ; Veltri, E. ; Sozzi, P. ; Barni, S. ; Ricci, V. ; Foltran, L. ; Nicolini, M. ; Biondi, E. ; Bramati, A. ; Turci, D. ; Lazzarelli, S. ; Verusio, C. ; Bergamo, F. ; Sobrero, A. ; Frontini, L. ; Menghi, M. ; Magnani, M. / Dihydropyrimidine dehydrogenase pharmacogenetics for predicting fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients. In: British Journal of Cancer. 2017 ; Vol. 117, No. 9. pp. 1269-1277.
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title = "Dihydropyrimidine dehydrogenase pharmacogenetics for predicting fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients",
abstract = "METHODS: The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg's False Discovery Rate (FDR) procedure was used.RESULTS: FAEs occurred in 194 out of 508 assessable patients (38.2{\%}). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR<0.0001), *2A rs3918290 A allele carriers (FDR<0.0001), and rs2297595 GG genotype carriers (FDR=0.0014). Neutropenia was the most common FAEs (28.5{\%}). *6 rs1801160 (FDR<0.0001), and *2A rs3918290 (FDR=0.0004) variant alleles were significantly associated with time to neutropenia.CONCLUSIONS: This study adds evidence on the role of DPYD pharmacogenetics for safety of patients undergoing fluoropyrimidine-based chemotherapy.BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85{\%} of the administered dose of fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients' risk of fluoropyrimidine-related severe toxicity.",
author = "A. Ruzzo and F. Graziano and Fabio Galli and Francesca Galli and E. Rulli and S. Lonardi and M. Ronzoni and B. Massidda and V. Zagonel and N. Pella and C. Mucciarini and R. Labianca and Ionta, {M. T.} and I. Bagaloni and E. Veltri and P. Sozzi and S. Barni and V. Ricci and L. Foltran and M. Nicolini and E. Biondi and A. Bramati and D. Turci and S. Lazzarelli and C. Verusio and F. Bergamo and A. Sobrero and L. Frontini and M. Menghi and M. Magnani",
year = "2017",
month = "10",
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doi = "10.1038/bjc.2017.289",
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volume = "117",
pages = "1269--1277",
journal = "British Journal of Cancer",
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TY - JOUR

T1 - Dihydropyrimidine dehydrogenase pharmacogenetics for predicting fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients

AU - Ruzzo, A.

AU - Graziano, F.

AU - Galli, Fabio

AU - Galli, Francesca

AU - Rulli, E.

AU - Lonardi, S.

AU - Ronzoni, M.

AU - Massidda, B.

AU - Zagonel, V.

AU - Pella, N.

AU - Mucciarini, C.

AU - Labianca, R.

AU - Ionta, M. T.

AU - Bagaloni, I.

AU - Veltri, E.

AU - Sozzi, P.

AU - Barni, S.

AU - Ricci, V.

AU - Foltran, L.

AU - Nicolini, M.

AU - Biondi, E.

AU - Bramati, A.

AU - Turci, D.

AU - Lazzarelli, S.

AU - Verusio, C.

AU - Bergamo, F.

AU - Sobrero, A.

AU - Frontini, L.

AU - Menghi, M.

AU - Magnani, M.

PY - 2017/10/24

Y1 - 2017/10/24

N2 - METHODS: The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg's False Discovery Rate (FDR) procedure was used.RESULTS: FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR<0.0001), *2A rs3918290 A allele carriers (FDR<0.0001), and rs2297595 GG genotype carriers (FDR=0.0014). Neutropenia was the most common FAEs (28.5%). *6 rs1801160 (FDR<0.0001), and *2A rs3918290 (FDR=0.0004) variant alleles were significantly associated with time to neutropenia.CONCLUSIONS: This study adds evidence on the role of DPYD pharmacogenetics for safety of patients undergoing fluoropyrimidine-based chemotherapy.BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% of the administered dose of fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients' risk of fluoropyrimidine-related severe toxicity.

AB - METHODS: The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg's False Discovery Rate (FDR) procedure was used.RESULTS: FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR<0.0001), *2A rs3918290 A allele carriers (FDR<0.0001), and rs2297595 GG genotype carriers (FDR=0.0014). Neutropenia was the most common FAEs (28.5%). *6 rs1801160 (FDR<0.0001), and *2A rs3918290 (FDR=0.0004) variant alleles were significantly associated with time to neutropenia.CONCLUSIONS: This study adds evidence on the role of DPYD pharmacogenetics for safety of patients undergoing fluoropyrimidine-based chemotherapy.BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% of the administered dose of fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients' risk of fluoropyrimidine-related severe toxicity.

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DO - 10.1038/bjc.2017.289

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JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

IS - 9

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