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Clinical Trial
. 2017 Oct 24;117(9):1269-1277.
doi: 10.1038/bjc.2017.289. Epub 2017 Aug 24.

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

A Ruzzo  1 , F Graziano  2 , Fabio Galli  3 , Francesca Galli  3 , E Rulli  3 , S Lonardi  4 , M Ronzoni  5 , B Massidda  6 , V Zagonel  4 , N Pella  7 , C Mucciarini  8 , R Labianca  9 , M T Ionta  6 , I Bagaloni  1 , E Veltri  10 , P Sozzi  11 , S Barni  12 , V Ricci  5 , L Foltran  13 , M Nicolini  14 , E Biondi  15 , A Bramati  16 , D Turci  17 , S Lazzarelli  18 , C Verusio  19 , F Bergamo  4 , A Sobrero  20 , L Frontini  21 , M Menghi  22 , M Magnani  1
Affiliations
Clinical Trial

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

A Ruzzo et al. Br J Cancer. .

Abstract

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.

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.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Kaplan-Meier curves. (A) TTT curves of the *6 rs1801160 minor A allele carriers (merged heterozygous plus homozygous minor allele carriers) and homozygous GG genotype carriers. (B) TTT curves of the rs2297595 minor G allele carriers (merged heterozygous plus homozygous minor allele carriers) and homozygous AA genotype carrier.
See this image and copyright information in PMC

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