228P - Pattern of dihydropyrimidine dehydrogenase genetic variants in patients with various degrees of tolerability of fluoropyrimidine treatment

Date 28 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anti-Cancer Agents & Biologic Therapy
Complications of Treatment
Presenter Marzia Del Re
Citation Annals of Oncology (2014) 25 (suppl_4): iv58-iv84. 10.1093/annonc/mdu326
Authors M. Del Re1, F. Pietrantonio2, M. Palombi1, S. Sameen3, F. Loupakis4, C. Barbara5, T. Latiano6, P. Ulivi7, E. Zafarana8, A. Passardi9, E. Maiello10, A. Brandes11, F. Cappuzzo12, S. Siena13, F.G.M. De Braud14, A. Falcone4, R. Labianca15, C. Zamagni16, C. Pinto17, R. Danesi1
  • 1Clinical And Experimental Medicine, University of Pisa, 56126 - Pisa/IT
  • 2Oncologia Medica 1, IRCCS Fondazione Istituto Nazionale dei Tumori, Milan/IT
  • 3Bioinformatic, University of Pisa, Pisa/IT
  • 4U.o. Oncologia Medica 2 Universitaria, Azienda Ospedaliero Universitaria S.Chiara, 56100 - Pisa/IT
  • 5Ospedale Civile Livorno, Livorno, U.O. Oncologia Medica, Livorno/IT
  • 6Medical Oncology Unit, IRCCS, Casa Sollievo della Sofferenza, San Giovanni Rotondo/IT
  • 7Thoracic Oncology, Istituto Romagnolo per lo Studio dei Tumori, 47014 - MELDOLA/IT
  • 8Medical Oncology Unit, Hospital of Prato, IT-59100 - PRATO/IT
  • 9Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), 47014 - Meldola/IT
  • 10Medical Oncology, Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG)/IT
  • 11Dept. Medical Oncology, Bellaria-Maggiore Hospital, Azienda USL - IRCCS Institute of Neurological Sciences, 40139 - Bologna/IT
  • 12U.o. Oncologia Medica, Istituto Toscano Tumori-Ospedale Civile-Livorno-Italy, 56100 - Pisa/IT
  • 13Struttura Complessa Di Oncologia Falck, A.O. Ospedale Niguarda Ca' Granda, Milano/IT
  • 14Division Of Oncology, Fondazione IRCCS - Istituto Nazionale dei Tumori, 20133 - Milano/IT
  • 15Director, Cancer Center, Azienda Ospedaliera Papa Giovanni XXIII, 24127 - Bergamo/IT
  • 16Breast & Gynaecological Medical Oncology Unit, S. Orsola-Malpighi Hospital, 40138 - Bologna/IT
  • 17Medical Oncology, Policlinico S.Orsola Malpighi, Bologna/IT

Abstract

Aim

The metabolic clearance of fluoropyrimidines is highly dependent on the rate-limiting enzyme dihydropyrimidine dehydrogenase (DPD). Deficiency of DPD is associated with drug accumulation and severe toxicities. The DPD gene (DPYD) is highly polymorphic; however, with the exception of the mutation in the splicing consensus sequence of intron 14 (IVS14 + 1G > A) and the c.2846A > T, which are responsible of severe impairment of enzyme activity, the association of other variants with adverse reactions is unclear. Therefore, this study was aimed at examining the prevalence of DPYD variants in patients with toxicities and in subjects with good tolerability to fluoropyrimidine-based regimens.

Methods

Patients affected by colorectal, breast and head/neck cancers to be given 5-FU or capecitabine in combination with cytotoxic agents (irinotecan, oxaliplatin, cyclophosphamide or methotrexate) and/or antibodies (cetuximab or bevacizumab) were enrolled; 700 subjects suffered from grade ≥2 non-hematological and ≥3 hematological toxicities (CTCAE v. 4) and 161 control patients developed adverse events to an extent not requiring dose-delay or reduction (i.e., <2 non-hematological and <3 hematological toxicities). DNA was extracted from blood and used to screen patients for known DPD variants (496A>G, 1601G > A, 1627A > G, 1896T > C, IVS14 + 1G > A, 2194G > A and 2846T > C) by automatic sequencing. The study was approved by the local Ethics Committee.

Results

A complex pattern of DPYD variants was identified in both cohorts. The following heterozygous or homozygous mutant genotypes were detected in patients with severe toxicities vs. controls: 496AG + GG: 16.94% vs 16.7%; 1601GA + AA: 12.5 vs 5.6%; 1627AG + GG: 37.1 vs 39.8%; 1896TC + TT: 6.25 vs 4%; IVS14 + 1GA + AA: 5.6 vs 0%; 2194GA + AA: 25.9 vs 14.9; 2846AT + TT: 1.7 vs 0%, suggesting that only IVS14 + 1GA and 2846AT are strong predictors of severe toxicities.

Conclusions

Although there was a higher prevalence of DPYD variants in patients with severe toxicities, their presence also in subjects with good tolerability suggest that their role needs to be re-evaluated in pre- or post-treatment screening programs to prevent or identify the cause of toxicities. The only exceptions were IVS14 + 1GA and 2846AT variants, which were found only in patients with severe toxicities. Supported a grant from AIRC and ITT to R. Danesi.

Disclosure

All authors have declared no conflicts of interest.