Annals of Oncology 25 (Supplement 4): iv167–iv209, 2014
doi:10.1093/annonc/mdu333.35
gastrointestinal tumours, colorectal
PROSPECTIVE OBSERVATIONAL STUDY FOR DPYD AND
UGT1A1 DEFICIENCY-ASSOCIATED TOXICITY IN PATIENTS
WITH METASTATIC COLORECTAL CANCER (MCRC)
RECEIVING TRIPLET CHEMOTHERAPY WITH CAPECITABINE,
IRINOTECAN AND OXALIPLATIN (COI)
Aim: Triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan is a
standard treatment of mCRC, even if toxicity is significantly increased over doublets.
Genetic variations in DPYD and UGT1A1 genes influence fluoropyrimdines and
irinotecan adverse events (AEs), respectively. Low-frequency variants - such as DPYD
c.1905 + 1G > A, c.1679T > G, c.2846A > T and homozygous UGT1A1*28 - are
validated. More common DPYD variants– such as c.496A > G and the deep intronic
variant c.1129-5923C > G–are controversial and not routinely used. Their assessment,
particularly in association with altered UGT1A1 metabolism, may be valuable for
patients receiving intensive triplet combinations.
Methods: From 2008 to 2013, 64 pts enrolled in two phase II trials of COI plus
bevacizumab [EudraCT No. 2008-008749-39] or cetuximab [EudraCT No.
2008-001062-93] - gave written consent at Fondazione IRCCS Istituto Nazionale dei
Tumori. All genotypes were determined by Real-Time PCR, using LightSNiP (Roche).
Inclusion criteria: absence of c.1905 + 1G > A, c.1679T > G, c.2846A > T. We aimed at
genotyping c.496A > G and c.1129-5923C > G and UGT1A1*28 to assess associations
with grade 3-4 chemotherapy-induced AEs (cAEs).
Results: We found heterozygous DPYD 1129-5923C > G and 496A > G variants in 4
(6,3%) and 12 (18,8%) pts (concomitantly only in 1); 32 (50%) pts heterozygous and 5
(7,8%) homozygous for UGT1A1*28; concomitant heterozygosis of DPYD 496A > G
and UGT1A1*28 in 7 (11%). Grade 3-4 cAE observed in 22 pts (35%; diarrhea 28%,
neutropenia 8%, asthenia 3%). Probably due to low frequency, DPYD 1129-5923C > G
was not significantly associated with severe toxicity. Grade 3-4 cAEs were observed in
58% pts with 496A > G polymorphism vs. 29% others ( p = 0.053). As expected, toxicity
was increased in pts with UGT1A1*28/*28 ( p = 0.038). Pts with concomitant
heterozygosis of DPYD 496A > G and UGT1A1*28 had higher incidence of cAEs as
compared to all others (71% vs. 30%; p = 0.029).
Conclusions: Concomitant DPYD 496A > G and UGT1A1*28 assessment is promising
to predict severe toxicity following triplet chemotherapy with COI regimen. A
prospective trial of dose modulation according to our pharmacogenetic panel is
recruiting at our Institution.
Disclosure: All authors have declared no conflicts of interest.
© European Society for Medical Oncology 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
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F.S. Falvella1, S. Cheli1, C. Maggi2, R. Iacovelli2, M. Pierotti3, M. Gariboldi4,
A. Martinetti2, F.G.M. De Braud2, I. Bossi2, M. Di Bartolomeo2, E. Sottotetti2,
F. Ricchini2, E. Clementi1, F. Pietrantonio5
1
Biomedical and Clinical Sciences, L.Sacco Hospital, Milan, ITALY
2
Department of Medical Oncology, Fondazione IRCCS - Istituto Nazionale dei
Tumori, Milan, ITALY
3
Scientific Directorate, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan,
ITALY
4
Department of Experimental Oncology, Fondazione IRCCS - Istituto Nazionale dei
Tumori, Milan, ITALY
5
Division of Oncology, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, ITALY
abstracts
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