532P - Prospective observational study for DPYD and UGT1A1 deficiency-associated toxicity in patients with metastatic colorectal cancer (mCRC) receiving t...

Date 29 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anti-Cancer Agents & Biologic Therapy
Complications of Treatment
Colon Cancer
Rectal Cancer
Presenter felicia Falvella
Citation Annals of Oncology (2014) 25 (suppl_4): iv167-iv209. 10.1093/annonc/mdu333
Authors 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
  • 1Biomedical And Clinical Sciences, L.Sacco hospital, 20100 - milan/IT
  • 2Department Of Medical Oncology, Fondazione IRCCS - Istituto Nazionale dei Tumori, 20133 - Milano/IT
  • 3Scientific Directorate, Fondazione IRCCS - Istituto Nazionale dei Tumori, IT-20133 - Milano/IT
  • 4Department Of Experimental Oncology, Fondazione IRCCS - Istituto Nazionale dei Tumori, 20133 - Milano/IT
  • 5Division Of Oncology, Fondazione IRCCS - Istituto Nazionale dei Tumori, 20133 - Milano/IT

Abstract

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.