- Email: [email protected]
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)
Annals of Oncology 25 (Supplement 4): iv167–iv209, 2014 doi:10.1093/annonc/mdu333.35
gastrointestinal tumours, colorectal
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 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. All rights reserved. For permissions, please email: [email protected].
Downloaded from https://academic.oup.com/annonc/article-abstract/25/suppl_4/iv181/2241301 by guest on 25 October 2019
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)
abstracts
532P
gastrointestinal tumours, colorectal
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 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. All rights reserved. For permissions, please email: [email protected].
Downloaded from https://academic.oup.com/annonc/article-abstract/25/suppl_4/iv181/2241301 by guest on 25 October 2019
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)
abstracts
532P