title: DPD and UGT1A1 deficiency in colorectal cancer patients receiving triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan.
abstract: OBJECTIVE
  Triplet chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan is a standard therapy for metastatic colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) in DPYD and UGT1A1 influence fluoropyrimdines and irinotecan adverse events (AEs). Low frequency DPYD variants (c.1905 + 1G > A, c.1679 T > G, c.2846A > T) are validated but more frequent ones (c.496A > G, c.1129-5923C > G and c.1896 T > C) are not. rs895819 T > C polymorphism in hsa-mir-27a is associated with reduced DPD activity. In this study, we evaluated the clinical usefulness of a pharmacogenetic panel for patients receiving triplet combinations.
  
  
  METHODS
  Germline DNA was available from 64 CRC patients enrolled between 2008 and 2013 in two phase II trials of capecitabine, oxaliplatin and irinotecan plus bevacizumab or cetuximab. SNPs were determined by Real-Time PCR. We evaluated the functional variants in DPYD (rare: c.1905 + 1G > A, c.1679 T > G, c.2846A > T; most common: c.496A > G, c.1129-5923C > G, c.1896 T > C), hsa-mir-27a (rs895819) and UGT1A1 (*28) genes to assess their association with grade 3-4 AEs.
  
  
  RESULTS
  None of the patients carried rare DPYD variants. We found DPYD c.496A > G, c.1129-5923C > G, c.1896 T > C in heterozygosity in 19%, 5% and 8%, respectively, homozygous rs895819 in hsa-mir-27a in 9% and homozygous UGT1A1*28 in 8%. Grade 3-4 AEs were observed in 36% patients and were associated with DPYD c.496A > G (odds ratio (OR) 4.93, 95% CI 1.29, 18.87; P = 0.021) and homozygous rs895819 in hsa-mir-27a (OR 11.11, 95% CI 1.21, 102.09; P = 0.020). Carriers of DPYD c.1896 T > C and homozygous UGT1A1*28 showed an OR of 8.42 (95% CI 0.88, 80.56; P = 0.052). Multivariate analysis confirmed an independent value for DPYD c.496A > G and c.1896 T > C.
  
  
  CONCLUSIONS
  Concomitant assessment of DPYD variants and the UGT1A1*28 allele is a promising strategy needing further validation for dose personalization.
authors.affiliation: Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, University Hospital 'Luigi Sacco', Università di Milano, Milan, Italy.
authors.forename: Felicia Stefania
authors.initials: FS
authors.lastname: Falvella
authors.affiliation: Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, University Hospital 'Luigi Sacco', Università di Milano, Milan, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Cheli
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Antonia
authors.initials: A
authors.lastname: Martinetti
authors.affiliation: Department of Biomedical and Clinical Sciences, University Hospital 'Luigi Sacco', Università di Milano, Milan, Italy.|Department of Management, Economics and Industrial Engineering, Politecnico di Milano, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Mazzali
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Iacovelli
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Maggi
authors.affiliation: Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.|FIRC Institute of Molecular Oncology Foundation, Milan, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Gariboldi
authors.affiliation: Scientific Directorate, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Marco Alessandro
authors.initials: MA
authors.lastname: Pierotti
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Di Bartolomeo
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Sottotetti
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Mennitto
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Bossi
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: de Braud
authors.affiliation: Scientific Institute, IRCCS E. Medea, Bosisio Parini, Lecco, Italy.|Unit of Clinical Pharmacology, Department of Biomedical, Clinical Sciences, Consiglio Nazionale delle Ricerche Institute of Neuroscience, University Hospital 'Luigi Sacco', Università di Milano, Milan, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Clementi
authors.affiliation: Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Pietrantonio
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D054067:Dihydropyrimidine Dehydrogenase Deficiency / Q000209:etiology / Q000235:genetics*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D014453:Glucuronosyltransferase / Q000172:deficiency / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D000099148:UGT1A1 Enzyme
chemical_list: D002166:Camptothecin; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil; D014453:Glucuronosyltransferase; D002955:Leucovorin; D035683:MicroRNAs; D009944:Organoplatinum Compounds; D000099148:UGT1A1 Enzyme; C531388:MIRN27 microRNA, human
keywords: colorectal cancer; fluoropyrimidines; irinotecan; pharmacogenetics; single nucleotide polymorphisms