PMID- 25782327
OWN - NLM
STAT- MEDLINE
DCOM- 20160603
LR  - 20220408
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Print)
IS  - 0306-5251 (Linking)
VI  - 80
IP  - 3
DP  - 2015 Sep
TI  - DPD and UGT1A1 deficiency in colorectal cancer patients receiving triplet 
      chemotherapy with fluoropyrimidines, oxaliplatin and irinotecan.
PG  - 581-8
LID - 10.1111/bcp.12631 [doi]
AB  - AIMS: 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.
CI  - (c) 2015 The British Pharmacological Society.
FAU - Falvella, Felicia Stefania
AU  - Falvella FS
AD  - Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, 
      University Hospital 'Luigi Sacco', Universita di Milano, Milan, Italy.
FAU - Cheli, Stefania
AU  - Cheli S
AD  - Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, 
      University Hospital 'Luigi Sacco', Universita di Milano, Milan, Italy.
FAU - Martinetti, Antonia
AU  - Martinetti A
AD  - Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 
      Milan, Italy.
FAU - Mazzali, Cristina
AU  - Mazzali C
AD  - Department of Biomedical and Clinical Sciences, University Hospital 'Luigi 
      Sacco', Universita di Milano, Milan, Italy.
AD  - Department of Management, Economics and Industrial Engineering, Politecnico di 
      Milano, Milan, Italy.
FAU - Iacovelli, Roberto
AU  - Iacovelli R
AD  - Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 
      Milan, Italy.
FAU - Maggi, Claudia
AU  - Maggi C
AD  - Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 
      Milan, Italy.
FAU - Gariboldi, Manuela
AU  - Gariboldi M
AD  - Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS 
      Istituto Nazionale dei Tumori, Milan, Italy.
AD  - FIRC Institute of Molecular Oncology Foundation, Milan, Italy.
FAU - Pierotti, Marco Alessandro
AU  - Pierotti MA
AD  - Scientific Directorate, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, 
      Italy.
FAU - Di Bartolomeo, Maria
AU  - Di Bartolomeo M
AD  - Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 
      Milan, Italy.
FAU - Sottotetti, Elisa
AU  - Sottotetti E
AD  - Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 
      Milan, Italy.
FAU - Mennitto, Roberta
AU  - Mennitto R
AD  - Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 
      Milan, Italy.
FAU - Bossi, Ilaria
AU  - Bossi I
AD  - Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 
      Milan, Italy.
FAU - de Braud, Filippo
AU  - de Braud F
AD  - Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 
      Milan, Italy.
FAU - Clementi, Emilio
AU  - Clementi E
AD  - Scientific Institute, IRCCS E. Medea, Bosisio Parini, Lecco, Italy.
AD  - Unit of Clinical Pharmacology, Department of Biomedical, Clinical Sciences, 
      Consiglio Nazionale delle Ricerche Institute of Neuroscience, University Hospital 
      'Luigi Sacco', Universita di Milano, Milan, Italy.
FAU - Pietrantonio, Filippo
AU  - Pietrantonio F
AD  - Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, 
      Milan, Italy.
LA  - eng
PT  - Journal Article
PT  - Observational Study
DEP - 20150622
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - 0 (MIRN27 microRNA, human)
RN  - 0 (MicroRNAs)
RN  - 0 (Organoplatinum Compounds)
RN  - EC 1.3.1.2 (Dihydrouracil Dehydrogenase (NADP))
RN  - EC 2.4.1.- (UGT1A1 enzyme)
RN  - EC 2.4.1.17 (Glucuronosyltransferase)
RN  - Q573I9DVLP (Leucovorin)
RN  - U3P01618RT (Fluorouracil)
RN  - XT3Z54Z28A (Camptothecin)
RN  - FOLFOXIRI protocol
SB  - IM
MH  - Adult
MH  - Aged
MH  - Antineoplastic Combined Chemotherapy Protocols/administration & dosage/*adverse 
      effects/therapeutic use
MH  - Camptothecin/administration & dosage/adverse effects/*analogs & 
      derivatives/therapeutic use
MH  - Colorectal Neoplasms/*drug therapy/genetics
MH  - Dihydropyrimidine Dehydrogenase Deficiency/etiology/*genetics
MH  - Dihydrouracil Dehydrogenase (NADP)/*genetics
MH  - Female
MH  - Fluorouracil/administration & dosage/adverse effects/therapeutic use
MH  - Glucuronosyltransferase/deficiency/*genetics
MH  - Heterozygote
MH  - Homozygote
MH  - Humans
MH  - Leucovorin/administration & dosage/adverse effects/therapeutic use
MH  - Male
MH  - MicroRNAs/genetics
MH  - Middle Aged
MH  - Organoplatinum Compounds/administration & dosage/adverse effects/therapeutic use
MH  - *Polymorphism, Single Nucleotide
MH  - Prospective Studies
PMC - PMC4574842
OTO - NOTNLM
OT  - colorectal cancer
OT  - fluoropyrimidines
OT  - irinotecan
OT  - pharmacogenetics
OT  - single nucleotide polymorphisms
EDAT- 2015/03/19 06:00
MHDA- 2016/06/04 06:00
PMCR- 2016/09/01
CRDT- 2015/03/19 06:00
PHST- 2014/12/03 00:00 [received]
PHST- 2015/03/10 00:00 [revised]
PHST- 2015/03/13 00:00 [accepted]
PHST- 2015/03/19 06:00 [entrez]
PHST- 2015/03/19 06:00 [pubmed]
PHST- 2016/06/04 06:00 [medline]
PHST- 2016/09/01 00:00 [pmc-release]
AID - 10.1111/bcp.12631 [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 2015 Sep;80(3):581-8. doi: 10.1111/bcp.12631. Epub 2015 Jun 
      22.