title: Predictive model for risk of severe gastrointestinal toxicity following chemotherapy using patient immune genetics and type of cancer: a pilot study.
abstract: OBJECTIVE
  Severe chemotherapy-induced gastrointestinal toxicity (CIGT) is common and results in treatment delays, dose reductions, and potential premature treatment discontinuation. Currently, there is no diagnostic marker to predict CIGT. Proinflammatory cytokines, produced via toll-like receptor signaling, are key mediators of this toxicity. Hence, this pilot study investigated the association between immune genetic variability and severe CIGT risk.
  
  
  METHODS
  Genomic DNA from 34 patients (10 with severe CIGT) who had received 5-fluoruracil-based chemotherapy regimens was analyzed for variants of IL-1B, IL-2, IL-6, IL-6R, IL-10, TNF-a, TGF-b, TLR2, TLR4, MD2, MYD88, BDNF, CRP, ICE, and OPRM1. Multivariate logistic regression created a prediction model of severe CIGT risk.
  
  
  RESULTS
  There were no significant differences between patients with and without severe CIGT with regards to age, sex, type of cancer, or chemotherapy treatment regimens. The prediction model of severe CIGT risk included TLR2 and TNF-a genetic variability and cancer type (colorectal and gastric). This prediction model was both specific and sensitive, with a receiver operator characteristic area under the curve of 87.3 %.
  
  
  CONCLUSIONS
  This is the first report of immune genetic variability, together with cancer type, being predictive of severe CIGT risk. These outcomes are being validated in a larger patient population.
authors.affiliation: Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, Level 5 Medical School North, Frome Road, Adelaide, South Australia, 5005, Australia, janet.coller@adelaide.edu.au.
authors.forename: Janet K
authors.initials: JK
authors.lastname: Coller
authors.forename: Imogen A
authors.initials: IA
authors.lastname: White
authors.forename: Richard M
authors.initials: RM
authors.lastname: Logan
authors.forename: Jonathan
authors.initials: J
authors.lastname: Tuke
authors.forename: Alison M
authors.initials: AM
authors.lastname: Richards
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Mead
authors.forename: Christos S
authors.initials: CS
authors.lastname: Karapetis
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Bowen
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D016207:Cytokines / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects* / Q000627:therapeutic use; D005767:Gastrointestinal Diseases / Q000139:chemically induced* / Q000453:epidemiology* / Q000276:immunology; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000473:pathology; D056426:Genetic Loci; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D009369:Neoplasms / Q000188:drug therapy*; D010865:Pilot Projects; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D012306:Risk; D051195:Toll-Like Receptor 2 / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D016207:Cytokines; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D005472:Fluorouracil