title: Genetic markers of toxicity from capecitabine and other fluorouracil-based regimens: investigation in the QUASAR2 study, systematic review, and meta-analysis.
abstract: OBJECTIVE
  Fluourouracil (FU) is a mainstay of chemotherapy, although toxicities are common. Genetic biomarkers have been used to predict these adverse events, but their utility is uncertain.
  
  
  METHODS
  We tested candidate polymorphisms identified from a systematic literature search for associations with capecitabine toxicity in 927 patients with colorectal cancer in the Quick and Simple and Reliable trial (QUASAR2). We then performed meta-analysis of QUASAR2 and 16 published studies (n = 4,855 patients) to examine the polymorphisms in various FU monotherapy and combination therapy regimens.
  
  
  RESULTS
  Global capecitabine toxicity (grades 0/1/2 v grades 3/4/5) was associated with the rare, functional DPYD alleles 2846T>A and *2A (combined odds ratio, 5.51; P = .0013) and with the common TYMS polymorphisms 5'VNTR2R/3R and 3'UTR 6bp ins-del (combined odds ratio, 1.31; P = 9.4 × 10(-6)). There was weaker evidence that these polymorphisms predict toxicity from bolus and infusional FU monotherapy. No good evidence of association with toxicity was found for the remaining polymorphisms, including several currently included in predictive kits. No polymorphisms were associated with toxicity in combination regimens.
  
  
  CONCLUSIONS
  A panel of genetic biomarkers for capecitabine monotherapy toxicity would currently comprise only the four DPYD and TYMS variants above. We estimate this test could provide 26% sensitivity, 86% specificity, and 49% positive predictive value-better than most available commercial kits, but suboptimal for clinical use. The test panel might be extended to include additional, rare DPYD variants functionally equivalent to *2A and 2846A, though insufficient evidence supports its use in bolus, infusional, or combination FU. There remains a need to identify further markers of FU toxicity for all regimens.
authors.affiliation: Dan Rosmarin, Claire Palles, David Church, Enric Domingo, Angela Jones, Ian Tomlinson, Wellcome Trust Centre for Human Genetics, NIHR Comprehensive Biomedical Research Centre, University of Oxford; Dan Rosmarin, David Church, Elaine Johnstone, Haitao Wang, Sharon Love, Patrick Julier, Claire Scudder, George Nicholson, Rachel Midgley, David Kerr, and George Nicholson, University of Oxford, Oxford; Michael Braun, The Christie NHS Foundation Trust, Manchester; Matthew Seymour, St James's University Hospital, Leeds; Lindsay Thompson, Medical Research Council Clinical Trials Unit; Rohini Sharma, Imperial College Healthcare NHS Trust, Hammersmith and Charing Cross Hospitals, London, United Kingdom; Anna Gonzalez-Neira, Spanish National Cancer Research Centre; Miguel Martin, Instituto de Investigacion Sanitaria Hospital General Universitario Gregorio Marañón, Universidad Complutense, Madrid; Nuria Ribelles, Hospital Universitario Virgen de la Victoria, Málaga; Eva Martinez-Balibrea, Institut Català d'Oncologia, Institut de Recerca Sanitària Germans Trias i Pujol, Barcelona; Jesus Garcia-Foncillas, University Clinic of Navarra, University of Navarra, Pamplona, Spain; Daniel Sargent, Erin Green, Mayo Clinic, Rochester, MN; Howard McLeod, University of North Carolina, Chapel Hill, NC; Ulrich M. Zanger, Matthias Schwab, Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart; Ulrich M. Zanger, Matthias Schwab, University Hospital Tuebingenl, Tuebingen, Germany; Benjamin Lacas, Valérie Boige, Jean-Pierre Pignon, Institut Gustave Roussy, Villejuif; Marie-Christine Etienne-Grimaldi, Gérard Milano, Centre Antoine Lacassagne, Nice; Thierry Lecomte, Pierre Laurent-Puig, Assistance Publique Hopitaux de Paris, Hopital Européen Georges Pompidou, Paris; Alain Morel, Institut National de la Sante et de la Recherche Medicale U564, Centre Paul Papin, Angers, France; Shoaib Afzal, Henrik Enghusen, Laboratory of Clinical Pharmacology, Rigshospitalet, Copenhagen; Sør
authors.forename: Dan
authors.initials: D
authors.lastname: Rosmarin
authors.forename: Claire
authors.initials: C
authors.lastname: Palles
authors.forename: David
authors.initials: D
authors.lastname: Church
authors.forename: Enric
authors.initials: E
authors.lastname: Domingo
authors.forename: Angela
authors.initials: A
authors.lastname: Jones
authors.forename: Elaine
authors.initials: E
authors.lastname: Johnstone
authors.forename: Haitao
authors.initials: H
authors.lastname: Wang
authors.forename: Sharon
authors.initials: S
authors.lastname: Love
authors.forename: Patrick
authors.initials: P
authors.lastname: Julier
authors.forename: Claire
authors.initials: C
authors.lastname: Scudder
authors.forename: George
authors.initials: G
authors.lastname: Nicholson
authors.forename: Anna
authors.initials: A
authors.lastname: Gonzalez-Neira
authors.forename: Miguel
authors.initials: M
authors.lastname: Martin
authors.forename: Daniel
authors.initials: D
authors.lastname: Sargent
authors.forename: Erin
authors.initials: E
authors.lastname: Green
authors.forename: Howard
authors.initials: H
authors.lastname: McLeod
authors.forename: Ulrich M
authors.initials: UM
authors.lastname: Zanger
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.forename: Michael
authors.initials: M
authors.lastname: Braun
authors.forename: Matthew
authors.initials: M
authors.lastname: Seymour
authors.forename: Lindsay
authors.initials: L
authors.lastname: Thompson
authors.forename: Benjamin
authors.initials: B
authors.lastname: Lacas
authors.forename: Valérie
authors.initials: V
authors.lastname: Boige
authors.forename: Nuria
authors.initials: N
authors.lastname: Ribelles
authors.forename: Shoaib
authors.initials: S
authors.lastname: Afzal
authors.forename: Henrik
authors.initials: H
authors.lastname: Enghusen
authors.forename: Søren Astrup
authors.initials: SA
authors.lastname: Jensen
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Etienne-Grimaldi
authors.forename: Gérard
authors.initials: G
authors.lastname: Milano
authors.forename: Mia
authors.initials: M
authors.lastname: Wadelius
authors.forename: Bengt
authors.initials: B
authors.lastname: Glimelius
authors.forename: Hans
authors.initials: H
authors.lastname: Garmo
authors.forename: Milena
authors.initials: M
authors.lastname: Gusella
authors.forename: Thierry
authors.initials: T
authors.lastname: Lecomte
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
authors.forename: Eva
authors.initials: E
authors.lastname: Martinez-Balibrea
authors.forename: Rohini
authors.initials: R
authors.lastname: Sharma
authors.forename: Jesus
authors.initials: J
authors.lastname: Garcia-Foncillas
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Kleibl
authors.forename: Alain
authors.initials: A
authors.lastname: Morel
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Pignon
authors.forename: Rachel
authors.initials: R
authors.lastname: Midgley
authors.forename: David
authors.initials: D
authors.lastname: Kerr
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D000069287:Capecitabine; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives*; D005819:Genetic Markers; D006801:Humans; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D013940:Thymidylate Synthase / Q000235:genetics*
chemical_list: D005819:Genetic Markers; D003841:Deoxycytidine; D000069287:Capecitabine; D042943:Dihydrouracil Dehydrogenase (NADP); D013940:Thymidylate Synthase; D005472:Fluorouracil