title: Fc-γ Receptor Polymorphisms, Cetuximab Therapy, and Survival in the NCIC CTG CO.17 Trial of Colorectal Cancer.
abstract: Two germline Fc-γ receptor (FCGR) polymorphisms, rs1801274 [FCGR2A;His(H)131Arg(R)] and rs396991 [FCGR3A;Phe(F)158Val(V)] produce altered proteins through amino acid substitutions; both are reported to be associated with cetuximab-related outcomes. We performed a validation of these polymorphisms in NCIC CTG CO.17, a randomized trial of cetuximab monotherapy in refractory, metastatic colorectal cancer expressing EGFR.
  
  
  
  DNA extracted from formalin-fixed paraffin-embedded tissue was genotyped. In addition to log-rank tests, Cox proportional hazard models assessed their relationships with overall (OS) and progression-free survival (PFS), adjusting for clinically important prognostic factors, along with a polymorphism-treatment arm interaction term.
  
  
  
  Somatic KRAS status was wild-type for exon 2 in 153 (52%) of 293 patients, from whom tumor DNA was available. For FCGR2A H/H, a genotype-treatment interaction for KRAS wild-type patients was observed for OS (P = 0.03). In KRAS wild-type patients carrying FCGR2A H/H, cetuximab (vs. no cetuximab) improved survival substantially, with adjusted HRs (aHR) of 0.36 (OS) and 0.19 (PFS) and absolute benefits of 5.5 months (OS; P = 0.003) and 3.7 months (PFS; P = 0.02). In contrast, patients carrying FCGR2A R alleles (H/R or R/R) had aHRs of only 0.78 (OS; 2.8-month benefit) and 0.53 (PFS; 1.6-month benefit). No relationships were found for rs396991 (FCGR3A).
  
  
  
  In the CO.17 trial, cetuximab worked best for patients with KRAS wild-type colorectal cancers carrying FCGR2A H/H genotypes. Significantly lower benefits were observed in patients carrying germline FCGR2A R alleles. Clin Cancer Res; 22(10); 2435-44. ©2016 AACR.
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Canada. geoffrey.liu@uhn.on.ca.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Liu
authors.affiliation: NCIC Clinical Trials Group and Queen's University, Kingston, Canada.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Tu
authors.affiliation: Transgenomic, Inc., Omaha, Nebraska.
authors.forename: Marcia
authors.initials: M
authors.lastname: Lewis
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Canada.
authors.forename: Dangxiao
authors.initials: D
authors.lastname: Cheng
authors.affiliation: Transgenomic, Inc., Omaha, Nebraska.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Sullivan
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Canada.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Morgen
authors.affiliation: University of Sydney, Sydney, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Simes
authors.affiliation: The Queen Elizabeth Hospital and University of Adelaide, Adelaide, Australia.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Price
authors.affiliation: Austin Health, Melbourne, Australia.
authors.forename: Niall C
authors.initials: NC
authors.lastname: Tebbutt
authors.affiliation: Cabrini Hospital, Monash University, Melbourne, Australia.
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Shapiro
authors.affiliation: Canterbury Regional Cancer and Blood Service, Christchurch Hospital, Christchurch, New Zealand.
authors.forename: G Mark
authors.initials: GM
authors.lastname: Jeffery
authors.affiliation: Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Australia.
authors.forename: J Daniel
authors.initials: JD
authors.lastname: Mellor
authors.affiliation: Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Australia. Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia. School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mikeska
authors.affiliation: NCIC Clinical Trials Group and Queen's University, Kingston, Canada.
authors.forename: Shakeel
authors.initials: S
authors.lastname: Virk
authors.affiliation: NCIC Clinical Trials Group and Queen's University, Kingston, Canada.
authors.forename: Lois E
authors.initials: LE
authors.lastname: Shepherd
authors.affiliation: The Ottawa Hospital, Ottawa, Canada.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Jonker
authors.affiliation: NCIC Clinical Trials Group and Queen's University, Kingston, Canada.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Callaghan
authors.affiliation: Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Australia.
authors.forename: John R
authors.initials: JR
authors.lastname: Zalcberg
authors.affiliation: Flinders Centre for Innovation in Cancer, Flinders University, Adelaide, Australia.
authors.forename: Christos S
authors.initials: CS
authors.lastname: Karapetis
authors.affiliation: Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Australia. Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia. School of Cancer Medicine, La Trobe University, Bundoora, Victoria, Australia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dobrovic
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000074322:Antineoplastic Agents, Immunological / Q000627:therapeutic use*; D000068818:Cetuximab / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D017452:Receptors, IgG / Q000235:genetics*; D012189:Retrospective Studies; D018631:ras Proteins / Q000235:genetics
chemical_list: D000074322:Antineoplastic Agents, Immunological; C445323:FCGR2A protein, human; C496124:FCGR3A protein, human; D017452:Receptors, IgG; D066246:ErbB Receptors; D018631:ras Proteins; D000068818:Cetuximab