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Title: Fc-γ Receptor Polymorphisms, Cetuximab Therapy, and Survival in the NCIC CTG CO.17 Trial of Colorectal Cancer.
Austin Authors: Liu, Geoffrey;Tu, Dongsheng;Lewis, Marcia;Cheng, Dangxiao;Sullivan, Leslie A;Chen, Zhuo;Morgen, Eric;Simes, John;Price, Timothy J;Tebbutt, Niall C ;Shapiro, Jeremy D;Jeffery, G Mark;Mellor, J Daniel;Mikeska, Thomas;Virk, Shakeel;Shepherd, Lois E;Jonker, Derek J;O'Callaghan, Christopher J ;Zalcberg, John R;Karapetis, Christos S;Dobrovic, Alexander 
Affiliation: Princess Margaret Cancer Centre, Toronto, Canada
NCIC Clinical Trials Group and Queen's University, Kingston, Canada
Transgenomic, Inc., Omaha, Nebraska
University of Sydney, Sydney, Australia
The Queen Elizabeth Hospital and University of Adelaide, Adelaide, Australia
Austin Health, Heidelberg, Victoria, Australia
Cabrini Hospital, Monash University, Melbourne, Australia
Canterbury Regional Cancer and Blood Service, Christchurch Hospital, Christchurch, New Zealand
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, Melbourne, Victoria, Australia
The Ottawa Hospital, Ottawa, Canada
Flinders Centre for Innovation in Cancer, Flinders University, Adelaide, Australia
Issue Date: 15-May-2016
Publication information: Clinical Cancer Research 2016; 22(10): 2435-44
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.
DOI: 10.1158/1078-0432.CCR-15-0414
PubMed URL: 27179112
ISSN: 1078-0432
Type: Journal Article
Appears in Collections:Journal articles

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