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Title: Fc-gamma receptor polymorphisms, cetuximab therapy, and overall survival in the CCTG CO.20 trial of metastatic colorectal cancer.
Austin Authors: Shepshelovich, Daniel;Townsend, Amanda R;Espin-Garcia, Osvaldo;Latifovic, Lidija;O'Callaghan, Chris J;Jonker, Derek J;Tu, Dongsheng;Chen, Eric;Morgen, Eric;Price, Timothy J;Shapiro, Jeremy;Siu, Lillian L;Kubo, Michiaki;Dobrovic, Alexander ;Ratain, Mark J;Xu, Wei;Mushiroda, Taisei;Liu, Geoffrey
Affiliation: Department of Biostatistics, Princess Margaret Cancer Centre, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
RIKEN Center for Integrative Medical Science, Yokohama, Japan
Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
Medical Oncology, University of Adelaide, Adelaide, South Australia, Australia
Epidemiology Division, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
Medical Oncology, The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada
Canadian Cancer Trials Group (CCTG), Queens University, Kingston, Ontario, Canada
Department of Laboratory Medicine and Pathology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
Department of Medical Oncology, Cabrini Health, Malvern, Victoria, Australia
Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, 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 University of Chicago, Chicago, Illinois
Issue Date: Nov-2018 2018-10-14
Publication information: Cancer medicine 2018; 7(11): 5478-5487
Abstract: Two germ line 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. We previously reported that the FCGR2A H/H genotype was associated with longer overall survival (OS) in cetuximab-treated chemotherapy-refractory patients with metastatic colorectal cancer. Here, we aimed to replicate and extend this finding in the Canadian Clinical Trials Group CO.20 trial. After germ line DNA genotyping, polymorphic relationships with survival were assessed using log-rank tests and hazard ratios (HR) from Cox proportional hazard models, adjusting for known prognostic factors. The dominant genetic inheritance model was used for the main analysis. Of 592 wild-type KRAS patients treated with cetuximab, those with the FCGR2A H/H genotype (n = 165, 28%) had improved OS (HR: 0.66, P < 0.001; median absolute benefit, 1.3 months) compared to those with R/- genotype (n = 427, 72%). Patients with H/R had intermediate results under a codominant genetic inheritance model (HR: 0.72, P = 0.003). No significant associations were found between FCGR3A genotype and OS. In an exploratory analysis, patients with the combination of FCGR2A H/H + FCGR3A F/F genotype had significantly better OS (HR: 0.33, P = 0.003; median absolute benefit, 12.5 months) than patients with the combination of double-variant R/R + V/V genotype. Progression-free survival results were similar to OS. Toxicity rates were not associated with either polymorphism. The FCGR2A genotype was associated with efficacy but not with toxicity in wild-type KRAS, cetuximab-treated colorectal cancer patients. FCGR3A genotype may modulate the relationship between FCGR2A polymorphism and outcome. FCGR2A is a promising biomarker for clinical management for these patients.
DOI: 10.1002/cam4.1819
ORCID: 0000-0003-3414-112X
PubMed URL: 30318772
Type: Journal Article
Subjects: FCGR2A
Appears in Collections:Journal articles

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