Fc-gamma receptor polymorphisms, cetuximab therapy, and overall survival in the CCTG CO.20 trial of metastatic colorectal cancer

Daniel Shepshelovich, Amanda R. Townsend, Osvaldo Espin-Garcia, Lidija Latifovic, Chris J. O’Callaghan, Derek J. Jonker, Dongsheng Tu, Eric Chen, Eric Morgen, Timothy J. Price, Jeremy Shapiro, Lillian L. Siu, Michiaki Kubo, Alexander Dobrovic, Mark J. Ratain, Wei Xu, Taisei Mushiroda, Geoffrey Liu

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish
Pages (from-to)5478-5487
Number of pages10
JournalCancer Medicine
Volume7
Issue number11
DOIs
Publication statusPublished - 11-2018

All Science Journal Classification (ASJC) codes

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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