Publications & Reports

Fc-gamma Receptor Polymorphisms, Cetuximab Therapy, and Survival in the NCIC CTG CO.17 Trial of Colorectal Cancer.

Geoffrey Liu, Dongsheng Tu, Marcia Lewis, Dangxiao Cheng, Leslie A Sullivan, Zhuo Chen, Eric Morgen, John Simes, Timothy J Price, Niall C Tebbutt, Jeremy D Shapiro, G Mark Jeffery, J Daniel Mellor, Thomas Mikeska, Shakeel Virk, Lois E Shepherd, Derek J Jonker, Christopher J O'Callaghan, John R Zalcberg, Christos S Karapetis, Alexander Dobrovic
Princess Margaret Cancer Centre, Toronto, Canada. [email protected]

Abstract

PURPOSE: Two germline Fc-gamma receptor (FCGR) polymorphisms, rs1801274 [FCGR2A;His(H)131Arg®] 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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). CONCLUSIONS: 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.

Publication

  • Journal: Clinical Cancer Research
  • Published: 15/05/2016
  • Volume: 22
  • Issue: 10
  • Pagination: 2435-2444

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