FCGR2A and FCGR3A polymorphisms and clinical outcome in metastatic colorectal cancer patients treated with first-line 5-fluorouracil/folinic acid and oxaliplatin +/- cetuximab.

Janne B Kjersem,Christian Kersten,Astrid M Dalsgaard,Elin H Kure,Tone Fokstuen,Kjell M Tveit,Tone Ikdahl,Mette K Yilmaz,Eva Skovlund,Tormod Guren

doi:10.1186/1471-2407-14-340

Abstract

BackgroundPolymorphisms of genes encoding the Fcy receptors (Fc fragment of IgG receptor 2A (FCGR2A) and 3A (FCGR3A)), which influence their affinity for the Fc fragment, have been linked to the pharmacodynamics of monoclonal antibodies. Most studies have been limited by small samples sizes and have reported inconsistent associations between the FCGR2A and the FCGR3A polymorphisms and clinical outcome in metastatic colorectal cancer (mCRC) patients treated with cetuximab. We investigated the association of these polymorphisms and clinical outcome in a large cohort of mCRC patients treated with first-line 5-fluorouracil/folinic acid and oxaliplatin (Nordic FLOX) +/- cetuximab in the NORDIC-VII study (NCT00145314).Methods504 and 497 mCRC patients were evaluable for the FCGR2A and FCGR3A genotyping, respectively. Genotyping was performed on TaqMan ABI HT 7900 (Applied Biosystems, Foster City, CA, USA) with pre-designed SNP genotyping assays for FCGR2A (rs1801274) and FCGR3A (rs396991).ResultsThe response rate for patients with the FCGR2A R/R genotype was significantly increased when cetuximab was added to Nordic FLOX (31% versus 53%, interaction P = 0.03), but was not significantly different compared to the response rate of patients with the FCGR2A H/H or H/R genotypes given the same treatment. A larger increase in response rate with the addition of cetuximab to Nordic FLOX in patients with KRAS mutated tumors and the FCGR2A R/R genotype was observed (19% versus 50%, interaction P = 0.04). None of the FCGR3A polymorphisms were associated with altered response when cetuximab was added to Nordic FLOX (interaction P = 0.63). Neither of the FCGR polymorphisms showed any significant associations with progression-free survival or overall survival.ConclusionPatients with KRAS mutated tumors and the FCGR2A R/R polymorphism responded poorly when treated with chemotherapy only, and experienced the most benefit of the addition of cetuximab in terms of response rate.

Highlights

Polymorphisms of genes encoding the Fcy receptors (Fc fragment of immunoglobulin G (IgG) receptor 2A (FCGR2A) and 3A (FCGR3A)), which influence their affinity for the Fc fragment, have been linked to the pharmacodynamics of monoclonal antibodies
Predictive analyses for benefit of cetuximab treatment The FCGR2A R/R genotype was associated with increased response rate when cetuximab was added to Nordic FLOX regardless of mutational status (31% in arm A versus 53% in arms B + C, interaction P = 0.03), but was not significantly different compared to the response rate of patients with the FCGR2A H/H or H/R genotypes given the same treatment, Table 3 and Figure 1
None of the FCGR3A polymorphisms were associated with altered response when cetuximab was added to Nordic FLOX, Table 3

Summary

Introduction

Polymorphisms of genes encoding the Fcy receptors (Fc fragment of IgG receptor 2A (FCGR2A) and 3A (FCGR3A)), which influence their affinity for the Fc fragment, have been linked to the pharmacodynamics of monoclonal antibodies. Most studies have been limited by small samples sizes and have reported inconsistent associations between the FCGR2A and the FCGR3A polymorphisms and clinical outcome in metastatic colorectal cancer (mCRC) patients treated with cetuximab. We investigated the association of these polymorphisms and clinical outcome in a large cohort of mCRC patients treated with first-line 5-fluorouracil/folinic acid and oxaliplatin (Nordic FLOX) +/- cetuximab in the NORDIC-VII study (NCT00145314). In the recent NORDIC-VII study, we did not find an improved outcome of adding cetuximab to first-line oxaliplatin-based chemotherapy in patients with KRAS wild-type tumors [5]. Similar results were found by the COIN trial and the recent EPOC study [6,7] The results of these trials demonstrate the necessity to explore predictive markers independent of KRAS status to avoid unnecessary drug toxicity and reduce treatment cost

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