Fc gamma receptor polymorphisms as predictive markers of Cetuximab efficacy in epidermal growth factor receptor downstream-mutated metastatic colorectal cancer

Rodríguez, Javier; Zarate, Ruth; Bandres, Eva; Boni, Valentina; Hernández, Amaia; Sola, Jesus Javier; Honorato, Beatriz; Bitarte, Nerea; García-Foncillas, Jesus

doi:10.1016/j.ejca.2012.01.007

« BackEuropean Journal of Cancer

Article in Press

Fc gamma receptor polymorphisms as predictive markers of Cetuximab efficacy in epidermal growth factor receptor downstream-mutated metastatic colorectal cancer

Javier Rodríguez
- Unit for the Research and Treatment of Gastrointestinal Malignancies, Department of Medical Oncology, University Clinic of Navarra (CUN), Pamplona-Navarra, Spain
- These authors contributed equally to this work.
Ruth Zarate
- Laboratory of Pharmacogenomics, Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona-Navarra, Spain
- Corresponding author: Address: Laboratory of Pharmacogenomics, Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Avda Pio XII 55, 31008-Pamplona, Spain. Tel.: +34 948 255400; fax: +34 948 296795.
- These authors contributed equally to this work.
Eva Bandres
- Laboratory of Pharmacogenomics, Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona-Navarra, Spain
Valentina Boni
- Unit for the Research and Treatment of Gastrointestinal Malignancies, Department of Medical Oncology, University Clinic of Navarra (CUN), Pamplona-Navarra, Spain
Amaia Hernández
- Unit for the Research and Treatment of Gastrointestinal Malignancies, Department of Medical Oncology, University Clinic of Navarra (CUN), Pamplona-Navarra, Spain
Jesus Javier Sola
- Department of Pathology, University Clinic of Navarra (CUN), Pamplona-Navarra, Spain
Beatriz Honorato
- Laboratory of Pharmacogenomics, Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona-Navarra, Spain
Nerea Bitarte
- Laboratory of Pharmacogenomics, Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona-Navarra, Spain
Jesus García-Foncillas
- Unit for the Research and Treatment of Gastrointestinal Malignancies, Department of Medical Oncology, University Clinic of Navarra (CUN), Pamplona-Navarra, Spain
- Laboratory of Pharmacogenomics, Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona-Navarra, Spain

published online 06 February 2012.
Corrected Proof

Abstract

Background

The immunoglobulin G1 (IgG₁) monoclonal antibody (MoAb) Cetuximab is active in metastatic colorectal cancer (mCRC) as first or subsequent lines of therapy. Efficacy seems restricted to KRAS wild-type tumours. IgG₁ may also induce antibody dependent cell mediated citotoxicity (ADCC) by recruitment of immune effector cells. ADCC is influenced by Fc gamma receptor (FcγR) polymorphisms. We investigated the association of FcγR polymorphisms and disease control rate (DCR) in mCRC patients treated with chemotherapy plus Cetuximab.

Patients and methods

Tumour tissues from 106 patients were screened for KRAS codon 12 and 13 mutations using a sensitive multiplex assay (DxS, Manchester, United Kingdom). NRAS (codons: 12, 13 and 61), PI3K (exon 20) and BRAF (exon 15) were analysed by direct sequencing. Fcγ RIIa and Fcγ RIIIa polymorphisms were genotyped by TaqMan assays.

Results

DCR was significantly higher in KRAS wild-type tumours (61% versus 39%, p=0.049). In epidermal growth factor receptor (EGFR) downstream-mutated mCRC patients, those harbouring an FcγRIIa H/H genotype had a higher DCR than alternative genotypes (67% versus 33%, p=0.017). By multivariate analysis, FcγRIIa-131H/H remained significantly correlated with DCR (p=0.008).

Conclusion

FcγR polymorphisms may play a role in the clinical efficacy of Cetuximab in EGFR downstream mutated mCRC patients. Further research into Cetuximab immune-based mechanisms in KRAS-mutated patients seems warranted.

Keywords: Colorectal cancer, Cetuximab, EGFR, FcγR polymorphisms, KRAS