Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

The influence of FCGR2A and FCGR3A polymorphisms on the survival of patients with recurrent or metastatic squamous cell head and neck cancer treated with cetuximab

A Correction to this article was published on 18 January 2019

This article has been updated

Abstract

FCGR2A-H131R and FCGR3A-V157F are single-nucleotide polymorphisms known to influence the outcome of patients treated with rituximab, cetuximab and trastuzumab. We investigated the impact of these polymorphisms on the clinical outcome of 103 patients with recurrent or metastatic squamous cell carcinoma of the head and neck treated with a platinum compound, fluorouracil and cetuximab as palliative first-line therapy. The survival of patients with FCGR2A-131H/H and/or FCGR3A-157V/V genotypes was significantly longer compared with patients carrying 131R and 157F alleles (median progression-free survival (PFS): 5.5 vs 4.1 months, P=0.02; median overall survival: 10.2 vs 7.2 months, P=0.04). In multivariate analysis, the FCGR2A and 3A genotypes as well as the time between initial diagnosis and relapse of disease not amenable to curative therapy remained the only independent prognostic factors for PFS. The results are in line with previous reports in colorectal cancer patients and confirm the possible value of genetic polymorphisms of immunocompetent cells for the success of cetuximab treatment.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

Change history

  • 18 January 2019

    "In the abstract and in other parts of the manuscript the authors wrote that the mutation rs396991 causes a valine (V) to phenylalanine (F) substitution at position 157. However, the correct codon number is 158. These errors have not been fixed in the original Article."

References

  1. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008; 359: 1116–1127.

    Article  CAS  PubMed  Google Scholar 

  2. Argiris A, Karamouzis MV, Raben D, Ferris RL . Head and neck cancer. Lancet 2008; 371: 1695–1709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Vermorken JB, Trigo J, Hitt R, Koralewski P, Diaz-Rubio E, Rolland F et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol 2007; 25: 2171–2177.

    Article  CAS  PubMed  Google Scholar 

  4. Weiner GJ . Monoclonal antibody mechanisms of action in cancer. Immunol Res 2007; 39: 271–278.

    Article  CAS  PubMed  Google Scholar 

  5. Arnould L, Gelly M, Penault-Llorca F, Benoit L, Bonnetain F, Migeon C et al. Trastuzumab-based treatment of HER2-positive breast cancer: an antibody-dependent cellular cytotoxicity mechanism? Br J Cancer 2006; 94: 259–267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kurai J, Chikumi H, Hashimoto K, Yamaguchi K, Yamasaki A, Sako T et al. Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines. Clin Cancer Res 2007; 13: 1552–1561.

    Article  CAS  PubMed  Google Scholar 

  7. Clynes RA, Towers TL, Presta LG, Ravetch JV . Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med 2000; 6: 443–446.

    Article  CAS  PubMed  Google Scholar 

  8. Alderson KL, Sondel PM . Clinical cancer therapy by NK cells via antibody-dependent cell-mediated cytotoxicity. J Biomed Biotechnol 2011; 2011: 379123.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Ravetch JV, Bolland S . IgG Fc receptors. Annu Rev Immunol 2001; 19: 275–290.

    Article  CAS  PubMed  Google Scholar 

  10. Clynes R . Antitumor antibodies in the treatment of cancer: Fc receptors link opsonic antibody with cellular immunity. Hematol Oncol Clin North Am 2006; 20: 585–612.

    Article  PubMed  Google Scholar 

  11. Weng WK, Levy R . Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol 2003; 21: 3940–3947.

    Article  CAS  PubMed  Google Scholar 

  12. Kim DH, Jung HD, Kim JG, Lee JJ, Yang DH, Park YH et al. FCGR3A gene polymorphisms may correlate with response to frontline R-CHOP therapy for diffuse large B-cell lymphoma. Blood 2006; 108: 2720–2725.

    Article  CAS  PubMed  Google Scholar 

  13. Musolino A, Naldi N, Bortesi B, Pezzuolo D, Capelletti M, Missale G et al. Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J Clin Oncol 2008; 26: 1789–1796.

    Article  CAS  PubMed  Google Scholar 

  14. van Sorge NM, van der Pol WL, van de Winkel JG . FcgammaR polymorphisms: implications for function, disease susceptibility and immunotherapy. Tissue Antigens 2003; 61: 189–202.

    Article  CAS  PubMed  Google Scholar 

  15. Bibeau F, Lopez-Crapez E, Di Fiore F, Thezenas S, Ychou M, Blanchard F et al. Impact of Fc{gamma}RIIa-Fc{gamma}RIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with cetuximab plus irinotecan. J Clin Oncol 2009; 27: 1122–1129.

    Article  CAS  PubMed  Google Scholar 

  16. Rodriguez J, Zarate R, Bandres E, Boni V, Hernandez A, Sola JJ et al. Fc gamma receptor polymorphisms as predictive markers of Cetuximab efficacy in epidermal growth factor receptor downstream-mutated metastatic colorectal cancer. Eur J Cancer 2012; 48: 1774–1780.

    Article  CAS  PubMed  Google Scholar 

  17. Liu G, Tu D, Lewis M, Cheng D, Sullivan LA, Chen Z et al. Fc-gamma receptor polymorphisms, cetuximab therapy, and survival in the NCIC CTG CO.17 trial of colorectal cancer. Clin Cancer Res 2016; 22: 2435–2444.

    Article  CAS  PubMed  Google Scholar 

  18. Taylor RJ, Chan SL, Wood A, Voskens CJ, Wolf JS, Lin W et al. FcgammaRIIIa polymorphisms and cetuximab induced cytotoxicity in squamous cell carcinoma of the head and neck. Cancer Immunol Immunother 2009; 58: 997–1006.

    Article  CAS  PubMed  Google Scholar 

  19. Lopez-Albaitero A, Lee SC, Morgan S, Grandis JR, Gooding WE, Ferrone S et al. Role of polymorphic Fc gamma receptor IIIa and EGFR expression level in cetuximab mediated, NK cell dependent in vitro cytotoxicity of head and neck squamous cell carcinoma cells. Cancer Immunol Immunother 2009; 58: 1853–1864.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhang W, Gordon M, Schultheis AM, Yang DY, Nagashima F, Azuma M et al. FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab. J Clin Oncol 2007; 25: 3712–3718.

    Article  CAS  PubMed  Google Scholar 

  21. de Mello RA, Geros S, Alves MP, Moreira F, Avezedo I, Dinis J . Cetuximab plus platinum-based chemotherapy in head and neck squamous cell carcinoma: a retrospective study in a single comprehensive European cancer institution. PLoS ONE 2014; 9: e86697.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Guo Y, Shi M, Yang A, Feng J, Zhu X, Choi YJ et al. Platinum-based chemotherapy plus cetuximab first-line for Asian patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck: results of an open-label, single-arm, multicenter trial. Head Neck 2015; 37: 1081–1087.

    Article  PubMed  Google Scholar 

  23. Lynggaard CD, Therkildsen MH, Kristensen CA, Specht L . The EXTREME regimen for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC): treatment outcome in a single institution cohort. Acta Oncol 2015; 54: 1071–1075.

    Article  PubMed  Google Scholar 

  24. Vermorken JB, Psyrri A, Mesia R, Peyrade F, Beier F, de Blas B et al. Impact of tumor HPV status on outcome in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck receiving chemotherapy with or without cetuximab: retrospective analysis of the phase III EXTREME trial. Ann Oncol 2014; 25: 801–807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Vermorken JB, Stohlmacher-Williams J, Davidenko I, Licitra L, Winquist E, Villanueva C et al. Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial. Lancet Oncol 2013; 14: 697–710.

    Article  CAS  PubMed  Google Scholar 

  26. Argiris A, Li S, Ghebremichael M, Egloff AM, Wang L, Forastiere AA et al. Prognostic significance of human papillomavirus in recurrent or metastatic head and neck cancer: an analysis of Eastern Cooperative Oncology Group trials. Ann Oncol 2014; 25: 1410–1416.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kawaguchi Y, Kono K, Mimura K, Sugai H, Akaike H, Fujii H . Cetuximab induce antibody-dependent cellular cytotoxicity against EGFR-expressing esophageal squamous cell carcinoma. Int J Cancer 2007; 120: 781–787.

    Article  CAS  PubMed  Google Scholar 

  28. Shields RL, Namenuk AK, Hong K, Meng YG, Rae J, Briggs J et al. High resolution mapping of the binding site on human IgG1 for Fc gamma RI, Fc gamma RII, Fc gamma RIII, and FcRn and design of IgG1 variants with improved binding to the Fc gamma R. J Biol Chem 2001; 276: 6591–6604.

    Article  CAS  PubMed  Google Scholar 

  29. Taylor RJ, Saloura V, Jain A, Goloubeva O, Wong S, Kronsberg S et al. Ex vivo antibody-dependent cellular cytotoxicity inducibility predicts efficacy of cetuximab. Cancer Immunol Res 2015; 3: 567–574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Srivastava RM, Lee SC, Andrade Filho PA, Lord CA, Jie HB, Davidson HC et al. Cetuximab-activated natural killer and dendritic cells collaborate to trigger tumor antigen-specific T-cell immunity in head and neck cancer patients. Clin Cancer Res 2013; 19: 1858–1872.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Pichler M, Winter E, Stotz M, Eberhard K, Samonigg H, Lax S et al. Down-regulation of KRAS-interacting miRNA-143 predicts poor prognosis but not response to EGFR-targeted agents in colorectal cancer. Br J Cancer 2012; 106: 1826–1832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Pichler M, Winter E, Ress AL, Bauernhofer T, Gerger A, Kiesslich T et al. miR-181a is associated with poor clinical outcome in patients with colorectal cancer treated with EGFR inhibitor. J Clin Pathol 2014; 67: 198–203.

    Article  CAS  PubMed  Google Scholar 

  33. Gomes SE, Simoes AE, Pereira DM, Castro RE, Rodrigues CM, Borralho PM . miR-143 or miR-145 overexpression increases cetuximab-mediated antibody-dependent cellular cytotoxicity in human colon cancer cells. Oncotarget 2016; 7: 9368–9387.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Schou JV, Rossi S, Jensen BV, Nielsen DL, Pfeiffer P, Hogdall E et al. miR-345 in metastatic colorectal cancer: a non-invasive biomarker for clinical outcome in non-KRAS mutant patients treated with 3rd line cetuximab and irinotecan. PLoS ONE 2014; 9: e99886.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Mountzios G, Rampias T, Psyrri A . The mutational spectrum of squamous-cell carcinoma of the head and neck: targetable genetic events and clinical impact. Ann Oncol 2014; 25: 1889–1900.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the PMU Research Funds PMU FFF (grant number: R-16/02/081-MAM), the Province of Salzburg and by an unrestricted grant from the company Merck.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to A Egle.

Ethics declarations

Competing interests

After submission of the first manuscript and during the review process, T Melchardt received an unrestricted grant from the company Merck. The other authors declare no conflict of interest.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Magnes, T., Melchardt, T., Hufnagl, C. et al. The influence of FCGR2A and FCGR3A polymorphisms on the survival of patients with recurrent or metastatic squamous cell head and neck cancer treated with cetuximab. Pharmacogenomics J 18, 474–479 (2018). https://doi.org/10.1038/tpj.2017.37

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2017.37

This article is cited by

Search

Quick links