Association of Epidermal Growth Factor Receptor Polymorphism, Skin Toxicity, and Outcome in Patients With Squamous Cell Carcinoma of the Head and Neck Receiving Cetuximab-Docetaxel Treatment

Clin Cancer Res. 2010 Jan 1;16(1):304-10. doi: 10.1158/1078-0432.CCR-09-1928. Epub 2009 Dec 22.

Abstract

Purpose: Cetuximab, a monoclonal antibody targeting epidermal growth factor receptor (EGFR), has shown clinical efficacy in squamous cell carcinoma of the head and neck with prolonged progression-free (PFS) and overall survival (OS). In this study, we analyzed whether cetuximab-induced skin rash was correlated with distinct polymorphisms within the EGFR gene known to modulate EGFR expression, ligand binding, or signaling activity.

Experimental design: Fifty-one patients enrolled in a single-arm phase II multicenter study for second-line treatment of recurrent or metastatic squamous cell carcinoma of the head and neck with cetuximab/docetaxel were genotyped for two genetic variations in the EGFR gene, a point substitution G-->A in exon 13 resulting in an amino acid substitution in position 521 (EGFR-R521K) and a CA repeat (CA-SSR) polymorphism in intron 1. Association between genotypes and incidence/grade of skin rash was determined by Fisher's exact test. The predictive value of genotypes for PFS and OS was determined using the log-rank test.

Results: Overall, 21 patients (41%) developed skin rash with grade >1 within 6 weeks of treatment. The common EGFR-R521K genotype (G/G) was significantly associated with increased skin toxicity (P = 0.024) and showed a trend toward reduced risk of tumor progression (hazard ratio, 0.55; 95% confidence interval, 0.27-1.08; P = 0.08), whereas no correlation of the EGFR-R521K genotype with OS could be observed (P = 0.20). No significant interaction between CA-SSR polymorphism and skin toxicity, PFS, or OS could be detected.

Conclusions: Our study revealed an influence of the EGFR-R521K genotype on skin toxicity and suggested its relation to clinical activity of cetuximab/docetaxel treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / adverse effects*
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / genetics*
  • Cetuximab
  • Disease-Free Survival
  • Docetaxel
  • Exanthema / chemically induced*
  • Exanthema / genetics*
  • Female
  • Genes, erbB-1*
  • Head and Neck Neoplasms / drug therapy*
  • Head and Neck Neoplasms / genetics*
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Genetic*
  • Survival Analysis
  • Taxoids / administration & dosage
  • Taxoids / adverse effects
  • Treatment Outcome

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Taxoids
  • Docetaxel
  • Cetuximab