Epidermal growth factor receptor (EGFR) pathway polymorphisms as predictive markers of cetuximab toxicity in locally advanced head and neck squamous cell carcinoma (HNSCC) in a Spanish population

Oral Oncol. 2016 Dec;63:38-43. doi: 10.1016/j.oraloncology.2016.10.006. Epub 2016 Nov 12.


Objectives: To examine the relationship between polymorphisms of the epidermal growth factor receptor (EGFR) pathway and toxicity in head and neck squamous cell carcinoma (HNSCC) patients treated with cetuximab.

Material and methods: Multicenter, retrospective, observational pilot study which included 110 patients with histologically-confirmed human papillomavirus (HPV) negative HNSCC in locally advanced stages (III-IVA-B) and who were treated with chemotherapy and radiotherapy plus cetuximab between 2003 and 2013. Genetic analyses for single nucleotide polymorphisms (SNP) in genes EGFR, CCDN1, FCGR2A, FCGR3A and KRAS-LCS6 were performed though available allelic discrimination assay and/or polymerase chain reaction-restriction fragment length polymorphism methods.

Results: Acneiform rash was observed in 55.5% of patients, dry skin in 45.5% and pruritus in 20.9%. A significant association with dry skin and global cetuximab-related toxicity was observed for the KRAS-LCS6 (rs61764370) variant (p<0.05); carriers of the G allele (genotypes TG+GG) in the dominant model were observed to have a decreased susceptibility of developing dry skin (OR=0.287 [95%CI=0.119-0.695]). Carriers of the A (GA+AA) allele for EGFR (rs2227983) showed a decreased risk of suffering from pruritus (OR=0.345 [0.124-0.958]). Similarly, KRAS (rs1801274) was related with lower global cetuximab-related toxicity (OR=0.266 [0.114-0.622]).

Conclusion: This pilot study provides preliminary evidence supporting genetic variation of EGFR (rs2227983), KRAS (rs61764370) and FCGR2A (rs180127) as useful biomarkers for predicting reduced skin toxicity in HNSCC patients treated with a cetuximab-based therapy. Alternative therapeutic options should be explored for these patients.

Keywords: CCDN1; Cetuximab; EGFR; Epidermal growth factor receptor (EGFR); FCGR2A; FCGR3A; Head and neck squamous cell carcinoma (HNSCC); KRAS-LCS6; Polymorphism; SNP; Toxicity.

MeSH terms

  • Antineoplastic Agents, Immunological / adverse effects*
  • Antineoplastic Agents, Immunological / therapeutic use
  • Carcinoma, Squamous Cell / drug therapy*
  • Cetuximab / adverse effects*
  • Cetuximab / therapeutic use
  • ErbB Receptors / genetics*
  • Female
  • Head and Neck Neoplasms / drug therapy*
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Genetic*
  • Spain
  • Squamous Cell Carcinoma of Head and Neck


  • Antineoplastic Agents, Immunological
  • EGFR protein, human
  • ErbB Receptors
  • Cetuximab