J Fernández-Mateos1, R Seijas-Tamayo2, R Mesía3, M Taberna3, M Pastor Borgoñón4, E Pérez-Ruiz5, J C Adansa Klain2, S Vázquez Fernández3, E Del Barco Morillo2, A Lozano6, R González Sarmiento7, J J Cruz-Hernández8. 1. Medical Oncology Service, University Hospital of Salamanca-IBSAL, Salamanca, Spain; Biomedical Research Institute of Salamanca (IBSAL), SACYL-University of Salamanca-CSIC, Salamanca, Spain; Molecular Medicine Unit-IBSAL, Department of Medicine, University of Salamanca, Spain; Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain. 2. Medical Oncology Service, University Hospital of Salamanca-IBSAL, Salamanca, Spain; Biomedical Research Institute of Salamanca (IBSAL), SACYL-University of Salamanca-CSIC, Salamanca, Spain. 3. Medical Oncology Department, Institut Català d'Oncologia L'Hospitalet de Llobregat, Barcelona, Spain. 4. Medical Oncology Service, Hospital Universitario Politécnico La Fe, Valencia, Spain. 5. Division of Medical Oncology, Oncology Department, Hospital Costa del Sol, Marbella, Spain. 6. Radiation Oncology Department, Institut Català d'Oncologia L'Hospitalet, Barcelona, Spain. 7. Biomedical Research Institute of Salamanca (IBSAL), SACYL-University of Salamanca-CSIC, Salamanca, Spain; Molecular Medicine Unit-IBSAL, Department of Medicine, University of Salamanca, Spain; Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain. Electronic address: gonzalez@usal.es. 8. Medical Oncology Service, University Hospital of Salamanca-IBSAL, Salamanca, Spain; Biomedical Research Institute of Salamanca (IBSAL), SACYL-University of Salamanca-CSIC, Salamanca, Spain; Molecular Medicine Unit-IBSAL, Department of Medicine, University of Salamanca, Spain. Electronic address: ttcc@seom.org.
Abstract
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.
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 HNSCCpatients treated with a cetuximab-based therapy. Alternative therapeutic options should be explored for these patients.