title: Association of Oncogenic Mutations in Patients With Advanced Cutaneous Squamous Cell Carcinomas Treated With Cetuximab.
abstract: OBJECTIVE
  Cetuximab was recently proposed for advanced cutaneous squamous cell carcinomas (cSCC); however, its efficacy is inconsistent and identification of predictive biomarkers for response is necessary.
  
  
  OBJECTIVE
  To search for somatic mutations of the HRAS, KRAS, NRAS, BRAF, and EGFR genes in patients with advanced cSCC treated with cetuximab; and to investigate the efficacy and tolerance of cetuximab according to these mutations.
  
  
  METHODS
  A multicentric and retrospective study of 31 patients (22 men, 9 women) with histologically confirmed advanced cSCC carried out in 1 department of dermatology and 2 departments of medical oncology in France between January 2008 and December 2014. The median age of participants was 86 years (range, 48-96 years).
  
  
  METHODS
  Mutational status was determined by pyrosequencing method, allelic discrimination, or Sanger sequencing. Patients were treated by single-agent cetuximab.
  
  
  METHODS
  The primary end point was the incidence of somatic mutations of the RAS, BRAF, and EGFR genes and association of cetuximab efficacy with these mutations was investigated by using Fisher test. Secondary end points were the disease control rate (DCR) at week 6, the progression free-survival (PFS), overall survival (OS), and safety profile of cetuximab.
  
  
  RESULTS
  Thirty-one samples of cSCC from 31 patients were analyzed. Only 2 RAS mutated samples (6.5%) were identified. The first harbored a NRAS point mutation (c.35G>A) in codon 12, resulting in a p.G12D substitution. The second sample presented a HRAS point mutation (c.38G>T) in codon 13, resulting in a p.G13V substitution. No mutation of KRAS, BRAF, and EGFR genes at the investigated loci was found. Two patients with NRAS and HRAS mutations showed a partial and complete response to cetuximab, respectively. The mean duration of follow-up was 19 months. At week 6, the disease control rate was 67.8%. The median OS was 13 months and the median PFS was 9 months. All patients could continue cetuximab treatment without dose reduction.
  
  
  CONCLUSIONS
  Even in elderly patients with advanced cSCC, cetuximab was efficacious and well-tolerated. This suggests that cetuximab is certainly warranted in the treatment of advanced cSCC. However, it is also important to identify tumor specific mutations that may determine response to treatment and prognosis for the disease. We have identified here that the incidence of RAS, BRAF, and EGFR mutations is low in cSCC.
authors.affiliation: Department of Dermatology, University Hospital of Nice, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Picard
authors.affiliation: Laboratory of Solid Tumors Genetics, Nice University Hospital and Institute of Research on Cancer and Aging (IRCAN), Faculty of Medicine, Nice, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Pedeutour
authors.affiliation: Medical Oncology Department, Antoine Lacassagne Center, Nice, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Peyrade
authors.affiliation: Medical Oncology Department, Cannes Hospital, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Saudes
authors.affiliation: Laboratory of Solid Tumors Genetics, Nice University Hospital and Institute of Research on Cancer and Aging (IRCAN), Faculty of Medicine, Nice, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Duranton-Tanneur
authors.affiliation: Biostatistics unit, Antoine Lacassagne Center, Nice, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Chamorey
authors.affiliation: Department of Pathology, University Hospital of Nice, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cardot-Leccia
authors.affiliation: Oncopharmacology and Pathology Departments, Antoine Lacassagne Center, Nice, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Sudaka
authors.affiliation: Biostatistics unit, Antoine Lacassagne Center, Nice, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Ettaiche
authors.affiliation: Department of Pathology, University Hospital of Nice, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Benchetrit
authors.affiliation: Department of Surgery, Comprehensive Cancer Center, Antoine Lacassagne, Nice, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Poissonnet
authors.affiliation: Medipath Frejus-Saint Raphaël, Pathology Center, Frejus, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Weinbreck
authors.affiliation: Laboratory of Solid Tumors Genetics, Nice University Hospital and Institute of Research on Cancer and Aging (IRCAN), Faculty of Medicine, Nice, France6Department of Pathology, University Hospital of Nice, France.
authors.forename: Bérengère
authors.initials: B
authors.lastname: Dadone
authors.affiliation: Department of Dermatology, University Hospital of Nice, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Lacour
authors.affiliation: Department of Dermatology, University Hospital of Nice, France10INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire, Team 12, Nice, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Passeron
authors.affiliation: Department of Dermatology, University Hospital of Nice, France.
authors.forename: Henri
authors.initials: H
authors.lastname: Montaudié
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000068818:Cetuximab / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D005602:France; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012189:Retrospective Studies; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000068818:Cetuximab