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Original Investigation
March 4, 2017

Association of Oncogenic Mutations in Patients With Advanced Cutaneous Squamous Cell Carcinomas Treated With Cetuximab

Author Affiliations
  • 1Department of Dermatology, University Hospital of Nice, France
  • 2Laboratory of Solid Tumors Genetics, Nice University Hospital and Institute of Research on Cancer and Aging (IRCAN), Faculty of Medicine, Nice, France
  • 3Medical Oncology Department, Antoine Lacassagne Center, Nice, France
  • 4Medical Oncology Department, Cannes Hospital, France
  • 5Biostatistics unit, Antoine Lacassagne Center, Nice, France
  • 6Department of Pathology, University Hospital of Nice, France
  • 7Oncopharmacology and Pathology Departments, Antoine Lacassagne Center, Nice, France
  • 8Department of Surgery, Comprehensive Cancer Center, Antoine Lacassagne, Nice, France
  • 9Medipath Frejus-Saint Raphaël, Pathology Center, Frejus, France
  • 10INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire, Team 12, Nice, France
JAMA Dermatol. Published online March 4, 2017. doi:10.1001/jamadermatol.2017.0270
Key Points

Question  What is the incidence of HRAS, KRAS, NRAS, BRAF, and EGFR mutations in patients with advanced cutaneous squamous cell carcinomas and the correlation with response to cetuximab?

Findings  In this retrospective study, samples from 31 patients with histologically confirmed advanced cutaneous squamous cell carcinoma treated with cetuximab were analyzed. Only 2 RAS mutated samples were identified. There was no correlation with response to cetuximab treatment.

Meaning  The incidence of RAS, BRAF, and EGFR mutations is very low in cutaneous squamous cell carcinomas. Thus, the search for mutations appears unnecessary before initiating a cetuximab treatment for advanced cutaneous squamous cell carcinomas.

Abstract

Importance  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.

Design, Setting, and Participants  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).

Interventions  Mutational status was determined by pyrosequencing method, allelic discrimination, or Sanger sequencing. Patients were treated by single-agent cetuximab.

Main Outcomes and Measures  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 and Relevance  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.

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