Alexandra Picard1, Florence Pedeutour2, Frédéric Peyrade3, Laurence Saudes4, Valérie Duranton-Tanneur2, Emmanuel Chamorey5, Nathalie Cardot-Leccia6, Anne Sudaka7, Marc Ettaiche5, Maxime Benchetrit6, Gilles Poissonnet8, Nicolas Weinbreck9, Bérengère Dadone10, Jean-Philippe Lacour1, Thierry Passeron11, Henri Montaudié1. 1. Department of Dermatology, University Hospital of Nice, France. 2. Laboratory of Solid Tumors Genetics, Nice University Hospital and Institute of Research on Cancer and Aging (IRCAN), Faculty of Medicine, Nice, France. 3. Medical Oncology Department, Antoine Lacassagne Center, Nice, France. 4. Medical Oncology Department, Cannes Hospital, France. 5. Biostatistics unit, Antoine Lacassagne Center, Nice, France. 6. Department of Pathology, University Hospital of Nice, France. 7. Oncopharmacology and Pathology Departments, Antoine Lacassagne Center, Nice, France. 8. Department of Surgery, Comprehensive Cancer Center, Antoine Lacassagne, Nice, France. 9. Medipath Frejus-Saint Raphaël, Pathology Center, Frejus, France. 10. 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. 11. Department of Dermatology, University Hospital of Nice, France10INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire, Team 12, Nice, France.
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.
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.
Authors: Ignazio Stanganelli; Francesco Spagnolo; Giuseppe Argenziano; Paolo A Ascierto; Franco Bassetto; Paolo Bossi; Vittorio Donato; Daniela Massi; Cesare Massone; Roberto Patuzzo; Giovanni Pellacani; Pietro Quaglino; Paola Queirolo; Iris Zalaudek; Giuseppe Palmieri Journal: Cancers (Basel) Date: 2022-01-13 Impact factor: 6.639