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Intramucosal Inoculation of Squamous Cell Carcinoma Cells in Mice for Tumor Immune Profiling and Treatment Response Assessment
Published on: April 22, 2019
Association of Oncogenic Mutations in Patients With Advanced Cutaneous Squamous Cell Carcinomas Treated With
Alexandra Picard1, Florence Pedeutour2, Frédéric Peyrade3
1Department of Dermatology, University Hospital of Nice, France.
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.
Insights
Cetuximab shows efficacy in advanced cutaneous squamous cell carcinomas (cSCC), with low incidence of RAS, BRAF, and EGFR mutations. Further research into tumor-specific mutations is crucial for predicting treatment response.
Area of Science:
- Oncology
- Dermatology
- Molecular Biology
Background:
- Advanced cutaneous squamous cell carcinomas (cSCC) have inconsistent responses to cetuximab.
- Predictive biomarkers are needed to optimize cetuximab treatment efficacy.
Purpose of the Study:
- To identify somatic mutations in HRAS, KRAS, NRAS, BRAF, and EGFR genes in advanced cSCC patients treated with cetuximab.
- To evaluate the efficacy and tolerance of cetuximab based on these mutations.
Main Methods:
- Retrospective analysis of 31 advanced cSCC patients treated with single-agent cetuximab.
- Somatic mutation status determined by pyrosequencing, allelic discrimination, or Sanger sequencing.
- Efficacy assessed by disease control rate, progression-free survival (PFS), and overall survival (OS).
Main Results:
- Only 2 RAS mutations (NRAS and HRAS) were identified in 6.5% of patients.
- No KRAS, BRAF, or EGFR mutations were found at the investigated loci.
- Patients with NRAS/HRAS mutations showed partial/complete response; overall disease control rate was 67.8%, median OS 13 months, median PFS 9 months.
Conclusions:
- Cetuximab is effective and well-tolerated in elderly patients with advanced cSCC.
- The incidence of RAS, BRAF, and EGFR mutations is low in this patient cohort.
- Identifying tumor-specific mutations is essential for predicting treatment response and prognosis in advanced cSCC.
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