Department of Dermatology, University Hospital of Nice, France.
Laboratory of Solid Tumors Genetics, Nice University Hospital and Institute of Research on Cancer and Aging (IRCAN), Faculty of Medicine, Nice, France.
JAMA Dermatol. 2017 Apr 1;153(4):291-298. doi: 10.1001/jamadermatol.2017.0270.
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.
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).
Mutational status was determined by pyrosequencing method, allelic discrimination, or Sanger sequencing. Patients were treated by single-agent cetuximab.
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.
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.
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.
西妥昔单抗最近被提议用于治疗晚期皮肤鳞状细胞癌（cSCC）；然而，其疗效不一致，有必要确定预测反应的生物标志物。
搜索接受西妥昔单抗治疗的晚期 cSCC 患者 HRAS、KRAS、NRAS、BRAF 和 EGFR 基因的体细胞突变；并根据这些突变来研究西妥昔单抗的疗效和耐受性。
设计、地点和参与者：这是一项在法国的一个皮肤科和两个肿瘤内科部门进行的多中心、回顾性研究，共纳入 31 例（22 名男性，9 名女性）经组织学证实的晚期 cSCC 患者，研究时间为 2008 年 1 月至 2014 年 12 月。参与者的中位年龄为 86 岁（范围：48-96 岁）。
通过焦磷酸测序法、等位基因鉴别或 Sanger 测序确定突变状态。患者接受单药西妥昔单抗治疗。
主要终点是 RAS、BRAF 和 EGFR 基因的体细胞突变发生率，并通过 Fisher 检验研究西妥昔单抗疗效与这些突变的关系。次要终点是第 6 周时的疾病控制率（DCR）、无进展生存期（PFS）、总生存期（OS）和西妥昔单抗的安全性特征。
对 31 名患者的 31 例 cSCC 样本进行了分析。仅发现 2 例 RAS 突变样本（6.5%）。第一个样本在 12 号密码子中存在 NRAS 点突变（c.35G>A），导致 p.G12D 取代。第二个样本在 13 号密码子中存在 HRAS 点突变（c.38G>T），导致 p.G13V 取代。在所研究的基因座未发现 KRAS、BRAF 和 EGFR 基因突变。2 例携带 NRAS 和 HRAS 突变的患者对西妥昔单抗分别表现出部分缓解和完全缓解。中位随访时间为 19 个月。第 6 周时，疾病控制率为 67.8%。中位 OS 为 13 个月，中位 PFS 为 9 个月。所有患者均无需减少剂量即可继续接受西妥昔单抗治疗。
即使在晚期 cSCC 的老年患者中，西妥昔单抗也是有效且耐受良好的。这表明西妥昔单抗在治疗晚期 cSCC 中肯定是合理的。然而，确定可能决定治疗反应和疾病预后的肿瘤特异性突变也很重要。我们在这里发现，cSCC 中 RAS、BRAF 和 EGFR 突变的发生率较低。
