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

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 PARTICIPANTSA 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 MEASURESThe 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 RELEVANCEEven 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.

Cetuximab is efficient and safe in patients with advanced cutaneous squamous cell carcinoma: a retrospective, multicentre study

“…The same proportion of patients achieved a DCR and 31% achieved an ORR with panitumumab, another monoclonal anti-EGFR antibody, in the phase II study conducted by Foote et al [17]. We reported also, in another retrospective cohort of 31 patients, a DCR and ORR at week 6 of 68% and 48%, respectively [12]. Of course, due to the present study's retrospective design, and because cross-study comparisons should be interpreted with care, our results have to be read with caution.…”

“…Of course, due to the present study's retrospective design, and because cross-study comparisons should be interpreted with care, our results have to be read with caution. One of the reasons that could explain our higher response rates is the fact that, in our cohort, ~66% of the population had local disease compared with 39% and 47% in the studies from Maubec et al and Picard et al, respectively [11,12]. Conversely, only ~14% of our patients had lymph node disease, while in the studies of Maubec et al and Picard et al, 47% and 44% of enrolled patients had regional disease, respectively.…”

“…Cetuximab has been tested in advanced cSCC and demonstrated a DCR of 69% at 6 weeks [11][12][13][14]. Additionally, there is a rationale based on preclinical data to block the programmed cell death protein 1 (PD-1) and/ or the PD-1 ligand (PD-L1) pathway in inoperable cSCC.…”

Current strategy of squamous cell carcinoma diagnosis and treatment

“…Цетуксимаб исследован в основном при распространенном ПКРК, панитумумаб оценивался в небольшой группе пациентов [153,154]. Данные для эрлотиниба, гефитиниба и лапатиниба крайне ограниченны [155,156].…”

Epidermolysis bullosa: Advances in research and treatment

“…Despite obvious progress, current knowledge to correlate clinical effectiveness of checkpoint inhibitors with the tumor immune microenvironment is still limited in SCCS and should be subject to further investigation …”