Evaluation of 122 advanced‐stage cutaneous squamous cell carcinomas by comprehensive genomic profiling opens the door for new routes to targeted therapies

Abstract

BACKGROUND:The authors hypothesized that comprehensive genomic profiling of advanced-stage cutaneous squamous cell carcinoma (cSCC) could identify genomic-derived drug targets of therapy for patients with conventional therapy-resistant disease. METHODS: Comprehensive genomic profiling of 315 cancer genes was applied to 50 ng of DNA from 122 cSCC cases for the evaluation of all classes of genomic alterations (GAs). Clinically relevant genomic alterations (CRGAs) were defined as those identifying anticancer drugs on the market or in registered clinical trials. RESULTS: There were 21 women (17%) and 101 men (83%) with a median age of 64.9 years (range, 21-87 years). Eleven cSCC cases (9%) were histologic AJCC grade 1, 69 (57%) were grade 2, and 42 (34%) were grade 3. The primary cSCC was used for sequencing in 77 cases (63%). Metastatic lesions were sequenced in 37% of cases. There were 1120 total GAs identified (average of 9.2 GAs per tumor), with 100% of cases harboring at least 1 alteration. Of the 122 cSCCs, 107 (88%) harbored at least 1 CRGA (2.5 CRGAs per cSCC) includingNOTCH1 (43%); patched 1 (PTCH1) (11%); BRCA2 (10%); HRAS (8%); ataxia telangiectasia mutated (ATM) (7%); erb-B2 receptor tyrosine kinase 4 (ERBB4) (7%); neurofibromatosis type 1 (NF1) (7%); erb-B2 receptor tyrosine kinase 2 (ERBB2) (6%); phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) (6%); cyclin D1 (CCND1) (6%); epidermal growth factor receptor (EGFR) (5%); and F-box and WD repeat domain containing 7, E3 ubiquitin protein ligase (FBXW7) (5%). CONCLUSIONS: In the current study, approximately 88% of patients with cSCC were found to harbor clinically relevant GAs that have the potential to guide the treatment of patients with advanced-stage tumors with targeted therapeutic agents. Cancer 2016;122:249-57.

Gefitinib for patients with incurable cutaneous squamous cell carcinoma: A single-arm phase II clinical trial

“…16–18 Unfortunately, many of these mutations occur in tumor suppressor genes, for which therapeutic interventions are challenging. Notably, EGFR activating mutations were infrequently seen in these reports and others, 19–21 and are therefore unlikely to explain the ORR associated with gefitinib in our study. In our previous trial of neoadjuvant gefitinib in CSCC, we did not identify any associations between EGFR mutations, gene copy number gains, or protein expression/phosphorylation and outcomes.…”

Clinical impact of targeted amplicon sequencing for meningioma as a practical clinical-sequencing system

“…Numerous studies using nextgeneration sequencers have revealed clinically relevant genetic alterations in various tumors, and some researchers have recently advocated the clinical use of next-generation sequencers. [15][16][17][18][19][20] This is the first study to establish a clinical sequencing system for meningioma, which is the most common brain tumor.…”

Molecular mechanisms of perineural spread of cutaneous carcinoma: a potential role for receptor tyrosine kinases and other biomarkers

“…(138) Comparable results were seen in more recent genomic profiling by Al-Rohil et al (2016) of 122 cSCC cases looking at both primary (63%) and metastatic (37%) lesions. (139) Across these samples they identified a total of 1120 genomic alterations with 88% of cSCCs harbouring at least one clinically relevant genomic alteration (CRGA) for which there is an anticancer drug already on the market or in clinical trial. The most common CRGA was in NOTCH1 (43%)…”

“…(140) To date, there have been very few gene-profiling studies to identify driver genes involved in perineural invasion or spread. Using microarray expression analysis to analyse more than 20,000 genes, Mays et al (2015) identified 24 differentially expressed genes between specimens of cSCC with and without microscopic PNI, none of which before had been implicated in perineural disease.…”