Is high-risk cutaneous squamous cell carcinoma of the head and neck a suitable candidate for current targeted therapies?

Abstract

<jats:sec><jats:title>Objective</jats:title><jats:p>Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy, most frequently affecting the head and neck. Treatment often requires surgery and can have significant functional morbidity. Research into disease pathogenesis and second line medical management of cSCC is limited. We assess genetic mutations in high-risk, primary head and neck cutaneous squamous cell carcinomas (HNcSCC) that may hinder or be beneficial for use of targeted therapy in disease management.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Genetic alterations and variant allele frequencies (VAFs) were analysed using a clinically relevant 48 gene panel in 10 primary high-risk non-metastatic treatment-naïve HNcSCC to evaluate applicability of targeted therapeutics. Variants present at all VAFs were evaluated for pathogenicity. Somatic mutation patterns of individual tumours were analysed.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>High-risk HNcSCC showed a high proportion (82%) of C to T transitions in keeping with ultraviolet-mediated damage. There was significant intratumour genetic heterogeneity in this cohort (MATH scores 20–89) with the two patients &lt;45 years of age showing highest intratumour heterogeneity. <jats:italic>TP53</jats:italic> was altered at VAF &gt;22% in all cases, and mutations with highest VAF were observed in tumour suppressor genes in 80%. 70% of cases demonstrated at least one mutation associated with treatment resistance (<jats:italic>KIT</jats:italic> S821F, <jats:italic>KIT</jats:italic> T670I, <jats:italic>RAS</jats:italic> mutations at codons 12 and 13).</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>We demonstrate high proportion tumour suppressor loss of function mutations, high intratumour genetic heterogeneity, and presence of well recognised resistance mutations in treatment naïve primary HNcSCC. These factors pose challenges for successful utilisation of targeted therapies.</jats:p></jats:sec>

A Novel Radiotherapeutic Approach to Treat Bulky Metastases Even From Cutaneous Squamous Cell Carcinoma: Its Rationale and a Look at the Reliability of the Linear-Quadratic Model to Explain Its Radiobiological Effects

“…Such an approach would appear to allow a deferral in the use of aggressive chemotherapy regimens even among those patients affected by oligometastatic mucosal HNSCC ( 34 ). The advanced and/or metastatic cSCC counterpart may be treated with targeted therapies, but such a consideration does not rule out a key role for ablative RT ( 35 , 36 ), not yet extensively tested due to the low rate of metastatic disease ( 37 ). However, bulky masses could not be treated with high-dose stereotactic RT without exceeding the normal tissue tolerance ( 38 ).…”

Expanding the role of combined immunochemotherapy and immunoradiotherapy in the management of head and neck cancer (Review)

“…Geographical location is also an influential factor for HNSCC; as frequently reported by the World Health Organization, exposure to pollution and some viral agents also increases the incidence of HNSCC ( 40 ). However, gene mutation and other genetic factors are also contributing agents for HNSCC ( 41 ), which require further research, since the mechanisms are not well understood.…”

lncRNA EZR‑AS1 knockdown represses proliferation, migration and invasion of cSCC via the PI3K/AKT signaling pathway

“…Although radiotherapy and chemotherapy have been widely used for the treatment of cSCC, these strategies are not recommended due to their side effects and inconsistent therapeutic effects (6,7). Targeted molecular therapy has become a recent trend in cSCC therapy (8), thus investigating the molecular mechanism underlying cSCC progression is important for the identification of novel therapeutic targets.…”