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

Authors

Catherine Zilberg, University of Sydney
Matthew Weicai Lee, University of Sydney
Spiridoula Kraitsek, Royal Prince Alfred Hospital
Bruce G. Ashford, University of WollongongFollow
Marie Ranson, University of WollongongFollow
Kerwin Shannon, University of Sydney, Sydney Head and Neck Cancer Institute, Chris O'Brien Lifehouse
Gopal Iyer, National Cancer Centre Singapore, Ingham Institute For Applied Medical Research
Sydney Ch'ng, University of Sydney, Royal Prince Alfred Hospital, Chris O'Brien Lifehouse
Tsu-Hui (Hubert) Low, University of Sydney, Chris O'Brien Lifehouse
Carsten Palme, University of Sydney, Chris O'Brien Lifehouse
Jonathan Clark, University of New South Wales, Nepean Blue Mountains Local Health District, University of Sydney, Chris O'Brien Lifehouse, Lifehouse, Royal Prince Alfred HospitalFollow
Ruta Gupta, Chris O'Brien Lifehouse, University of Sydney, Royal Prince Alfred Hospital, University of SydneyFollow
Bing Yu, University of Sydney, Royal Prince Alfred Hospital

RIS ID

137792

Publication Details

Zilberg, C., Lee, M. Weicai., Kraitsek, S., Ashford, B., Ranson, M., Shannon, K., Iyer, N. Gopalakrishna., Ch'ng, S., Low, T., Palme, C., Clark, J., Gupta, R. & Yu, B. (2019). Is high-risk cutaneous squamous cell carcinoma of the head and neck a suitable candidate for current targeted therapies?. Journal of Clinical Pathology, Online First 1-6.

Abstract

Objective: 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. Methods: 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. Results: 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 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 (KIT S821F, KIT T670I, RAS mutations at codons 12 and 13). Conclusion: 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.