Beyond first line – Potential targets in high-risk and advanced cutaneous squamous cell carcinoma

Cutaneous Squamous Cell Carcinoma (cSCC) is the second most common human cancer in Canada, and the second most common skin cancer. In fair-skin individuals, the lifetime risk approaches 15-20%, second only to another skin cancer, basal cell carcinoma. Like other non-melanoma skin cancers, the incidence rates for cSCC have increased ~200% in the last decades and are still increasing. The risk of metastasis from cSCC is estimated at 4%, but in some high-risk tumors, such as those that are thick or those occurring on certain body locations (lips, ears), it can approach 16%. Although ultraviolet (UV) radiation is the major risk factor for developing cSCC, environmental exposures (radiation, arsenic, chemicals), viruses (HPV), and medical conditions (like solid organ transplantation) may worsen the risk of developing high-risk, advanced, and fatal cSCC, up to 250 times the risk in organ transplant patients. cSCC is responsible of more than double the absolute number of deaths from melanoma, with a societal cost 50% higher. Surgery remains the primary modality for cSCC patients. Radiation may be used in certain cases as well. Systemic options are extremely sparse. First-line anti-PD-1 therapy has been used for locally advanced and metastatic cSCC, with an overall response rate of ~50%. However, if this fails, no other options exist. Targeted therapies, including EGFR inhibitors, have all given very poor survival benefits. Thus, there is a significant need to identify novel therapeutic options and to understand the progression from high-risk cSCC to advanced cSCC at a molecular level.

The JGH skin cancer biobanking initiative broadly collects patient-derived tumors from all types of skin cancers, including the 3 most common varieties – basal cell carcinoma, squamous cell carcinoma, and melanoma, and from all stages (early low risk, early high risk, locally advanced, recurrent, metastatic, resistant to therapy). Our biobank takes advantage of unique multidisciplinary skin cancer clinics (melanoma, non-melanoma skin cancer, cutaneous lymphoma) and a busy Mohs micrographic surgery centre, having a catchment area across Québec and Eastern Canada. Our biobank is both retrospective and prospective as a second-generation biobank. For example, a patient might come with a high-risk primary, then with a local metastasis, undergo immunotherapy, and then experience a skin relapse – for which all the events would be collected through tissue sampling.

Using precision medicine, we aim to identify potential molecular targets for eventual testing in experimental models (cell line, xenografts) towards development of novel therapeutics. Given the shear volume of cSCC cases, prediction of those that are more likely to spread and recur, for more aggressive initial management, would improve patients’ outcomes and quality of life. Given their high tumor burden (50 mutations per megabase), second only to basal cell carcinoma, these accessible tumors are a great model to understand tumor heterogeneity and cellular changes in the microenvironment. Finally, cSCC are quite understudied despite their high prevalence, relatively high absolute mortality, and importantly, extreme morbidity (even local cases may lead to non-healing wounds, impaired quality of life from large surgeries) – we hope to raise more awareness on this preventable cancer.