Title: Innovative Prognostic Test for Early-Stage Cutaneous Melanoma (AMLo)
Funder: Department of Health and Social Care

Abstract: Background We have identified two protein markers, Ambra1 and loricrin (AMLo) in the epidermis overlying melanomas, whose expression is lost in early-stage, high-risk AJCC stage I disease and which are retained in the epidermis overlying genuinely low-risk tumours. AMLo has the potential to identify patients with genuinely low-risk disease and allow their early discharge. Conversely AMLo has the potential to identify patients with genuinely high-risk disease who can be offered personalised clinical and radiological surveillance and potentially early access to therapeutic intervention. Production of AMLo prognostic kit We propose to produce an immunohistochemical CE-marked prognostic kit for deployment in the NHS in the UK and in the major markets worldwide. The existing pathway of analysis for melanomas is not a barrier to implementation; it is an active facilitator to its adoption as immunohistochemistry is already routinely used as part of the routine analysis of primary melanomas. We will carry out optimisation and validation of the prognostic kit for immunohistochemical analysis of melanoma biopsies and provide data to support CE marking. Confirmation of prognostic accuracy and utility The development of the AMLo prognostic test has followed Cancer Research UK guidelines though the &ldquo;Biomarker Roadmap&rdquo;. Validation has taken place in two independent cohorts of stage I melanomas comprising more than 400 individual cases with known outcomes, following the &ldquo;reporting recommendations for tumour marker prognostic studies (REMARK)&rdquo; guidelines. AMLo demonstrated a negative predictive value of 98.7% and positive predictive value of 14.9%, supporting utility in AJCC stage I melanoma (Supporting data Fig.1). We propose to extend the validation of the biomarkers to two additional powered, geographically distinct cohorts with appropriate prevalence of metastases (2), of AJCC Stage I biopsies from Buffalo, USA and Tauranga, New Zealand. We will also evaluate the potential prognostic utility of AMLo in two further cohorts (statistically powered according to our previously defined hazard ratios) of AJCC Stage II biopsies derived from Tyne and Wear, UK, and Tauranga, New Zealand. Health Economics and Route to Market We propose developing a health economic case to support the adoption of AMLo into clinical practice by defining the current pathway for current and future prognostic usage to estimate cost-effectiveness and budget impact of AMLo as well as informing price thresholds for the NHS. Economic modelling will identify where resources can be reallocated to identify and improve outcomes for high-risk patients and will be used to prepare the NICE submission. We also propose to engage with relevant stake holders to identify barriers and facilitators to adoption of AMLo into clinical practice. Furthermore we will carry out detailed freedom to operate analysis and an option appraisal of the best route to market for AMLo.

Lay abstract: Melanoma, the most dangerous form of skin cancer, has an increasing worldwide incidence. Currently the risk of spread of the primary tumour is estimated by microscopic appearance and depth of the original tumour. Patients with tumours classified as low risk (Stage I) are followed up regularly every 6 months for five years; however, approximately 10% of these tumours will spread resulting in extremely poor prospects for patients despite advances in chemo/immunotherapy. Thus, there is an urgent and unmet need to develop new tests which can accurately determine an individual s risk of disease progression. We have identified that loss of two proteins, Ambra1 and loricrin (AMLo) in the skin overlying the primary tumour predicts which AJCC Stage I melanomas will spread with a high degree of accuracy. We have validated this test in over 400 Stage I biopsies from patients with known clinical outcomes and have shown that this test accurately predicts Stage I melanomas which are genuinely low risk as well as identifying those which may spread and need increased surveillance and treatment. We intend to produce a prognostic kit to measure AMLo in melanoma biopsies which is suitable for large-scale manufacture and will fit seamlessly into existing processes for melanoma diagnosis. We will demonstrate that the AMLo test provides value for money, reducing waste of resources for the NHS and develop a plan to help the NHS adopt it. Our team has the skills and experience necessary to achieve these aims including experts in: diagnosis and management of melanoma (dermatologists, pathologists and oncologists), health economics, NICE Technology Appraisal and commissioning NHS services. The use of AMLo in clinical practice has real potential to reduce costs to the NHS, providing reassurance for genuinely low-risk patients whilst identifying and opening the possibility of improving outcomes for high-risk melanoma patients.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS