Past projects

SLN Predict: Sentinel Lymph Node Predictor to optimise melanoma care

Clinical Investigators:

Professor Fadi Issa; Associate Professor/Wellcome Trust CRCD Fellow & Consultant Burns & Plastic Surgeon
Mr Oliver Cassell; Consultant Plastic and Reconstructive Surgeon & Honorary Senior Clinical Lecturer University of Oxford

Co-Investigators

Charlotte Proby, Professor of Dermatology
Dr Rubeta Matin, Consultant Dermatologist
Mr Rowan Pritchard Jones, Consultant Plastic Reconstructive Surgeon

Project start date

01/06/2021

Proposed project duration

18months (for the feasibility study, not the prospective trial)

Project Summary

Melanoma patients are treated with wide local excision surgery and sentinel lymph node biopsy (SLNB) as their primary treatment if their melanoma tumour is 0.8mm or thicker. If melanoma cells are found in this first (sentinel) lymph node, patients are offered additional (or adjuvant) drug treatments which can reduce their chances of the melanoma returning.

Less than one in five SLNBs are positive, particularly in thinner melanomas. There are side effects to SLNB which may cause significant lifelong problems for patients, including a swollen leg. It is also important to concentrate the surgical resources for SLNB on those patients that most need it.

American and Dutch researchers have therefore developed a more precise method to select which melanoma patients should have SLNB procedures. The predictor test (SLN Predict) could accurately identify patients with a <5% risk of melanoma cells having spread to a lymph node.

This feasibility study will validate (retrospectively) the SLN Predict test in 1,500 UK melanoma patients for whom the SLNB result is known, which will allow this predictor test to be used in a future larger prospective clinical trial.

There are 2 main aims of the feasibility study

• To validate the predictor test that can identify patients with <5% risk of melanoma cells spreading to a lymph node. If this test is accurate, future patients with <5% risk might not need to have an SLNB, reducing side effects for patients and also saving NHS resources.
• To see if the predictor test can predict the risk of the melanoma recurring after a negative sentinel lymph node biopsy. This will identify high-risk patients with thin (<0.8mm) melanoma that may benefit from having adjuvant drug treatment after their surgery, and who don’t currently receive this as standard.

The funding from Melanoma Focus will allow:

• The retrospective validation of the predictor test (SLN Predict) within an NHS setting
• Feasibility work to support a funding application for a prospective multi-centre clinical trial

Comment from Clinical Investigators

“The funding from melanoma focus has helped kick start this study, which will aim to reduce the need for surgery. It has helped with database management for the sentinel node results and for collecting pathology tissue for analysis.”

Project update, June 2023

There has been significant progress in the SLN Predict Project driven by a clinical fellow.  

After successfully securing ethical approval for the feasibility study, the study logistics were planned which involved selecting a ‘real world sample’ patient cohort and a process for acquiring samples from a research biobank in Wales.  

In collaboration with the NIHR Research Design Service a comprehensive Patient and Public Involvement (PPI) strategy was developed.  

The first round of analyses has been completed. This process involved histological verification of tissue samples and tissue sectioning. These were then delivered to partners in the Netherlands to validate the SLN Predict test. A second batch of samples is now being prepared for delivery, which will be dispatched once the current batch data has been assessed to ensure its quality.  

Gene expression data is also expected to be received for analysis in July 2023, and a PPI focus group meeting is provisionally scheduled for early 2024. 

Identifying the costs and consequences of the diagnosis and management of melanoma – to assess the impact of melanoma prevention programmes

Clinical Investigators:

Katherine Payne, Professor of Health Economics

Co-Investigators

Martin Eden, Research Fellow in Health Economics
Louisa Gordon, Associate Professor in Health Economics
Adele Green, Professor of Epidemiology
Paul Lorigan, Professor of Medical Oncology

Project start date

12/2021

Proposed project duration

6 months

Project Summary

Preventing melanoma from occurring is far better than having to treat it. Evidence-based public health campaigns are aimed at reducing melanomas by removing exposure to ultraviolet radiation including from indoor tanning (sunbed) facilities. Sunbed use for cosmetic purposes causes melanoma affecting quality and length of life and imposing significant financial burden on healthcare systems. However, policies to ban commercial sunbeds and reduce melanoma must be shown to have a positive impact on NHS costs and patient health before being considered by governments.

This study, that is tailored specifically to the UK, feeds into a global agenda to prevent melanoma caused by the use of commercial sunbeds. It builds on the published work of co-investigators Gordon and Green, including studies that led to commercial sunbeds being banned in Australia.
This research is a vital step on the move towards implementing legislation to ban removal of sunbeds for public use in the UK, which is hoped will achieve wide benefit by reducing the number of patients diagnosed and living with melanoma in the future.

The main aims of the study

This project aims to gather information for the effectiveness and costs of diagnosing, treating, and monitoring different stages of melanoma based on current UK clinical practice.These data will then be used to update a published analysis assessing the impact of reducing the use of sunbeds on the costs and health-consequences of the management of melanoma.Preventing melanoma development through public health initiatives will save many lives, reduce the related morbidity and avoid unnecessary NHS spending. Ultimately, this proposed study will help promote the timely approval of health-improving interventions for use in UK healthcare system.

The funding from Melanoma Focus will allow:

The initial cost-effectiveness analysis to be updated with costs of current melanoma diagnosis and management practices.

Comment from Clinical Investigators

“The support from Melanoma Focus is crucial to enable us to generate the data needed to understand the impact of removing access to commercial sunbeds supported by a public health campaign. This work will be a step towards the goal of reducing the number of melanomas and the harmful consequences on people and healthcare systems.”

Project update, June 2023

The data collection and analysis for this project are now completed.  

The project has mapped diagnosis and treatment pathways for the dermatological, surgical and oncological management of melanoma. This is to help the researchers understand how many people within the population would follow each route through the treatment pathways.  

The proportion of people receiving each intervention in the relevant pathway was estimated, and then online interviews were used to conduct the exercise and collect the data from each expert. Seven dermatologists, five oncologists and four surgeons completed the exercise (August 2022-February 2023). 

For each proportion of people in a population receiving each intervention in the relevant pathway, a group estimate was generated so that it could be multiplied by intervention costs (price year 2021-22) to estimate the mean cost of treating a patient by management phase (dermatological, surgical and oncological).  

The next step is to use these results and update a published model which can show the cost-effectiveness of a policy-based invention to reduce melanoma and other skin cancers associated with indoor tanning.

Validation of Ambra-1 and Loricrin as prognostic biomarkers for the early detection of high-risk melanomas

Principal Investigators:

Dr Rob Ellis, The James Cook University Hospital, Middlesbrough and Institute of Cellular Medicine, Newcastle University
Professor Penny Lovat, Institute of Cellular Medicine, Newcastle University

Co-Investigators

Dr Marie Labus, Business Development Manager, Research and Enterprise Services, Newcastle University

Summary

 If melanoma spreads (or ‘metastasises’) from the skin to other parts of the body, the prognosis or likelihood of recovery will be affected. Thankfully, most patients can be cured if their melanomas are surgically removed from the skin before this happens. Analysing melanomas after their removal can help clinicians predict which patients remain likely to develop metastatic disease. Currently the accuracy of using this method for prognosis is not exact.

Loss of the surface layer of the skin over a melanoma is known as ulceration. Patients whose melanomas become ulcerated have a worse outcome, but the exact reason for this is unclear. In an initial group of melanoma patients, it was shown that the loss of two proteins, Ambra-1 and loricrin, in this skin layer is linked to the development of ulceration, and a greater risk of the disease spreading.

This research project looked for changes in these two proteins in the ulcerated skin layer of melanomas from a large group of patients. The aim was to find out how to predict which patients are at a higher risk of metastatic melanoma, and who will therefore need to be followed up more closely by clinicians after surgery.

The researchers gained a better understanding of the link between these proteins and skin ulceration, as well as their relationship with another protein, known as transforming growth factor beta-2 (TGFβ2). TGFβ2 is linked to how cells in the body grow and divide and is found in melanomas. Gaining understanding of these proteins may help to develop new treatments for patients who are identified as being at higher risk of disease spread.
Discovering earlier and more effective therapies would reduce the rate of metastasis and overall mortality from this most serious form of skin cancer.

Comment from Principal Investigators

“We are extremely delighted to receive this award as we feel that the results we have seen in a previous cohort of patients, as well as multiple laboratory experiments, suggests that we may have begun to unravel the enigma of melanoma ulceration. In doing so, we have identified two proteins in the epidermis overlying melanomas that when lost in the early stages of melanoma development suggest that a patient is at high risk of disease spread and higher mortality.
By further understanding this process, we may be able to develop new drug treatments to prevent the spread of disease and so impact greatly on the mortality from the condition.
The support of the Melanoma Focus has enabled us to take this project forward, allowing potential patient benefit as soon as possible”

Next Steps

The project resulted in the first melanoma test to identify those at low risk of cancer spreading.
By applying the test – called AMBLor® – to the standard biopsy of the primary melanoma on its removal, patients who are at low risk of the disease reoccurring or spreading can be identified. Melanoma Focus are delighted to fund the initial research that developed this test – which may change the follow-up pathways for patients with stage 1a-2b melanomas.

The effectiveness of the AMLo test is yet to be fully evaluated by the NHS, BAD and NICE.  However, if endorsed, this test may be offered to early-stage melanoma patients to potentially reduce the need for some follow-up which will be great news for patients.

Strategic biomarkers for aggressive melanoma

Principal Investigators:

Professor Charlotte Proby, Medical Research Institute, University of Dundee

Co-Investigators

Dr Tim Crook
Dr Colin Fleming
Dr Mathieu Boniol
Professor Catherine Harwood
Dr Rubeta Matin

Summary

Melanoma in its advanced stages tends to spread (metastasise) to distant organs including the liver, lungs and brain. When this happens, it can become incurable and reduces the life expectancy of the patient significantly.
There is increasing evidence that the early and adjuvant use of systemic anti-melanoma drugs allows more effective treatment and better clinical outcomes. Development of simple, non-invasive tests (particularly blood tests) to detect metastatic disease before the patient develops symptoms is therefore a high priority for melanoma research. Tests have been developed in which changes in the DNA profile can be detected in blood samples from patients with metastatic melanoma.
The tests that have been developed only require a blood sample to be taken at a routine clinical follow up and are extremely sensitive and specific for detection of metastatic melanoma.

This research project wants to increase how useful these tests are by including additional genes (identified in their laboratory) that may increase the effectiveness of the test and greatly increase the number of patients tested. This will mean the tests can be improved to a level that they will be useful for testing patients in melanoma clinics.
By achieving this it would mean that these blood tests can be introduced into routine clinical practice. This will increase the detection of metastasis that don’t show up on current standard tests and would help to initiate a change in the treatment of patients with metastatic melanoma, for example, being able to use drugs to treat the melanoma earlier rather than later.
The researchers believe that this would result in markedly improved clinical outcomes.

Comment from the Principal Investigator

“This Melanoma Focus funded research was very productive leading to 4 publications revealing epigenetic mechanisms involved in melanoma progression and metastasis (see below).
We made good progress in better understanding the epigenetic mechanisms that drive melanoma metastasis, but this work has not led to a commercially exploitable test for a variety of reasons, one being the introduction of adjuvant systemic therapy for high risk melanomas. In terms of defining melanoma ‘risk’ (i.e., risk of lymph node metastasis), it has been superseded by work on gene expression profiling (GEP) and we are currently validating a clinic-pathological-GEP algorithm that appears to robustly identify those low-risk melanomas with a less than 10% risk of a positive SLNB. Ultimately, we are hopeful that this test will identify those melanoma patients who will benefit from adjuvant systemic therapy without the need to perform SLNB, as SLNB is an imperfect and potentially morbid procedure.”

References and Publications relating to this project

• Wang H, Lee S, Nigro CL, Lattanzio L, Merlano M, Monteverde M, Matin R, Purdie K, Mladkova N, Bergamaschi D, Harwood C, Syed N, Szlosarek P, Briasoulis E, McHugh A, Thompson A, Evans A, Leigh I, Fleming C, Inman GJ, Hatzimichael E, Proby C, Crook T. NT5E (CD73) is epigenetically regulated in malignant melanoma and associated with metastatic site specificity. Br J Cancer. 2012;106(8):1446-52. doi: 10.1038/bjc.2012.95

• Lo Nigro C, Wang H, McHugh A, Lattanzio L, Matin R, Harwood C, Syed N, Hatzimichael E, Briasoulis E, Merlano M, Evans A, Thompson A, Leigh I, Fleming C, Inman GJ, Proby C, Crook T. Methylated tissue factor pathway inhibitor 2 (TFPI2) DNA in serum is a biomarker of metastatic melanoma. J Invest Dermatol. 2013;133(5):1278-85. doi: 10.1038/jid.2012. 493.

• Atkinson A, Renziehausen A, Wang H, Lo Nigro C, Lattanzio L, Merlano M, Rao B, Weir L, Evans A, Matin R, Harwood C, Szlosarek P, Pickering JG, Fleming C, Sim VR, Li S, Vasta JT, Raines RT, Boniol M, Thompson A, Proby C, Crook T, Syed N. The collagen prolyl hydroxylases are bifunctional growth regulators in melanoma. J Invest Dermatol. 2018; 139(5):1118-1126. doi: 10.1016/j.jid.2018.10.038.

• Renziehausen A, Wang H, Rao B, Weir L, Nigro CL, Lattanzio L, Merlano M, Vega-Rioja A, Del Carmen Fernandez-Carranco M, Hajji N, Matin R, Harwood C, Li S, Sim VR, O’Neill K, Evans A, Thompson A, Szlosarek P, Fleming C, Stebbing J, Proby C, Tzakos AG, Syed N, Crook T. The renin angiotensin system (RAS) mediates bifunctional growth regulation in melanoma and is a novel target for therapeutic intervention. Oncogene 2019;38(13):2320-2336. doi: 10.1038/ s41388-018-0563-y