By Deborah Borfitz
March 8, 2022 | Old-fashioned technology is the basis of a pioneering test that reliably predicts the spread or return of the deadliest form of skin cancer among the 20% of patients diagnosed with stage I or II melanomas that have not ulcerated. The new immunohistochemistry (IHC) test, developed by a team of scientists and clinicians at Newcastle University in the U.K., could offer relief to anxious patients as well as help shorten “ever-challenging waiting lists” for follow-up care as melanoma cases continue to rise, according to Penny Lovat, professor of cellular dermatology and oncology.
The test is called AMBLor and it is the first product of AMLo Biosciences, where Lovat serves as chief scientific officer. AMBRA1 and loricrin testing is currently available in the U.K. through a private-pay referral service, although an application has been submitted to make the test a covered service by the National Health Service (NHS), she says. The company is also investigating marketing options in the U.S.
Unlike the currently available genetic testing options, the IHC-based test is simple, cost-effective, and could easily be incorporated into existing diagnostic pathways, says Lovat. It is also backed by an explainable, proven scientific mechanism, as recently reported in the British Journal of Dermatology (DOI: 10.1111/bjd.20889).
Early-stage melanomas at risk of spreading secrete a growth factor (TGFβ2) that causes the downregulation of the proteins AMBRA1 and loricrin found in the skin overlying the tumor as well as loss of claudin-1 facilitating ulceration. The three proteins are key to maintaining the integrity of the upper layer of the skin, much like mortar and bricks holding together a wall, Lovat explains. When gaps develop, the tumor is allowed to spread and ultimately ulcerate—a process associated with higher risk tumors.
The AMBLor test analyzes the expression of AMBRA1 and loricrin that are retained in that epidermal layer and indicative of tumors at low risk of metastasis, she says. Low-risk patients can be identified with high sensitivity (95.6%) and specificity (18.6%) and with impressively high negative predictive value—more than 97%—"better than any other test of its kind.”
Loss of the two biomarkers indicates “no change in risk,” Lovat stresses, referencing the other 80% of patients who should get follow-up procedures as recommended in guidelines issued by the U.K.’s National Institute for Health and Care Excellence (NICE).
Melanoma is increasing worldwide and every year more than 16,000 people in the U.K. and 96,000 people in the U.S. are diagnosed with the cancer. Non-ulcerated early-stage melanoma accounts for about 75% of all new diagnoses, she notes.
The current NICE follow-up recommendations for early-stage melanomas are two to four visits in year one for stage IA and four visits for three years and then two visits each in years four and five for stages IB and IIB. For those deemed low risk by the AMBLor test, surveillance might be stepped down respectively to one visit after 12 months (for stage IA patients) and one visit per year for four years for all others.
Cost savings for management of early-stage melanoma patients will come from the fewer number of follow-up appointments needed by early-stage melanoma patients identified as genuinely low risk, she says. The basis of regulatory approval in the U.K. is both clinical utility and budgetary impact on the NHS.
AMBRA1 and loricrin were patented as biomarkers for disease progression in melanoma in Europe in 2019 and in the U.S. and Australia in 2020.
Testing Process
Presently, as a newly launched referral service accredited by the United Kingdom Accreditation Service, AMBRA1 and loricrin testing is done by sending sections from a patient’s tumor to the CellPath diagnostic laboratory at Newcastle-upon-Tyne Hospitals Trust. The test is generally done on the diagnostic biopsy storied in local pathology departments, so no extra tissue needs to be taken from patients, Lovat says.
Actual testing of a tumor section takes a matter of hours, but the entire process—shipping of the biopsy sample, IHC staining, and getting the report emailed back to the ordering dermatologist—is generally completed within one week, before patients’ first follow-up appointment, she adds.
Per the AMLo Biosciences website, patients are charged £293 (equivalent to $393) for the test, excluding any pathology services for the Trust to prepare and send the samples to CellPath.
AMBRA1 and loricrin testing is currently only available in the U.K., although the company has formally requested feedback from the U.S. Food and Drug Administration via its pre-submission program, says Lovat. The possibility of offering the test through a lab certified under the Clinical Laboratory Improvement Amendments is also being explored.
Lovat will be presenting data on the test at several upcoming meetings, including one hosted by the American Academy of Dermatology Association in Boston at the end of March and another by the European Association for Dermato Oncology in Seville, Spain the following month.
AMLo Biosciences has another product under development for squamous cell carcinoma, intended to aid in the identification of a high-risk patient subset, she says.