TERT epigenetic and genomic variants in stage II melanoma as biomarkers of outcome

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PROJECT SUMMARY In contrast to the dramatic progress in the treatment of metastatic melanoma, prognostication for localized melanoma has not advanced beyond the histomorphological measures of tumor thickness and ulceration that comprise the staging system. The prognostic accuracy of these measures for locally advanced, node-negative melanoma (Stage II) is generally poor. Post-surgical recurrence rates for stage II melanoma vary between 24% for stage IIA to 46% for stage IIC. In contrast to breast and colon cancers, where molecular pathology tests are routinely used to improve the accuracy of disease prognostication over routine histopathology, there are no validated molecular tests for primary melanoma, despite claims from commercial entities to the contrary. Recently, data from a randomized, placebo-controlled clinical trial of pembrolizumab, an anti-PD-1 immunotherapeutic agent, was used to support its approval as adjuvant therapy for surgically resected stage IIB and IIC melanoma. Although recurrence-free survival (RFS) at the 18-month post-surgical follow up showed a statistically significant benefit associated with permbrolizumab, 11 patients needed to be treated to prevent one recurrence. This is because the RFS in the placebo group is fairly high. Given the potential toxicity of immunotherapy, and its variable efficacy and high cost, we need more accurate tools to appropriately select patients for treatment who have a high probability of tumor recurrence, and spare surgically cured patients the risks of overtreatment. A major obstacle to this approach is the lack of validated biomarkers that accurately distinguish between high- and low-risk patients. Several publications as well as our own Preliminary Data support alterations of the upstream regulatory region of the telomerase reverse transcriptase gene (TERT) as potentially high-value prognostic biomarkers in melanoma. These alterations include hotspot mutations in the promoter region (possibly cooperating with an inherited germline variant), and/or methylation of an upstream regulatory region. In addition, data from large published studies suggest that NRAS, and possibly BRAF mutations may each be associated with decreased survival in stage II melanomas. In some datasets the effect is stronger if the mutations co-occur with TERT promoter mutations. The current proposal will test the hypothesis that adding molecular measurements of the upstream regulatory regions of TERT and mutations in NRAS or BRAF, either singly or in combination, will improve the accuracy of a recurrence prediction model for stage II melanoma. Successful creation of an improved model will generate interest from outside groups to collaborate on subsequent larger, multicenter validation and clinical utility studies where the biomarkers may eventually be used to assist in treatment decision-making.