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.