High levels of PRAME mRNA appeared associated with increased metastasis risk among patients with class 1 uveal melanoma, according to study results published in Clinical Cancer Research.
Between 2,000 and 3,000 cases of uveal melanoma are diagnosed in the U.S. each year. Gene expression profiling is used to classify these tumors as class 1 or class 2, with class 1 tumors considered much less likely to metastasize, according to study background.
J. William Harbour, MD
“The class 2 tumors have a certain genetic profile that appears to point to metastasis,” J. William Harbour, MD, associate director for basic research and leader of the Eye Cancer Site Disease Group at Sylvester Comprehensive Cancer Center at University of Miami Miller School of Medicine, as well as professor, vice chairman for translational research, and director of the ocular oncology service at Bascom Palmer Eye Institute, told HemOnc Today. “These tumors often have mutations in the tumor-suppressor gene BAP1 and copy losses to chromosome 3. However, with longer follow-up, we found that about 10% of class 1 patients will eventually develop metastatic disease, and these patients did not have the same genetic risk factors strongly associated with metastasis.”
Thus, Harbour and colleagues sought to determine potential biomarkers for the identification of those patients with class 1 tumors at an increased risk for metastasis.
The researchers had access to tumor samples from 389 consecutive patients with uveal melanoma (class 1, n = 216; class 2, n = 173). They performed global gene expression profiling and used single nucleotide polymorphism microarrays to analyze potential biomarkers in these tumors.
Sixty-four class 1 tumors were analyzed for PRAME mRNA expression.
Sixty-three patients with class 2 tumors developed metastatic disease, compared with 12 patients with class 1 tumors (log rank P < .0001).
The liver served as the most frequent metastatic site among patients with class 1 (50%; n = 6) and class 2 (90%; n = 36) tumors (P = .02). Other metastatic sites among class 1 patients included the lungs (n = 4), bone (n = 3) and stomach (n = 2).
The researchers identified PRAME mRNA as a significant predictor of metastatic disease in patients with class 1 tumors (P = .0006).
After a median follow-up of 8.2 months (interquartile range, 3.3-57.1), patients with PRAME-positive class 1 tumors demonstrated a 5-year actuarial metastasis rate of 38%, compared with 0% for patients with PRAME-negative class 1 tumors.
The 5-year metastasis rate observed among all patients with class 2 tumors was 71%.
Still, patients with PRAME-positive class 1 tumors achieved a significantly longer metastasis-free survival than patients with class 2 tumors (median, 88 months vs. 32 months; P = .04).
The researchers validated these findings in three independent datasets, including one dataset that used disomy 3 to identify patients with low-risk uveal melanoma.
Copy number alterations associated with PRAME positivity in class 1 tumors included gains of 1q, 6p, 8q and 9q, as well as the loss of 6q and 11q.
Further, PRAME expression appeared associated with larger tumor diameter (P = .005) and SF3B1 mutations (P = .003) in class 1 patients.
The researchers acknowledged the small number of patients with PRAME-positive class 1 tumors as a study limitation. They further noted that certain patients with PRAME-negative class 1 tumors may have developed metastatic disease after the end of follow-up.
“Metastatic uveal melanoma is notorious for not responding to medications that cutaneous melanoma will often respond to — in particular, the immunotherapies that have revolutionized the treatment of metastatic cutaneous melanoma,” Harbour said. “However, approximately 5% of patients with uveal melanoma will respond to immunotherapy, and it is known from other cancers that PRAME expression often predicts good responses to immunotherapies. Our next step is to determine a correlation between uveal melanomas that are responsive to immunotherapy and PRAME expression, because then we would have not only a prognostic marker but a predictive marker for patients.” – by Cameron Kelsall
For more information:
J. William Harbour, MD, can be reached at firstname.lastname@example.org.
Disclosure: The study was funded in part by the NIH, NCI, Research to Prevent Blindness, Melanoma Research Alliance, Melanoma Research Foundation, 2015 AACR Ocular Melanoma Foundation Fellowship and Department of Defense. Harbour reports inventing intellectual property used in the conduct of this study, as well as royalties associated with its commercialization. He further reports a consultant role with Castle Biosciences, which licensed the intellectual property used in this study. The other researchers report no relevant financial disclosures.