Integrated 15-GEP and PRAME Classifier Shows Prognostic Accuracy in Uveal Melanoma

J. William Harbour, MD

An integrated 15-gene expression profile (15-GEP) and PRAME RNA expression classifier demonstrated prognostic accuracy in patients with uveal melanoma, according to data from the Collaborative Ocular Oncology Group Study Number 2 (COOG2) published in the Journal of Clinical Oncology.

In the largest prospective multicenter prognostic biomarker study performed to date, the 5-year metastasis-free survival (MFS) rate among patients with PRAME-negative tumors (n = 1106) was 86.6% (95% CI, 84.2%-89.1%) compared with 63.7% (95% CI, 58.5%-69.3%) among patients with PRAME-positive tumors (n = 471). At the median follow-up of 43.6 months, the 5-year melanoma-specific survival (MSS) rates were 93.1% (95% CI, 91.2%-95.0%) vs 78.5% (95% CI, 73.9%-83.3%), respectively.

Additionally, patients who had class 1 tumors experienced superior actuarial survival compared with those with class 2 tumors. Those with class 1 tumors (n = 1082) achieved a 5-year MFS rate of 92.3% (95% CI, 90.2%-94.4%) vs 52.1% (95% CI, 47.0%-57.8%) for those with class 2 tumors (n = 495); 5-year MSS rates were 97.4% (95% CI, 96.2%-98.7%) vs 68.8% (95% CI, 63.6%-74.5%), respectively.

“This report provides prospective multicenter validation, the highest level of biomarker evidence, for integrating 15-GEP with PRAME expression status into a 4-group prognostic classification system. This integrated prognostic tool is a uniquely valuable resource to establish standardized entry criteria for high-risk adjuvant clinical trials, and it provides a gold standard for evaluating other prognostic biomarkers,” J. William Harbour, MD, and coauthors wrote. Harbour is professor and chair of the Department of Ophthalmology at UT Southwestern Medical Center in Dallas, Texas.

Data from the study revealed that patients with PRAME-positive tumors experienced worse MFS compared with those with PRAME-negative disease in both the class 1 and class 2 tumor subgroups. Five-year MFS rates were 95.6% (95% CI, 93.9%-97.4%) among patients with class 1 PRAME-negative tumors (n = 836), 80.6% (95% CI, 73.9%-87.9%) for those with class 1 PRAME-positive tumors (n = 246), 58.3% (95% CI, 51.1%-66.4%) for patients with class 2 PRAME-negative tumors (n = 270), and 44.8% (95% CI, 37.9%-52.8%) among those with class 2 PRAME-positive tumors (n = 225). The respective MSS rates were 98.8% (95% CI, 97.9%-99.7%), 92.6% (95% CI, 88.3%-97.1%), 74.7% (95% CI, 68.0%-82.2%), and 61.3% (95% CI, 53.5%-70.2%).

COOG2 enrolled adult patients with uveal melanoma involving the choroid, ciliary body, and/or iris between January 2017 and April 2020 in the US and Canada. Those who received prior radiotherapy or had primary iris melanoma or metastatic uveal melanoma at baseline were excluded. Further, 5.9% of patients with a class 1 tumor compared with 41.4% of patients with a class 2 tumor developed metastatic disease (P < .001).

“To our knowledge, COOG2 is the largest multicenter prospective biomarker study to date in uveal melanoma, with longer follow-up and more representative, real-world distribution of tumor size, ciliary body involvement, and AJCC tumor stage than [data from] COOG1 or The Cancer Genome Atlas and more similar to a large international database encompassing the full spectrum of uveal melanoma. This may explain, at least in part, the more favorable outcomes in COOG2,” study authors wrote.

Among 1577 patients with melanoma enrolled in the study, the median age was 64 years (range, 18-99). Most patients had PRAME-negative disease (70.1%), were White (96.3%), and were male (51.3%). Patients had blue/green (38.9%), brown (15.1%), intermediate (8.1%), or not specified (38.0%) colored irises. The median tumor diameter was 12 mm (range, 2-32) and the median tumor thickness was 4.1 mm (range, 0.5-18). Patients also had AJCC T1 (33.6%), T2 (35.8%), T3 (22.8%), or T4 (7.8%) disease and received prior tumor treatment with 125I plaque brachytherapy (80.2%), enucleation (10.2%), proton beam radiotherapy (7.3%), external beam radiotherapy (0.7%), laser therapy (0.5%), or other/unspecified (1.1%).

Patients enrolled in COOG2 had class 1 tumors (68.6%) that were class 1A (43.9%) or class 1B (24.7%) or had class 2 tumors (31.4%). Further, 17.1% of patients had distant metastases and 15.9% had ciliary body involvement.

Additional findings from a multivariable Cox proportional hazards analysis revealed that the most important independent predictors of MFS were 15-GEP (HR, 5.95; 95% CI, 4.43-7.99; P < .001) and PRAME status (HR, 1.82; 95% CI, 1.42-2.33; P < .001).

“Tumor diameter was found to be the only clinical variable to provide additional prognostic information. This prognostic classifier provides an advanced resource for risk-adjusted metastatic surveillance and adjuvant trial stratification in patients with uveal melanoma,” study authors noted.

“Key findings include [the] prospective validation of 15-GEP and PRAME as independent prognostic biomarkers in uveal melanoma, superiority of PRAME status over the 1A/1B system for class 1 tumors, establishment of a new 4-group 15-GEP/PRAME system, and validation of tumor diameter as the only clinical factor that improves the accuracy of 15-GEP/PRAME,” study authors wrote in conclusion.

Reference

Harbour JW, Correa ZM, Schefler AC, et al. 15-gene expression profile and PRAME as integrated prognostic test for uveal melanoma: First report of collaborative ocular oncology group study no. 2 (COOG2.1). J Clin Oncol. Published online July 25, 2024. Accessed July 30, 2024. doi:10.1200/JCO.24.00447