The Collaborative Ocular Oncology Group Study No. 2 (COOG2) is the largest multicentre prospective biomarker study to date in uveal melanoma, with longer follow-up and more representative, real-world distribution of tumour size, ciliary body involvement, and AJCC tumour stage than COOG1 or The Cancer Genome Atlas and more similar to a large international database encompassing the full spectrum of uveal melanoma.
Key COOG2 findings include prospective validation of 15-gene expression profile (15-GEP) and the cancer-testis antigen Preferentially Expressed Antigen in Melanoma (PRAME) as independent prognostic biomarkers in uveal melanoma, superiority of PRAME status over the 1A/1B system for class 1 tumours, establishment of a new 4-group 15-GEP/PRAME system, and validation of tumour diameter as the only clinical factor that improves the accuracy of 15-GEP/PRAME. The findings are published by Dr. J. William Harbour of the Department of Ophthalmology and the Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center in Dallas, TX, US and colleagues on 25 July 2024 in the JCO.
The authors wrote in the background that there are numerous clinical, histopathologic, and molecular factors that have been proposed as prognostic variables in uveal melanoma; however, GEP has been shown to provide prognostic accuracy superior to other factors. A standardised 15-GEP was developed to classify primary uveal melanomas from a biopsy sample. The 15-GEP has undergone analytic optimisation for use on fine needle and formalin-fixed samples. The 15-GEP was prospectively validated by the COOG1 and subsequent studies.
RNA expression of PRAME was found to provide additional prognostic information independent of 15-GEP, being associated with increased metastatic risk in both class 1 and class 2 tumours. Although the initial COOG1 study did not identify any clinical factors that provided prognostic information independent of 15-GEP, subsequent retrospective studies have suggested that tumour diameter may enhance the accuracy of 15-GEP.
In this first report of the COOG2, the study team evaluate the prognostic value of 15-GEP, PRAME, and clinical prognostic factors in developing an integrated prognostic classifier suitable for routine clinical practice and clinical trial stratification. This study included 1,577 patients with uveal melanoma of the choroid and/or ciliary body who were prospectively monitored across 26 North American centres. Test results for 15-GEP (class 1 or class 2) and PRAME expression status (negative or positive) were available for all patients. The primary endpoint was metastasis-free survival (MFS).
15-GEP was class 1 in 1,082 (68.6%) and class 2 in 495 (31.4%) patients. PRAME status was negative in 1,106 (70.1%) and positive in 471 (29.9%) patients. The study team reported the 5-year MFS of 95.6% (95% confidence interval [CI] 93.9 to 97.4) for class 1/PRAME-negative, 80.6% (95% CI 73.9 to 87.9) for class 1/PRAME-positive, 58.3% (95% CI 51.1 to 66.4) for class 2/PRAME-negative, and 44.8% (95% CI 37.9 to 52.8) for class 2/PRAME-positive.
By multivariable Cox proportional hazards analysis, 15-GEP was the most important independent predictor of MFS (hazard ratio [HR] 5.95, 95% CI 4.43 to 7.99; p < 0.001), followed by PRAME status (HR 1.82 [95% CI 1.42 to 2.33]; p < 0.001). The only clinical variable demonstrating additional prognostic value was tumour diameter.
According to the authors, this integrated prognostic tool is a uniquely valuable resource to establish standardised entry criteria for high-risk adjuvant clinical trials, and it provides a gold standard for evaluating other prognostic biomarkers.
The study findings were previously presented in part at the Retina Society Annual Meeting (11-19 September 2019; London, UK), American Academy of Ophthalmology Annual Meeting (13-15 November 2020; virtual), Association for Research in Vision and Ophthalmology Annual Meeting (1-7 May 2021; virtual), International Society of Ocular Oncology Meeting (17-22 June 2022; Leiden, the Netherlands), American Society of Retina Specialists Annual Meeting (10 July 2022; New York City, NY, US), and the FLORetina Meeting (30 November-3 December 2023; Rome, Italy).
The study was supported by grants and awards from different entities.
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). JCO; Published online 25 July 2024. DOI: https://doi.org/10.1200/JCO.24.00447