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)

Abstract

PURPOSEValidated and accurate prognostic testing is critical for precision medicine in uveal melanoma (UM). Our aims were to (1) prospectively validate an integrated prognostic classifier combining a 15-gene expression profile (15-GEP) and PRAME RNA expression and (2) identify clinical variables that enhance the prognostic accuracy of the 15-GEP/PRAME classifier.MATERIALS AND METHODSThis study included 1,577 patients with UM of the choroid and/or ciliary body who were enrolled in the Collaborative Ocular Oncology Group Study Number 2 (COOG2) and prospectively monitored across 26 North American centers. Test results for 15-GEP (class 1 or class 2) and PRAME expression status (negative or positive) were available for all patients. The primary end point was metastasis-free survival (MFS).RESULTS15-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. Five-year MFS was 95.6% (95% CI, 93.9 to 97.4) for class 1/PRAME(-), 80.6% (95% CI, 73.9 to 87.9) for class 1/PRAME(+), 58.3% (95% CI, 51.1 to 66.4) for class 2/PRAME(-), and 44.8% (95% CI, 37.9 to 52.8) for class 2/PRAME(+). 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 < .001), followed by PRAME status (HR, 1.82 [95% CI, 1.42 to 2.33]; P < .001). The only clinical variable demonstrating additional prognostic value was tumor diameter.CONCLUSIONIn the largest prospective multicenter prognostic biomarker study performed to date in UM to our knowledge, the COOG2 study validated the superior prognostic accuracy of the integrated 15-GEP/PRAME classifier over 15-GEP alone and clinical prognostic variables. 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 UM.

FIG 1.

Overview of Collaborative Ocular Oncology Group Study 2 (COOG2) and patients included in this report.

FIG 2.

Metastasis-free survival (left panels) and melanoma-specific survival (right panels) stratified by (A) and (B) 15-gene expression profile (15-GEP) class, (C) and (D) PRAME RNA expression status, and (E) and (F) integrated 15-GEP/PRAME subclassifications. Five-year point estimates are indicated by the gray dotted line. P value, log-rank test, and number of patients at risk at each 12-month interval are shown. Censoring events are marked with a vertical hash across the survival curve (See Appendix Table A3 for complete 3-year and 5-year outcomes with 95% CIs, along with total number of metastasis/death events on study). MFS, metastasis-free survival; MSS, melanoma-specific survival.

FIG A1.

Kaplan-Meier survival curves for patients with class 1 15-gene expression profile results, separated by subclass 1A and 1B. (A) MSS and (B) MFS. Five-year point estimates and 95% CIs, along with the number of events (detection of distant metastasis or uveal melanoma-related death) are shown in the tables above each curve. P value, log-rank test. Number of patients at risk at each 12-month time point is shown below the plots. Censoring events are marked with a vertical hash across the survival curve. 15-GEP, 15-gene expression profile; MFS, metastasis-free survival; MSS, melanoma-specific survival; n.s., not statistically significant.

FIG A2.

Five-year metastasis-free survival by AJCC 8th edition T stage, subclassified by GEP/PRAME groups. (A) T1, (B) T2, (C) T3, and (D) T4. P value, log-rank test. Number of patients at risk at each 12-month time point is shown below the plots. Censoring events are marked with a vertical hash across the survival curve. 15-GEP, 15-gene expression profile; AJCC, American Joint Committee on Cancer; MFS, metastasis-free survival.