Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma

Abstract

Purpose: This study evaluates the prognostic performance of a 15 gene expression profiling (GEP) assay that assigns primary posterior uveal melanomas to prognostic subgroups: class 1 (low metastatic risk) and class 2 (high metastatic risk).

Design: Prospective, multicenter study.

Participants: A total of 459 patients with posterior uveal melanoma were enrolled from 12 independent centers.

Testing: Tumors were classified by GEP as class 1 or class 2. The first 260 samples were also analyzed for chromosome 3 status using a single nucleotide polymorphism assay. Net reclassification improvement analysis was performed to compare the prognostic accuracy of GEP with the 7th edition clinical Tumor-Node-Metastasis (TNM) classification and chromosome 3 status.

Main outcome measures: Patients were managed for their primary tumor and monitored for metastasis.

Results: The GEP assay successfully classified 446 of 459 cases (97.2%). The GEP was class 1 in 276 cases (61.9%) and class 2 in 170 cases (38.1%). Median follow-up was 17.4 months (mean, 18.0 months). Metastasis was detected in 3 class 1 cases (1.1%) and 44 class 2 cases (25.9%) (log-rank test, P<10(-14)). Although there was an association between GEP class 2 and monosomy 3 (Fisher exact test, P<0.0001), 54 of 260 tumors (20.8%) were discordant for GEP and chromosome 3 status, among which GEP demonstrated superior prognostic accuracy (log-rank test, P = 0.0001). By using multivariate Cox modeling, GEP class had a stronger independent association with metastasis than any other prognostic factor (P<0.0001). Chromosome 3 status did not contribute additional prognostic information that was independent of GEP (P = 0.2). At 3 years follow-up, the net reclassification improvement of GEP over TNM classification was 0.43 (P = 0.001) and 0.38 (P = 0.004) over chromosome 3 status.

Conclusions: The GEP assay had a high technical success rate and was the most accurate prognostic marker among all of the factors analyzed. The GEP provided a highly significant improvement in prognostic accuracy over clinical TNM classification and chromosome 3 status. Chromosome 3 status did not provide prognostic information that was independent of GEP.

Figure 1

Schematic of study design. COOG = Collaborative Ocular Oncology Group; GEP = gene expression profiling.

Figure 2

Comparison of gene expression profile (GEP) classification to other prognostic factors. Kaplan-Meier plots for the indicated prognostic factors. P-values were determined by log rank method. Age indicates patient age at the time of primary tumor diagnosis. D3, disomy 3; M3, monosomy 3. Threshold values for dichotomizing continuous variables (tumor thickness and diameter) were determined by receiver operating characteristic (ROC) analysis.

Figure 3

Comparison of gene expression profile (GEP) classification to chromosome 3 status. (A) Pie chart showing relationship between GEP class and chromosome 3 status in 293 patients. (B) Kaplan-Meier plot showing metastasis-free survival after primary tumor diagnosis in cases where GEP class and chromosome 3 status were discordant (class 1/monosomy 3 or class 2/disomy 3). Cases in which GEP and chromosome 3 status were concordant are shown for comparison in gray. P-value was determined by log rank method.