Elsevier

Ophthalmology

Volume 119, Issue 8, August 2012, Pages 1596-1603
Ophthalmology

Original article
Collaborative Ocular Oncology Group Report Number 1: Prospective Validation of a Multi-Gene Prognostic Assay in Uveal Melanoma

https://doi.org/10.1016/j.ophtha.2012.02.017Get rights and content

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.

Financial Disclosure(s)

Proprietary or commercial disclosure may be found after the references.

Section snippets

Patient Data and Tumor Samples

This study was conducted with the approval of the institutional review board or ethics committee of each participating institution. Informed consent was obtained from each patient, and the study adhered to the tenets of the Declaration of Helsinki. All work using patient information was performed in compliance with the Health Insurance Portability and Accountability Act. Inclusion criteria for the study patients were (1) clinical diagnosis of uveal melanoma and (2) investigational informed

Baseline Information

The study design is outlined in Figure 1. The GEP prognostic assay was performed on 459 posterior uveal melanomas obtained prospectively from 12 participating institutions. A total of 224 patients were female, and 235 patients were male. The mean age was 61.7 years (median, 61.0 years). The mean tumor diameter was 12.8 mm (median, 12.7 mm), and mean tumor thickness was 6.3 mm (median, 5.5 mm). Ciliary body involvement was absent in 308 cases, present in 139 cases, and unknown in 12 cases. Tumor

Comparison of Gene Expression Profiling with Chromosome 3 Status

Because monosomy 3 has been widely used as a prognostic marker for uveal melanoma, we wanted to study more closely the relationship between GEP and chromosome 3 status. Chromosome 3 status was collected from the first 260 cases, of which the GEP/chromosome 3 status was class 1/disomy 3 in 119 (45.8%), class 2/monosomy 3 in 87 (33.5%), class 1/monosomy 3 in 38 (14.6%), and class 2/disomy 3 in 16 (6.2%) (Fig 3A). As expected, there was a significant association between class 1 and disomy 3, and

Discussion

In this prospective multicenter collaborative study, the prognostic accuracy of a 15-gene prognostic assay for uveal melanoma was assessed. A strong association was observed between GEP class 2 and other adverse prognostic factors, including increased patient age, ciliary body involvement, larger tumor diameter and thickness, epithelioid cell type, and monosomy 3. However, GEP class was more strongly associated with metastasis than these other factors. In multivariate analysis, no combination

Acknowledgments

The authors thank Dr. Steve Kymes for statistical consultation.

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  • Cited by (0)

    Manuscript no. 2011-1353.

    Financial Disclosure(s): The author(s) have made the following disclosure(s): Dr. Harbour and Washington University may receive royalties based on a license of related technology by the University to Castle Biosciences, Inc. This research was not funded by Castle Biosciences, Inc.

    This work was supported by grants (to J.W.H.) from the National Cancer Institute (R01 CA125970), Barnes-Jewish Hospital Foundation, Kling Family Foundation, Tumori Foundation, Horncrest Foundation, and a Research to Prevent Blindness David F. Weeks Professorship, and by awards to the Department of Ophthalmology and Visual Sciences at Washington University from a Research to Prevent Blindness Inc unrestricted grant, and the National Institutes of Health Vision Core Grant P30 EY02687c.

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