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 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 to the 7th edition clinical Tumor-Node-Metastasis (TNM) classification and to chromosome 3 status. Main Outcome Measures Patients were managed for their primary tumor and monitored for metastasis. Results The GEP assay successfully classified 446/459 (97.2%) cases. 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 (1.1%) class 1 cases and 44 (25.9%) class 2 cases (log rank test, P<10−14). Although there was an association between GEP class 2 and monosomy 3 (Fisher exact test, P<0.0001), 54/260 (20.8%) tumors were discordant for GEP and chromosome 3 status, among which GEP demonstrated superior prognostic accuracy (log rank test, P=0.0001). 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 three 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. 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.

(Br J Ophthalmol 1999;83:98-103)

(Br J Ophthalmol 1997;81:386-390) Orbital metastases are an infrequent aetiology of adult proptosis; approximately 3-7% of orbital biopsies have domonstrated a metastatic tumour, and this diagnosis is often unexpected.1-5 Metastatic orbital deposits are less common than uveal metastases; in several series the relative incidence was approximately one to eight. 4 6 7 In both sites, a metastatic tumour may present with ophthalmic symptons before the discovery of the primary neoplasm; this more common with lung, gastrointestinal, thyroid, and renal carcinomas.4 5 In contrast, as many as 90% of breast cancers that metastasise to ocular structures have had treatment for the primary tumour.

Purpose:To compare a gene expression^based classifier versus the standard genetic prognostic marker, monosomy 3, for predicting metastasis in uveal melanoma. Experimental Design: Gene expression profiling, fluorescence in situ hybridization (FISH), and array comparative genomic hybridization (aCGH) were done on 67 primary uveal melanomas. Clinical and pathologic prognostic factors were also assessed. Variables were analyzed by Cox proportional hazards, Kaplan-Meier analysis, sensitivity, specificity, positive and negative predictive value, and positive and negative likelihood ratios. Results: The gene expression^based molecular classifier assigned 27 tumors to class 1 (low risk) and 25 tumors to class 2 (high risk). By Cox univariate proportional hazards, class 2 signature (P = 0.0001), advanced patient age (P = 0.01), and scleral invasion (P = 0.007) were the only variables significantly associated with metastasis. Only the class 2 signature was needed to optimize predictive accuracy in a Cox multivariate model. A less significant association with metastasis was observed for monosomy 3 detected by aCGH (P = 0.076) and FISH (P = 0.127). The sensitivity and specificity for the molecular classifier (84.6% and 92.9%, respectively) were superior to monosomy 3 detected by aCGH (58.3% and 85.7%, respectively) and FISH (50.0% and 72.7%, respectively). Positive and negative predictive values (91.7% and 86.7%, respectively) and positive and negative likelihood ratios (11.9 and 0.2, respectively) for the molecular classifier were also superior to those for monosomy 3. Conclusions: Molecular classification based on gene expression profiling of the primary tumor was superior to monosomy 3 and clinicopathologic prognostic factors for predicting metastasis in uveal melanoma.In recent years, there has been increasing interest in individualized management of cancer patients based on predictive molecular testing (1, 2). Uveal (ocular) melanoma represents an ideal cancer for applying this strategy. Uveal melanoma is the most common primary cancer of the eye and has a strong predilection for hematogenous metastasis, particularly to the liver (3). Investigators have searched for clinical and pathologic prognostic factors for over a century and have identified several that are statistically associated with metastasis, including advanced patient age, anterior tumor location, increased tumor size, epithelioid cell type, and local tumor invasion through the sclera. However, predictive accuracy of these factors has not been adequate for making individualized clinical decisions, such as whether a given patient is at sufficiently high risk for metastasis to necessitate more intense and frequent metastatic surveillance or whether prophylactic systemic therapy may be appropriate. More recently, investigators have identified genetic alterations, such as monosomy 3, which are significantly associated with metastasis (4 -6). With the development of more precise techniques for detecting chromosomal alterations, such as spectral karyoty...

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