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 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.

Molecular pathology of uveal melanoma

“…139 The GEP-based test has been patented (DecisionDx-UM; www.castlebiosciences.com/test_UM.html) and has received a considerable amount of publicity in the lay press, as it is claimed by Harbour and associates, its originators, to be superior to all other testing methods. 137,138 A recent study was performed to compare the prognostic accuracy of the GEP assay and monosomy 3, detected by a ''multi-SNP'' assay, which was designed by the authors as a research tool and still requires external validation as a clinical molecular test. 128,138 Although the GEP-based assay is marketed as a 'stand-alone' assay for prognostication, MLPA has been demonstrated to provide as accurate prognostication when considered with clinical and histomorphological features of UM.…”

“…137,138 A recent study was performed to compare the prognostic accuracy of the GEP assay and monosomy 3, detected by a ''multi-SNP'' assay, which was designed by the authors as a research tool and still requires external validation as a clinical molecular test. 128,138 Although the GEP-based assay is marketed as a 'stand-alone' assay for prognostication, MLPA has been demonstrated to provide as accurate prognostication when considered with clinical and histomorphological features of UM. Consequently, the study by Onken et al, that assessed monosomy 3 alone, fails to compare the most robust approach to genetic prognostic testing available.…”

Prognostication in eye cancer: the latest tumor, node, metastasis classification and beyond

“…Gene expression profiling is available as a commercial, internally validated service from Castle Biosciences Inc. (Friendswood, TX, USA). An advantage of this technique is that it needs a smaller amount of 36 suggesting a need for refining the classification. Analysis of very long-term survival data show that metastases of uveal melanoma can remain occult for three decades after enucleation of the primary tumour.…”

The pathology of ocular cancer

“…21 A proprietary GEP assay using a microarray of only 13 genes has been reported to be the most accurate prognostic marker for melanoma mortality and metastasis, although this remains controversial. 22,23 Although greatly inferior to chromosomal analysis and GEP, clinical examination and routine histopathological examination of uveal melanoma can reveal a number of important prognostic factors. Tumor size (largest tumor diameter and thickness) and the presence or absence of ciliary body involvement and extraocular extension are the most important factors that can be determined on clinical examination.…”