DecisionDx-UM and PRAME Improve Metastatic Risk Prediction in Uveal Melanoma

Uveal melanoma (UM) remains the most common primary intraocular malignancy in adults and one of the most challenging ocular cancers to manage. Despite advances in local tumor control, survival outcomes have changed little over decades because of UM’s strong propensity for early hematogenous metastasis, particularly to the liver. Accurate risk assessment at the time of diagnosis is therefore central to guiding surveillance intensity, referral to medical oncology, and enrollment in clinical trials.¹ A recently published multicenter prospective study by the Collaborative Ocular Oncology Group (COOG) offers new data comparing prognostic approaches and provides important insights for clinicians caring for patients with UM.²

The study, titled “Early Genetic Evolution of Driver Mutations in Uveal Melanoma,” and published in Nature Communications, represents the largest prospective, multicenter comparison to date of next-generation sequencing (NGS)–based mutation profiling versus combined gene expression profiling using DecisionDx-UM and PRAME. Investigators analyzed 1,140 primary UM tumors, including 131 small, early-stage lesions, with the goal of understanding how genetic changes drive progression from benign nevi to malignant melanoma and how best to translate these changes into clinically meaningful risk prediction.

Traditionally, UM prognostication has relied heavily on identifying recurrent driver mutations such as BAP1, SF3B1, and EIF1AX, which have been associated with high-, intermediate-, and low-risk metastatic behavior, respectively. Using NGS, the COOG investigators assessed 7 clusters of recurrent genetic alterations across the cohort. These results were then compared with outcomes predicted by combining DecisionDx-UM gene expression profiling and PRAME expression.

The central finding was that the combined DecisionDx-UM + PRAME approach outperformed mutation analysis alone in predicting both metastasis-free survival (MFS) and overall survival (OS). While individual mutations retained associations with risk in univariate analyses, their prognostic significance became non-significant and redundant when gene expression profiling was included in multivariate models.

"The recently published COOG2 study validated that combining DecisionDx-UM test results and PRAME gene expression data provides more precise metastatic risk prediction for patients with UM than either test used independently," said J. William Harbour, MD, ocular oncologist, and professor and chair of the Department of Ophthalmology at UT Southwestern Medical Center in Dallas, in a news release. "Our latest research builds on these findings and shows that the combination of DecisionDx-UM and PRAME delivers superior predictions of metastasis-free survival and overall survival compared to NGS-based mutation analysis. While gene mutation analysis remains valuable for other purposes, such as confirming tumor sampling quality and identifying patients for appropriate clinical trials, the DecisionDx-UM + PRAME combination offers the most comprehensive risk stratification available to guide more informed treatment pathway decisions for patients with UM.”

A key biological explanation proposed by the study authors lies in the scope of information captured by each testing modality. Targeted NGS focuses on DNA mutations within tumor cells, providing insight into oncogenic drivers and clonal evolution. In contrast, DecisionDx-UM measures gene activity not only from tumor cells but also from surrounding immune and stromal components, effectively incorporating features of the tumor microenvironment. This broader biological context may better reflect metastatic potential, particularly in early-stage tumors where mutations alone may not fully capture aggressive behavior.

Importantly, the authors do not dismiss the clinical value of mutation analysis. NGS remains useful for confirming biopsy adequacy, understanding tumor biology, and identifying patients who may be eligible for mutation-specific clinical trials. However, when the clinical question is prognostication and risk-adapted management, the combined gene expression approach appeared to provide the most comprehensive stratification in this prospective dataset.

From a practical standpoint, Castle Biosciences currently offers DecisionDx-UM, DecisionDx-PRAME, and DecisionDx-UMSeq from a single biopsy sample, allowing clinicians to integrate gene expression and mutation data without requiring additional tissue. This is particularly relevant in UM, where biopsy samples are often small and tumor manipulation must be minimized.

The findings also reinforce the importance of molecular testing even in small or early-stage tumors. UM lesions are known to metastasize while still relatively small and clinically subtle, making early biological risk assessment critical. The inclusion of 131 small tumors in this study strengthens the relevance of the results to real-world diagnostic dilemmas faced by ocular oncologists.

By prospectively comparing mutation-based and gene expression–based prognostic tools across a large, multicenter cohort, this study provides evidence that integrating DecisionDx-UM and PRAME offers superior prediction of clinically meaningful outcomes. For clinicians, these data support a nuanced, complementary approach to molecular testing—one that recognizes the strengths of both mutation analysis and gene expression profiling while prioritizing tools that most accurately inform patient management and long-term surveillance strategies.

References

1. Jager MJ, Shields CL, Cebulla CM, et al. Uveal melanoma. Nat Rev Dis Primers. 2020;6(1):24. Published 2020 Apr 9. doi:10.1038/s41572-020-0158-0
2. Landmark study shows combination of Castle Biosciences' DecisionDx®-UM and PRAME outperforms gene mutation analysis in predicting survival outcomes in uveal melanoma. News release. Castle Biosciences. Published December 17, 2025. Accessed December 17, 2025. https://www.globenewswire.com/news-release/2025/12/17/3206851/0/en/Landmark-Study-Shows-Combination-of-Castle-Biosciences-DecisionDx-UM-and-PRAME-Outperforms-Gene-Mutation-Analysis-in-Predicting-Survival-Outcomes-in-Uveal-Melanoma.html