New Biomarker Stratifies High vs Low Risk Uveal Melanoma

MedicalResearch.com Interview with:

J. William Harbour, MD Professor & Vice Chairman Dr. Mark J. Daily Endowed Chair Director, Ocular Oncology Service Bascom Palmer Eye Institute Interim Associated Director for Basic Research Leader, Eye Cancer Site Disease Group Sylvester Comprehensive Cancer Center Member Interdisciplinary Stem Cell Institute University of Miami Miller School of Medicine Biomedical Research Building, Room 824 Miami FL 33136

Dr. J. William Harbour

J. William Harbour, MD
Professor & Vice Chairman
Dr. Mark J. Daily Endowed Chair
Director, Ocular Oncology Service
Bascom Palmer Eye Institute
Interim Associated Director for Basic Research
Leader, Eye Cancer Site Disease Group
Sylvester Comprehensive Cancer Center
Member Interdisciplinary Stem Cell Institute
University of Miami Miller School of Medicine
Biomedical Research Building, Room 824
Miami FL 33136

Medical Research: What is the background for this study? What are the main findings?

Dr. Harbour: Gene expression profiling has become the predominant means of molecular prognostic testing in uveal melanoma, with primary tumors being divided into Class 1 (low metastatic risk, about two thirds of cases) and Class 2 (high metastatic risk, about one third of cases).  In this study, we identified a new biomarker for uveal melanoma that subdivides Class 1 tumors based on the mRNA expression of the oncogene PRAME. Class 1 tumors not expressing PRAME have an extremely low metastatic risk, whereas those expressing PRAME have an intermediate metastatic risk.

Medical Research: What should clinicians and patients take away from your report?

Dr. Harbour: It is important to take into consideration the risk and pattern of metastasis associated with each molecular subtype of uveal melanoma when planning management. Our results would suggest that there are currently three clinically relevant subtypes of uveal melanoma:

Class 1/PRAME negative, Class 1/PRAME positive and Class 2.  Class 2 uveal melanomas, which almost always harbor BAP1 mutations, have a 70-80% 5 year metastatic rate, metastasis involves the liver in over 90% of cases, and they rarely respond to immunotherapy checkpoint inhibitors.  Class 1 uveal melanomas that express PRAME rarely harbor BAP1 mutations, have a ~30% 5 year metastatic rate, involve the liver in only about 50% of cases (thus surveillance of non-hepatic sites may be important), and there is at least a theoretical rational for investigating the use of immunotherapy.  Class 1 uveal melanomas not expressing PRAME have <5% 5 year metastatic risk and we do not recommend adjuvant therapy trials for these patients, who we manage only with a low intensity systemic surveillance protocol. 

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Harbour: Future research questions that need to be addressed:

  • (1) can PRAME expression be used to distinguish small uveal melanomas from the much more common benign uveal nevi?  this could have enormous implication for early treatment of small melanomas;
  • (2) does PRAME expression predict response to immunotherapy in uveal melanoma?

Medical Research: Is there anything else you would like to add?

Dr. Harbour: This prognostic test is available through Castle Biosciences as the DecisionDX-UM test, which is typically performed on a fine needle biopsy sample from the primary ocular tumor but can also be performed from archival FFPE samples.  This is the most widely used prognostic test and the only one to have been prospectively validated in a multicenter study.  The DecisionDX-UM test currently provides a subclassification of Class 1 tumors as Class 1A (low metastatic risk) versus Class 1B (intermediate metastatic risk.  The 1A/1B subclassification is being compared to PRAME for prognostic accuracy in a 27-center study to determine which is superior.  We anticipate that PRAME status may replace the 1A/1B system.

Citation:

PRAME as an Independent Biomarker for Metastasis in Uveal Melanoma

Matthew G. Field, Christina L. Decatur, Stefan Kurtenbach, Gülçin Gezgin,Pieter A. van der Velden, Martine J. Jager, Kaleigh N. Kozak,and J. William Harbour

Clin Cancer Res March 1, 2016 22:12341242; doi:10.1158/1078-0432.CCR-15-2071

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Dr. William Harbour (2016). New Biomarker Stratifies High vs Low Risk Uveal Melanoma