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Test Predicts Metastatic Potential of Ocular Melanomas


CHICAGO -- A test that seems to be able to predict the metastatic potential of ocular melanomas could help clinicians and patients get a jump on prevention and treatment of the malignancy.

CHICAGO, Sept. 13 -- A test that seems to be able to predict the metastatic potential of ocular melanomas could help clinicians and patients get a jump on prevention and treatment of the malignancy, researchers reported here.

The RNA- and DNA-based test of tumor samples can be performed with only small quantities of tissue and can accurately predict both metastatic risk and time to metastasis in patients with ocular (uveal) melanomas, reported J. William Harbour, M.D., of Washington University in St. Louis, and colleagues, at a meeting of the American Association for Cancer Research.

The test, currently limited to clinical research protocols, also has the potential to predict which patients with cutaneous melanomas are most likely to develop metastatic disease, the investigators suggested.

Despite local therapies such as radiation or enucleation, about half of all ocular melanomas will metastasize to liver, at which point the malignancy may be fatal within a few months.

"The delay from ocular diagnosis and treatment to clinical detection of liver metastasis varies from a few months to many years, indicating that micrometastases can remain dormant for long periods of time," Dr. Harbour and colleagues wrote in their abstract. "By the time metastatic disease becomes clinically detectable, it has grown to a large tumor burden that is highly resistant to therapy."

The investigators have been working for several years on molecular screens that could identify specific characteristics that confer metastatic potential on ocular tumors. Much of their research has been done on whole tumors in enucleated eyes. But only about 10% of eyes with melanoma required complete removal, and they wanted a means for testing the metastatic propensity of tumors in eyes spared from enucleation through radiation therapy.

In the current study, they demonstrated that even minute quantities of tumor tissues obtained through fine-needle aspiration biopsy can yield definitive clues to the potential lethality of micrometastases.

The screen, based on earlier work by Dr. Harbour and colleagues, divides primary tumors into low-risk (class 1) and high-risk (class 2) signatures, depending on the expression profile of three to 10 genes in the signature. Tumors with the class 2 signature have a greater than 90% chance of metastasizing to liver, the researchers have found.

In the study, presented at the AACR's meeting on molecular diagnostics in cancer therapeutic development, the investigators reported that they have adapted their gene expression assay to a small-scale format requiring only nanogram quantities of RNA that can be obtained through minimally invasive biopsy. They also examined the question of whether changes in the DNA copy number might provide additional prognostic information.

They first validated their modified screen by confirming that tumor classification was identical between needle-biopsy samples and larger tumor samples from the same enucleated eyes.

They then tested fine-needle biopsy samples obtained from the eyes of ocular melanoma patients who were about to undergo brachytherapy, and found that the discriminating gene list was "highly similar" to the gene list they had previously discovered in enucleated eyes.

The investigators also found that among class 2 tumors, there were two subtypes with differing degrees or risk, depending on the presence or absence of DNA copies on chromosome 8p, the short arm of chromosome eight.

They found that among tumors with 8p loss, the median time to metastasis was 25.8 months, compared with 37.4 months for tumors without 8p loss (P=0.02).

"We conclude that RNA- and DNA-based testing of fine needle aspirates is clinically feasible and accurately predicts metastatic risk and time to metastasis in ocular melanoma patients," the researchers wrote. "This predictive testing strategy could be used to guide the prophylactic systemic treatment of high risk patients with presumed micrometastatic disease."

Although they apparently have different mechanisms of malignant transformation, uveal melanomas and some cutaneous melanomas may be genetically related, Dr. Harbour noted.

"When we look at skin melanomas, we see similar molecular signatures that distinguish the lower-grade, horizontal growth pattern from the higher-grade, vertical growth pattern," he said. "So we are working very closely with other researchers at Washington University who study skin melanoma to see whether this test might be useful in predicting whether some patients with skin cancer might be at increased risk for metastasis."

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