By RON WINSLOW - The Wall Street Journal

Researchers said they have identified a combination of four genes that appear to play a critical role in determining whether prostate cancer in its early stages will go on to become an aggressive, lethal disease.

The information could enable doctors and patients to make better decisions after the diagnosis of prostate cancer, a disease that is commonly overtreated today, researchers said.

A genetic test based on the findings is being developed and could be available within a couple of years to help decide how aggressively to treat early-stage cancer, said Ronald DePinho, senior author of a paper published Wednesday in the journal Nature.

Closely held Metamark Genetics Inc., based in Cambridge, Mass., is developing the genetic test. Dr. DePinho, who is director of the Belfer Institute of Applied Cancer Science at Dana Farber Cancer Institute, Boston, said he had equity in Metamark.

Genomic Health Inc., of Redwood City, Calif., which markets similar tests for breast and colon cancers, is also developing one for prostate cancer.

Dr. DePinho said the four genes governed processes of cell division and cell invasion that determine whether a tumor is aggressive. Similar biology affects the fate of some other cancers.

Some 1 in 6 men will eventually get prostate cancer, according to the American Cancer Society. Roughly 32,000 die of it each year, making it the second leading cancer killer of men, after lung cancer.

About 220,000 new cases of prostate cancer are diagnosed in the U.S. each year, thanks to the widely used PSA tests which can detect the disease in early stages. But for a large majority of patients, the cancers are slow-growing and unlikely to cause symptoms or affect survival.

Conventional efforts to predict which tumors are likely to progress, based in part on looking at tumor cells under a microscope, are accurate about 60% to 70% of the time. As a result, many men undergo aggressive surgery and radiation treatments that provide little benefit; some may delay or forgo treatment that would help them.

Dr. DePinho said studies showed 48 men with prostate cancer were treated with either surgery or radiation to prevent one death from the disease. He said the new study suggested a test based on the four genes, when added to current prediction protocols, could improve accuracy to about 90%.

Charles Sawyers, a cancer expert and Howard Hughes Medical Institute Investigator at Memorial Sloan Kettering Cancer Center in New York, said if it turned out that such a test is 90% accurate, "it would have a huge impact." Many men with a "favorable profile" might want to monitor the progress of their cancer for a while before deciding to undergo aggressive treatment, he said.

Dr. Sawyers, who wasn't involved in the research, cautioned that such gene signatures had been proposed to predict cancer progression in the past and hadn't panned out. He said the genes the new research focuses on appeared to have a functional role in regulating cancer development. But more research would be necessary to validate whether a test would have value for doctors and patients.

"It takes a lot of confirmatory studies by independent groups for the field to reach consensus," he said.

To find the genetic signature for aggressive prostate cancer, Dr. DePinho and his colleagues initially analyzed mice lacking a gene called PTEN. Such mice develop cancer, but generally an indolent kind that doesn't metastasize or spread elsewhere in the body. Further gene studies revealed that cancer associated with PTEN became aggressive when activity of another gene, SMAD4, was "extinguished," he said.

SMAD4 in turn regulated two other genes, one associated with tumor growth and the other with movement. Without SMAD4, these two genes were active, making proteins that promote the growth and spread of cancer.

"These four genes are directly linked to the aggressive behavior of the cancers," Dr. DePinho said.

The researchers screened tumor samples taken years ago from more than 400 men with prostate cancer, including some who had died, to find the improved predictability for the four-gene signature. The men had participated in the long-running Physicians Health Study at Harvard Medical School.

Write to Ron Winslow at ron.winslow@wsj.com

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