Molecular Markers Help Identify Men with High-Risk Prostate Cancer

A newly discovered four-gene signature might someday be used to help clinicians distinguish between indolent and aggressive prostate cancer at diagnosis and end the ongoing debate over immediate versus delayed treatment. “The vast majority of prostate cancers would not become life-threatening, even if left untreated. But because we can't accurately forecast which are likely to spread and which aren’t, there is a tendency to unnecessarily subject many men to draconian interventions,” said Ronald DePinoh, MD, director of Dana-Farber’s Belfer Institute for Applied Cancer Science, in a press release. DePinoh expressed optimism that Metamark Genetics, a biotechnology company operated by Belfer Institute and the study’s primary sponsor, will be able to develop a clinical test for the gene signature within a year.

 

The investigators began by looking at prostate tumor samples from mice with inactive PTEN genes. Previous studies have observed that PTEN loss is associated with prostate cancer that tends to remain localized. They theorized that the lack of PTEN led to activation of a pathway responsible for suppressing the disease and identified the TGFβ-SMAD4 pathway as a likely candidate. To confirm the theory, DePinho said they knocked out PTEN expression in some of the mice and observed that signaling along this pathway “shot through the roof.” In addition, mice lacking the PTEN gene and the SMAD4 gene quickly developed large tumors and distant metastases.

 

Comparing molecular expression patterns between mice with indolent prostate cancer and mice with aggressive disease, the researchers identified 300 genes possibly involved. They narrowed these down to two: SPP1 and CyclinD1.

 

To determine whether the four genes predicted aggressive versus indolent disease in humans, the researchers screened prostate cancer tissue samples from physicians enrolled in the Physician's Health Study. The test accurately predicted prognosis in 83% of cases. In comparison, said DePinho, the Gleason score has a 60% to 70% accuracy rate. Combining the four-gene signature with Gleason scoring proved the most effective, with an accuracy rate of nearly 90%.

 

Adverse effects of prostate cancer treatment include impotence and incontinence, and DePinho said 48 men in the United States receive unnecessary treatment for every life saved, at a cost of more than $600 million annually. These statistics underscore the need for a test that lets clinicians identify which men need immediate treatment and which ones are candidates for a watch-and-wait approach. Complete findings from the study were published last week in the journal Nature.