New Test Can Help Predict Aggressive Cancers               

prostate cancer
Lotan and De Marzo hope the test for PTEN loss will become an 
important part of the diagnosticarsenal for prostate cancer
PTEN is a pretty important gene. It's a tumor suppressor, which means that it helps prevent the out-of-control cell growth that can lead to cancer. "It acts like the brakes on a car for cancer cells," says urologic pathologist Angelo De Marzo, M.D., Ph.D., whose laboratory has been studying this gene's loss in prostate cancer for nearly a decade. When PTEN is knocked out – as it is in about half of lethal prostate tumors – cancer cells behave more aggressively. "The loss of PTEN leads to uncontrolled cancer cell growth, and the prevention of cancer cell death. PTEN is one of the few genes whose loss has been consistently associated with aggressive prostate cancer."

"Most studies have found that PTEN loss is a powerful predictor of which prostate tumors are likely to recur or metastasize," says urologic pathologist Tamara Lotan, M.D. In recent animal studies, Charles Bieberich, Ph.D., and his team from the University of Maryland-Baltimore County, working with Hopkins scientists De Marzo, Lotan, and Srinivasan Yegnasubramanian M.D., Ph.D., have discovered that the loss of PTEN in mice enables certain prostate cancer cells that overexpress the MYC oncogene to metastasize and kill the mice.

Measuring the loss of PTEN in prostate cancer tissue has not been terribly easy or effective; for years, pathologists have relied on a slow and relatively more expensive test called "fluorescent in situ hybridization," or FISH, and because the test has been so cumbersome, PTEN loss is not routinely tested when a man is diagnosed with prostate cancer. Thanks to a novel, commercially available antibody that was tested and validated extensively several years ago by De Marzo's laboratory, this may soon change.

Compared to FISH, the new test is less expensive, faster, and much easier for pathologists to interpret. New studies led by Lotan with De Marzo and others at Hopkins suggest this new PTEN test, based on a relatively simple immunohistochemistry, or IHC, assay, is nearly ready for widespread routine use. In a study of radical prostatectomy patients followed closely for many years by Patrick Walsh, M.D., Lotan evaluated a large number of tissue specimens using a technology called "high throughput Tissue Micro Array." Using the IHC test, she discovered a strong correlation between the loss of PTEN and the signs of aggressive prostate cancer, including the Gleason grade of the tumor as well as the stage of the tumor and the time it took for metastases to develop; this work was published in Clinical Cancer Research. In a larger follow-up study published in Modern Pathology, Lotan and De Marzo, along with pathologist George Netto, M.D., urologist Misop Han, M.D., and epidemiologist Elizabeth Platz, Sc.D., M.P.H, the IHC test found that PTEN loss correlated with faster recurrences after radical prostatectomy, "again indicating a link between PTEN loss in tumors and aggressive behavior," notes De Marzo.

"The new test is less expensive,
faster, and much easier for
pathologists to interpret."

In another study recently published in Modern Pathology, Lotan, along with De Marzo and Jonathan Epstein, the Rose-Lee and Keith Reinhard Professor in Urologic Pathology, showed that the PTEN test can help pathologists identify an important subtype of non-invasive tumor called intraductal carcinoma of the prostate. Intraductal cancers spread in ducts within the prostate and don't venture outside the gland, but they keep bad company: "They have been known for years to be associated with highly aggressive and often deadly invasive prostate cancers," she says. Intraductal cancers are often difficult for pathologists to diagnose under the microscope, but Lotan has shown that these tumors have almost always lost PTEN, and she believes that this finding may help pathologists "better recognize these tumors and identify men who are at risk for developing metastases and lethal prostate cancer."

Also using the new IHC assay, De Marzo's lab, helped by Lotan's group, has been able to establish a timetable of what happens in many prostate cancers on the genetic level – key molecular changes that can pinpoint precisely how prostate cancer develops and progresses to become a lethal disease. These results were published in Prostate Cancer Prostatic Disease. "We showed that PTEN loss happens after the fusion of two genes, TMPRSS2 and ERG," says De Marzo, "which occurs in about half of all prostate cancers."

With these new insights into prostate cancer's timetable, De Marzo and Lotan hope – now that PTEN loss can be checked more easily and efficiently with the new IHC test – that PTEN will become an important part of the diagnostic arsenal. Say a needle biopsy shows that a man apparently has low-risk disease. Does he need treatment right away? Two studies still in progress may provide definitive evidence. One study relates to work done by epidemiologist Bruce Trock, M.D., and De Marzo's group that found when PTEN loss was present in low-grade prostate cancer, it strongly indicated that higher-grade cancer was nearby. The second study, still under way and led by former Hopkins pathologist David Berman, M.D., Ph.D. (now at Queen's University in Ontario) and Lotan, working with De Marzo and Platz's group, showed that patients whose prostate biopsies showed loss of PTEN were "significantly more likely to harbor tumors at radical prostatectomy that were higher-grade than those without a loss of PTEN," says De Marzo. In related work, Lotan is heading up the Hopkins effort in a large Department of Defense "Transformative Impact" award, spearheaded out of Memorial Sloan Kettering Cancer Center, to examine whether the PTEN test can help identify men who could benefit from specially targeted drugs to metastatic prostate tumors.

PTEN is one of the few genes
whose loss has been consistently
associated with aggressive
prostate cancer.

"Putting together all of these findings over the last several years," says De Marzo, "it is clear that there is compelling clinical evidence that PTEN loss is associated with aggressive prostate cancer, which is paving the way for the ultimate widespread use of the PTEN IHC test in the clinic for men with low- to intermediate-risk prostate cancer."

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