The prostate cancer quandary_ how aggressive is that tumor -

The Prostate Cancer Quandary: How Aggressive Is That Tumor - Dow Jones Reprints: This copy is for your personal, non-commercial use only. To order presentation-ready copies for distribution to your colleagues, clients or customers, use the Order Reprints tool at the bottom of any article or visit The Prostate Cancer QuandaryBy MELINDA BECK Scientists may soon be able to answer the agonizing question facing men with prostate cancer: Doestheir cancer need immediate treatment or can it be left alone? Some 218,000 American men will be diagnosed with prostate cancer this year. An estimated 85% ofthose tumors will grow so slowly that they will never cause problems. But the rest are aggressive andlethal. As of now, there's no way to tell early on which cancers are which, so tens of thousands of menundergo surgery or radiation each year for cancers that never needed treatment, risking impotence orincontinence in the process.
Several recent genetic discoveries could help doctors evaluate how aggressive a man's prostate cancer ismuch earlier. Scientists at the University of Michigan have identified at least 24 different kinds ofprostate cancer of varying virulence whose DNA signatures can be read like a bar code. Memorial Sloan-Kettering Cancer Center researchers have identified other genetic subtypes of prostate cancer that seemto predict whether the tumor will be low or high risk. And Harvard Medical School scientists have founda specific gene that causes prostate cancers to spread. Some of the discoveries also could lead to newtreatments, tailored specifically for the kind of prostate tumor a man has.
Such genetic tests for prostate cancers would go well beyond the current PSA test (for prostate-specificantigen) used for screening men in general. PSA tests have helped find prostate cancers at much earlierstages, saving thousands of lives in recent years. But PSA levels also rise for reasons that have nothing todo with cancer, prompting many men to have prostate biopsies each year that don't find cancer or thatfind tumors of the slow-growing variety.
Scientists say new prostate-cancer tests could be available in the not-too-distant future. "It won't be o : Diagnosing Several
tomorrow, but if you go by the pace at which such technology entered the field of breast cancer, it will beseveral years [for new prostate tests], not a decade," says Charles Sawyers, chairman of human oncology and pathogenesis at Memorial Sloan-Kettering.
At the University of Michigan, researchers have focused mainly on what are known as gene fusions, in The Prostate Cancer Quandary: How Aggressive Is That Tumor - which DNA from some genes gets stuck to other genes, altering what they do. Two of the 24 types theyhave identified involve the same gene, known as RAF, that drives malignant melanoma, according to areport in the journal Nature Medicine this month. Although those two types make up only about 2% ofthe tumors studied so far, they are highly aggressive, killing an estimated 3,600 men each year.
Treatment for those prostate cancers is on the horizon. Several anti-RAF drugs to treat melanoma haveregulatory approval or are in late-stage clinical trials. Early lab tests show that some of those drugs areeffective against RAF prostate-cancer cells.
Most of the remaining prostate-cancer types involve fusions of a gene called ETS, and they are more or less Researchers are closing in on ways to determine virulent depending on which fragments of other genes whether a prostate tumor is likely to metastasize,based on gene analyses. Click to enlarge image.
are fused to them. Jonathan Simons, chief executiveofficer of the Prostate Cancer Foundation, which fundsmuch of the Michigan research, likens the process torebuilding car engines out of random automotive parts.
"If you have a tumor with a lawn-mower engine, it maylook like a cancer, we may call it a cancer, but it maynever be a problem in the life of a 72-year old man," hesays. "But if you have a cancer with a bulky Dodge Hemistuck to a BMW 850csi V-12 engine, that needstreatment." Four of the 24 cancer types discovered, which together make up over 50% of the prostate cancers classified so far, have the equivalent of lawn-mower enginesand probably don't have enough power to grow past the prostate gland, Dr. Simons says. Another 20%are more highly powered and could pose problems in the presence of other gene fusions.
Getting AggressiveAnd one of the most aggressive types, representing 10% to 15% of prostate cancers, appears to follow adifferent mechanism: It results when there are excess amounts of a protein known as SPINK1. Since theprotein shows up in urine, the researchers say a urine test could be designed to measure its presence.
There could be more types, represented by different genetic bar codes. "We are finding more everymonth or so, filling in the gaps," says the lead investigator Arul Chinnaiyan, director of the MichiganCenter for Translational Pathology. To validate the findings, researchers, who so far have studied some300 tumor samples, plan to analyze at least 1,000 samples and to follow how the patients progress.
"We are not there yet, but within the next year, we hope to have a clinical lab test where we can predictwhat kind of cancer a man has," says Dr. Chinnaiyan.
Researchers at Memorial Sloan-Kettering are studying a different kind of genetic error involved inprostate cancer. Instead of two copies of a gene, some cancer cells have too many or too few, known ascopy-number alterations.
In a study in the journal Cancer Cell last week, the researchers analyzed the copy-number alterations in218 cancerous prostates surgically removed at Sloan-Kettering and found that they fell into six clusters.
Those clusters corresponded closely with how quickly the patients' cancer returned, judging by theirPSA. The Prostate Cancer Quandary: How Aggressive Is That Tumor - "It was a surprise to us that so much prognostic information was there in the original samples aftersurgery," Dr. Sawyers says. Ideally, "we'd be able to tell a man, 'Your tumor looks like it's in cluster five,so you should get surgery and radiation and perhaps even more aggressive therapy. Or, you are incluster two, so you can relax and maybe just get another biopsy in another year and see if your clusterhas changed," he says.
Tracking PatientsFurther testing at Sloan Kettering is continuing. The researchers have 1,000 additional samples fromprostates removed more than 10 years ago and can correlate their findings with how the patients faredin that time.
In still another recent breakthrough, researchers at Harvard Medical School identified a gene pathwaydirectly involved in prostate-cancer metastasis. They isolated a gene, DAB2IP, that acts as a brake forcancer. When too much of an enzyme, EZH2, is present, the DAB2IP gene is suppressed, removing thebrake and allowing the cancer to spread.
"It's more than just correlation; it's cause and effect," says lead researcher Karen Cichowski, a cancerbiologist, who demonstrated the process in mice in a study in Nature Medicine this year. The Harvardresearchers also studied data from human prostate cancers and found that the patients with the mostaggressive tumors had either excess EZH2 or too little DAB2IP or both.
These findings, too, could yield tests to predict how aggressive a patient's prostate cancer could be.
Several biotech companies have drugs in the works to inhibit EZH2.
The various research findings complement each other by describing different ways that genes mutate ascancers evolve, says Dr. Chinnaiyan. He expects that diagnostic tests in the future will look at a variety ofgenes, as well as proteins, molecules and other "biomarkers" to predict how aggressive a cancer mightbe.
Another technique being applied to prostate cancer involves magnetic resonance spectroscopy, a form of The Man, the Gland, the Dilemmas (3/31/2009) imaging that tracks chemical changes in tissues. In a Prostate Cancer: Weighing Options (4/7/2009) small study in the journal Science Translational Medicine this year, researchers at Harvard showed that 'Watchful Waiting' for Prostate Cancer(4/17/2009) the scanning technology can not only locate cancerswithin the prostate, but also has the potential to distinguish fast and slow-moving cancers.
Progress is also being made on ways to measure prostate cancers through simple blood and urine tests,or what scientists call "liquid biopsies." The biotech firm Gen-Probe Inc., working with the University ofMichigan researchers, has developed a test for a gene called PCA3 that shows up in urine only when aman has prostate cancer.
For now, the PCA3 test is mainly useful to tell men who have a rising PSA level that they should have abiopsy as well, or for men who have a negative biopsy that might have missed cancer. Dr. Chinnaiyanhopes the PCA3 test can also check for gene fusions that can identify which type of prostate cancer aman has. The Prostate Cancer Quandary: How Aggressive Is That Tumor - The PCA3 test is not yet approved by the Food and Drug Administration, but it is approved for use inEurope and is available in several U.S. labs on an investigational basis.
In other prostate-cancer news, there's more evidence that cholesterol-lowering statin drugs may play arole in controlling the spread of prostate cancer. In a study in the journal Cancer, researchers at DukeUniversity Medical Center and elsewhere analyzed the records of 1,319 men who had their prostatesremoved between 1988 and 2008 and found that 304 of them had a rising PSA level after surgery,which generally indicates that the cancer has reoccurred and spread. Men who were taking theequivalent of 20 mg of simvastatin a day were 43% less likely to see a recurrence. In men taking ahigher dose, the risk of recurrence was reduced by 50%.
The researchers cautioned that the reduced risk could be due to factors other than statins, such as diet,exercise or smoking habits; only a randomized clinical trial could tell for sure. Five other recent studiesalso have found that statins appear to lower the risk for advanced prostate cancer.
Write to Melinda Beck at
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