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Health & Medicine for Senior Citizens

Study Finds Way to ID Aggressive Prostate Cancers; Save Men from Aggressive Therapy

Many prostate cancer patients treated unnecessarily; vast majority would not become life-threatening, even if left untreated

Feb. 3, 2011 – A new discovery lays the ground work for the first gene-based test for determining whether a man's prostate cancer is likely to remain dormant within the prostate gland, or spread lethally to other parts of the body. Today, many men, mostly senior citizens, endure drastic procedures that are used unnecessarily on unaggressive cancers.

Dana Farber Cancer Institute researchers have found that prostate tumors that carry a "signature" of four molecular markers have the potential to become dangerously metastatic if not treated aggressively.

Their study is reported online today by the journal Nature.

 

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More Links Below Story


 
 

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By analyzing prostate cancer tissue from hundreds of men participating in a national health study, dozens of whom died of the disease, investigators led by Ronald DePinho, MD, Lynda Chin, MD, and Zhihu Ding, PhD, of Dana-Farber, found that the four-gene/protein signature more accurately predicted which patients would die from metastatic spread than did the conventional method.

The standard measure of prostate cancer's aggressiveness, known as the Gleason score (which is based on cancer cells' appearance under a microscope), is accurate about 60 to 70 percent of the time depending on the skill of the pathologist. The four-gene signature method alone was accurate 83 percent of the time. Combining the markers and Gleason methods produced an accuracy of approximately 90 percent.

"It's widely recognized that many prostate cancer patients are treated unnecessarily," says DePinho, who is the director of Dana-Farber's Belfer Institute for Applied Cancer Science.

"What Is Prostate Cancer?"
[1 min 41 sec]

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Transcript, Video help

"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."

The result, DePinho says, is that approximately 48 men are treated for prostate cancer for every life saved. The cost of such overtreatment is estimated at more than $600 million a year in the United States alone. There is a physical price as well. The main forms of prostate cancer treatment — surgery and radiation therapy — can produce a range of lasting complications, such as impotence and urinary problems, including incontinence.

The main obstacle to developing better prognostic tests for prostate cancer has been the lack of uniformity of cells in different tumors, and even within a single tumor. In 85 percent of prostate cancer cases, the prostate gland holds more than one tumor focus, each of which may contain a different assortment of cancer cells with a distinct set of gene abnormalities. Such diversity makes it difficult to identify genes or other features that reliably indicate a tumor's potential to spread.

In the current study, researchers began with the well-established fact that prostate cancers without a working copy of the Pten gene tend to remain fairly idle and don't trespass beyond the prostate gland itself. Researchers theorized that the loss of Pten in turn activates a collection of genes — a pathway — functioning to constrain the tumor's growth and invasion. If that pathway was shut down, they reasoned, the tumor would begin to break loose from the prostate and spread insidiously through the body.

Using computational biology techniques to analyze gene activity in mouse prostate cancer cells with inactive Pten, the investigators found a few pathways that seemed to play a constraining role. One, known as TGFβ-SMAD4 (for some of the genes that comprise it), was particularly intriguing as this pathway had been implicated in the metastasis of other tumor types in the past.

When researchers conducted confirmatory molecular signaling studies to see what happens when Pten is knocked out of commission, signaling in the TGFβ-SMAD4 pathway "shot through the roof," DePinho says, suggesting that the pathway had sprung into action.

When researchers generated mice whose prostate cells lacked both Pten and the Smad4 gene, the animals developed large, fast-growing tumors that spread to their lymph nodes and beyond. Guided by these insights, they then examined whether something similar was happening in human prostate cancers.

Comparing the gene expression profiles of indolent versus aggressive mouse prostate cancers, they found about 300 genes that distinguished the two groups.

"We then categorized them for known functions," DePinho says. "We were encouraged to see that the top functional category were genes playing that have roles in cell division and movement" — actions that are needed for cancer cells to grow and spread with lethal consequences.

The researchers conducted an elaborate series of experiments to identify the genes most closely linked to the aggressive biology of prostate cancer. Among the hundreds of genes analyzed, two such genes stood out: SPP1 and CyclinD1, both of which, intriguingly, are close working partners of Smad4.

The four-gene signature — Pten, Smad4, SPP1, and CyclinD1 — showed its effectiveness as a predictive tool for survival when researchers drew on data from the Physicians' Health Study, which has been tracking the health of thousands of U.S. physicians for nearly 30 years. When the investigators screened prostate cancer samples from study participants for the four-gene/protein signature, it was more accurate in predicting the ultimate course of the illness than conventional methods were.

Study Leaders are Co-Founders of Metamark Genetics

“The study published in Nature represents a landmark breakthrough in our understanding of proteins that are critical for aggressive forms of human prostate cancer. We believe that the findings will have important implications for our ability to improve the prognosis and treatment of prostate cancer patients," said Peter Blume-Jensen, M.D., Ph.D., Chief Scientific Officer for Metamark Genetics, Inc., a privately-held oncology molecular diagnostics company.

Metamark has exclusively licensed a portfolio of technologies, including those described in this study, from The Dana Farber Cancer Institute. The study was led by Metamark scientific co-founders, Lynda Chin, M.D. and Ronald DePinho, M.D.

Based on the results of the Nature study, Metamark is developing a novel test for prostate cancer prognosis. Metamark scientists are also developing precise, molecularly-based prognostic tests for additional cancer types that will help guide physicians in determining the most appropriate treatment for each patient, potentially including the identification of those that can be spared from unnecessary aggressive treatment and procedures.

"By integrating a variety of techniques — computational biology, genetically engineered model systems, molecular and cellular biology, and human tissue microarrays — we've identified a signature that has proven effective in distinguishing which men with prostate cancer are likely to progress and die from their disease and those who are not," DePinho remarks.

"Efforts are already underway to use this knowledge to develop a clinical test — which we hope will occur within a year or so — that will enable doctors and patients to make more accurate treatment decisions and avoid unnecessary aggressive interventions which adversely impact on quality of life and deplete over-extended healthcare resources. This science holds potential to illuminate a long-sought answer for optimal management of this complex disease."

Collaborating on the study were Massimo Loda, MD, of Dana-Farber and Brigham and Women's Hospital, and Lorelei Mucci, PhD, of Brigham and Women's and Harvard School of Public Health,

The paper's other co-authors are Chang-Jiun Wu, MD, PhD, Gerald C. Chu, MD, Yonghong Xiao, PhD, Dennis Ho, Samuel R. Perry, Emma S. Labrot, Xiaoqiu Wu, Rosina Lis, MD, Y. Alan Wang, David E. Hill, PhD Baoli Hu, PhD, Shan Jiang, PhD, Hongwu Zheng, PhD, Alexander H. Stegh, PhD, Kenneth L. Scott, PhD, Dana-Farber; Jingfang Zhang, University of Wisconsin, Madison; Yujin Hoshida, MD, PhD, and Todd R. Golub, MD, Dana-Farber and the Broad Institute of Harvard and MIT; David Hiller, PhD, and Wing H. Wong, PhD, Stanford University; Sabina Signoretti, MD, Dana-Farber/Harvard Cancer Center; Nabeel Bardeesy, PhD, Massachusetts General Hospital Cancer Center; and Meir J. Stampfer, MD, DrPH, Brigham and Women's Hospital and Harvard School of Public Health.

The research was funded in part by the Belfer Institute for Applied Cancer Science and the National Cancer Institute.

The Belfer Institute for Applied Cancer Science at Dana-Farber Cancer Institute says it consists of leading academic and industry seasoned scientists working as multidisciplinary teams supported by powerful platforms in computational science, oncogenomics, engineered model systems, clinicopathological analyses, and drug discovery.

The Belfer Institute's mission is to convert insights gleaned from cancer genomics and deep biology research into the next generation of highly effective drugs and drug combinations, as well as breakthrough diagnostics for improved patient management. The Belfer Institute technology has launched a new biotechnology company, Metamark Genetics, and has enabled cancer drug discovery through highly productive strategic alliances within the pharmaceutical sector, including Merck and Sanofi-Aventis.


More Links to Reports on Prostate Cancer in SeniorJournal.com Archives

Prostate Cancer Victims Should Be Especially Watchful for Precancerous Colon Polyps

Study is first to show that men with prostate cancer are at increased risk of colon cancer – two most common cancers for older men

Oct. 20, 2010


Popular ADT Prostate Cancer Treatment Associated with Bone Decay

'Virtual bone biopsies' may help identify men at risk for fractures after androgen deprivation therapy

Oct. 8, 2010


Older Men with Low Baseline PSA Do Not Benefit from Early Prostate Cancer Detection

Prostate cancer is the most commonly diagnosed malignancy and the third leading cause of death from cancer in men in Western countries

Sept. 13, 2010


Most Men With Just Low-Risk Prostate Cancer Receive Aggressive Treatment

Over 90% of prostate cancers diagnosed before they spread and the 5-year survival rate for these is almost 100%

July 27, 2010

New Study Finds Gene Fusions May be ‘Smoking Gun’ in Prostate Cancer Development

Gene fusion – not the androgen receptor – is the more specific “bad actor” in prostate cancer  - May 21, 2010


Provenge Approved as Vaccine for Advanced Prostate Cancer; Activates Immune System

Survival for Provenge patients was 25.8 months, compared to 21.7 months for those receiving placebo

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Prostate Cancer Treatment Choices Vary Based on Type of Specialist Men Choose to See

About half of all men seen just by a urologist; last week the attention was on the type of prostate cancer screening men should pursue - March 9, 2010


Study of Senior Men Finds Similar Results With Open or Laparoscopic Prostate Surgery

Researchers studied almost 6,000 senior citizens, suggest patients be informed about the differences and similarities in expected outcomes, make treatment decisions with an experienced surgeon - Feb. 22, 2010


ADT Therapy for Prostate Cancer Can Increase Heart Risk Factors

Androgen-deprivation therapy (ADT) may increase cardiovascular risk, but unclear whether it’s linked to increased death from heart disease - Feb. 3, 2010


Favorite Drink of Senior Citizens Coffee Appears to Fight Advanced Prostate Cancer

More good news for senior men is FDA consideration of prostate cancer vaccine, Provenge

Dec. 8, 2009


Study Uncovers Key to How ‘Triggering Event’ in Prostate Cancer Occurs

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Oct. 29, 2009


Cancer Society Stands Firm: Older Women Need Mammograms, Men Need Advice on Prostate Tests

‘Mammography is effective – mammograms work and women should continue to get them,’ ACS

Oct. 23, 2009


Minimally Invasive Radical Prostatectomy Has Advantages, But Higher Rate of Complications

MIRP, especially with robotic assistance, increased from 1% to 40% of radical prostatectomies from 2001 to 2006,despite limited data on outcomes and costs

Oct. 14, 2009


Study Says Men are Not Adequately Involved in Prostate Cancer Screening Discussions

Another new study finds screened men up to four times more likely to be diagnosed with prostate cancer than unscreened men

Sept. 28, 2009


Keep up with the latest news for senior citizens, baby boomers

Study Shows Seed Implants a Suitable Prostate Cancer Treatment Option for Older Men

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Aug. 4, 2009


Men Who Delay Radical Treatment of Prostate Cancer Don’t Seem to Worry About It

Men with neurotic personalities and those in poor physical health exhibited more anxiety and distress than others

July 27, 2009


Heavy Alcohol Drinking Spurs High-Grade Prostate Cancer, Stops Prevention by Finasteride

Four or more drinks on 5 or more days per week doubles risk of high-grade prostate cancer

July 13, 2009


Predicting the Return of Prostate Cancer Improved by Results from John Hopkins Study

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July 2, 2009


PARP Drugs May Be Miracle Cure for Cancer Suggests Success with Breast, Ovarian, Prostate Cancer

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June 25, 2009


Veterans Badly Mistreated for Prostate Cancer at VA Hospital, Reports NY Times

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June 22, 2009


Prostate Cancer Test Proven to Offer Early Prediction of Bone Metastasis, Mortality

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New Blood Test Significantly Increases Accuracy of PSA Screening for Prostate Cancer

Greatly reduces false-positives in prostate cancer screening that often require a biopsy of the gland to check for tumors

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Men Should Not Give Up on PSA Prostate Cancer Screening, Just Yet

Urologists argue that men should not be swayed from getting the test - it still saves lives

May 13, 2009

 

Statins Protect Against Prostate Cancer, Erectile Dysfunction and Prostate Enlargement, Mayo Study Finds

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April 27, 2009


Elderly Men with Short Life Expectancy Do Not Need Prostate Cancer Screening, Study Shows

U.S. trial shows no early mortality benefit from current annual screening for prostate cancer - watch video, link in story

March 19, 2009


Enough is Enough of Prostate-Specific-Antigen Testing Once Men Reach Age 75

PSA test has decreased prostate cancer deaths but other problems more likely to kill elderly

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Simple Urine Test May Reveal the Aggressiveness of Your Prostate Cancer

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Artificial Light at Night Contributes to Prostate Cancer and Breast Cancer Say Researchers

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GPS for the Body Sometimes Needed for a Moving Prostate During Radiation Therapy

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Selenium or Vitamin E to Stop Prostate Cancer May Do More Harm Than Good

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Benign Prostatic Hyperplasia Strikes Up to 90 Percent of Oldest Men, Can Be Life-Threatening

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High Cholesterol Bad for Heart but May Also Increases Prostate Cancer Risk

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Common Painkillers Like Aspirin Seem to Lower PSA Level that Predicts Prostate Cancer

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Height Linked to Prostate Cancer Development, Growth in Review of 58 Studies

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Brachytherapy May Be Best Prostate Cancer Treatment Choice for Obese Men

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Aug. 19, 2008


Prostate Screening Bias Against Obese Men Leads to Late Detection, Less Surgical Success

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Aug. 8, 2008


Task Force Says Men Age 75 and Older Should Not Be Screened for Prostate Cancer

Chances are they will die of something else before the cancer gets them

Aug. 5, 2008


Androgen Deprivation Does Not Improve Survival for Seniors with Prostate Cancer

Conservative management of the disease does a better job, says study

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Radiation for Cancer Recurrence after Radical Prostatectomy Shows Increased Survival

Provocative evidence that even men with adverse prognostic features may benefit from salvage radiotherapy

June 17, 2008


Older Men With Prostate Cancer at Much Greater Risk of Bone Fractures

Patients should be checked for osteoporosis, particularly if treated with ADT

May 14, 2008

 

 

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