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PROSTATE CANCER NEWSLETTER - March 2009

Scientists ID New Biomarker for Prostate Cancer.

Study finds cleaved galectin-3 may serve as treatment target against disease progression
A newly identified marker for prostate cancer progression may also offer a new target for treatment, University of Michigan researchers say.

Previous research has found that decreased levels of the marker galectin-3 are linked with neoplastic progression in prostate cancer. However, increased levels of galectin-3 are believed to be associated with tumorigenicity in a number of other tumor types.

The University of Michigan team believed this difference was due to the fact that galectin-3 was cleaved during prostate cancer progression. Their study found that cleaved galectin-3 is present in a late-stage prostate cancer and that reducing levels of galectin-3 inhibited development of metastatic prostate cancer.

The findings suggest that cleaved galectin-3 may serve as a diagnostic marker and treatment target for prostate cancer progression.

The study shows "that galectin-3 is cleaved during the progression of prostate cancer and might be associated with metastasis, cell growth and tumorigenicity. Expression of intact versus cleaved galectin-3 thus might be used as a marker for prognosis of prostate cancer and a therapeutic target for the treatment of prostate cancer," wrote study author Avraham Raz and colleagues.

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No benefit of radiotherapy after radical prostatectomy

LIn men with prostate cancer, follow-up radiotherapy after complete removal of the prostate (radical prostatectomy) does not improve overall or cancer-specific survival, according to a report in the March issue of BJU International.

Recent trials have suggested a benefit of follow-up (adjuvant) radiotherapy in terms of recurrence-free survival, the authors explain, but there is controversy regarding the benefits of adjuvant radiotherapy on other endpoints.

Dr. Pierre I. Karakiewicz from the University of Montreal, Quebec, Canada, and colleagues examined cause-specific survival and overall survival using data from 752 patients treated with radical prostatectomy, 118 of whom underwent adjuvant radiotherapy.

Patients who received adjuvant radiotherapy had higher pathological tumor stage, higher pathological tumor cell type, and higher rate of positive surgical margins and received hormonal therapy more frequently than did patients who did not receive adjuvant radiotherapy, the investigators report.

In unmatched analyses, they found, patients who received adjuvant radiotherapy had lower probabilities of overall survival and cancer-specific survival after radical prostatectomy than those who did not receive adjuvant radiotherapy.

However, in matched analyses, there was no statistically significant difference in overall survival and cancer-specific survival.

"Our analysis showed that adjuvant radiotherapy has no effect on overall survival and cancer-specific survival," Karakiewicz and colleagues conclude. Additional random, controlled trials are needed to confirm or disprove the benefit of adjuvant radiotherapy."

Six annual screenings for prostate cancer led to more diagnoses of the disease, but no fewer prostate cancer deaths, according to a major new report from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, a 17-year project of the National Cancer Institute (NCI), part of the National Institutes of Health. The PLCO was designed to provide answers about the effectiveness of prostate cancer screening.

"What this report tells us is that there may be some men who are diagnosed with prostate cancer and have the side-effects of treatment, such as impotence and incontinence, with little chance of benefit," said John E. Niederhuber, M.D., director of the NCI. "Clearly, we need a better way of detecting prostate cancer at its earliest stages and as importantly, a method of determining which tumors will progress. Many of the molecular studies we're currently sponsoring will hopefully yield new, better ways of definitively classifying which men need treatment and which can consider watchful waiting. Until we have developed and verified a new test's benefits and harms, as we have done with the PLCO, regular visits to your doctor to monitor your health are still strongly recommended."

Results appear online March 18, 2009, in the New England Journal of Medicine, to coincide with presentation of the data at the European Association of Urology meeting in Stockholm, Sweden. The print version of the results will appear in the March 26, 2009 issue.

NCI does not have a recommendation about prostate cancer screening. The U.S. Preventive Services Task Force, whose recommendations are considered the gold standard for clinical preventive services, recently concluded that there is insufficient evidence to assess the balance of benefits and harms of prostate cancer screening in men younger than age 75 and recommended against prostate cancer screening in men age 75 and older.

There were 76,693 men in the PLCO trial that was conducted at 10 centers around the United States. Of the men in the trial, 38,343 were randomly assigned to screening with annual prostate-specific antigen (PSA) tests for six rounds and digital rectal exams (DRE) for four rounds. A DRE is an exam whereby a doctor inserts a lubricated, gloved finger into the rectum and feels for anything that is not normal. The other 38,350 men were randomly assigned to usual care, but received no recommendations for or against annual prostate cancer screening.
Of those men who were screened annually, 85 percent had PSA tests and 86 percent had DREs.

Men in the usual-care arm sometimes had these tests as well, due to the growing public acceptance of such screening. Screening by PSA in this usual-care group increased from 40 percent at the beginning of the study to 52 percent of men by the last screening year, and screening with DRE ranged from 41 percent initially to 46 percent by the last screening year. Men in the screening arm were referred to their usual health care provider for follow-up testing for prostate cancer if their PSA level was greater than 4.0 nanograms per milliliter (ng/mL) or if a DRE found an abnormality.

This report includes data for all participants at seven years after they joined the trial and for 67 percent of participants at 10 years after they joined the trial. Other important findings include:

At seven years, 22 percent more prostate cancers were diagnosed in the screening arm (2,820 men vs. 2,322 in the usual-care group). This excess is continuing to be observed in data collected up to 10 years (currently a 17 percent excess, 3,452 men vs. 2,974 men).

The vast majority of men in both groups who developed prostate cancer were diagnosed with relatively early stage II (out of IV stages, of which IV is late stage) disease, and the number of later-stage cases was similar in the two groups. However, using the Gleason scoring system, which assesses tumor aggressiveness, men in the usual-care group had more prostate cancers that fell into the Gleason 8 to10 range, which marks them as more aggressive. The smaller number of men with prostate cancer with a Gleason score of 8 to10 in the intervention group may eventually lead to a mortality difference between men in the two groups but data analyzed so far have not shown such a difference.

Men in both groups who were diagnosed with prostate cancer at the same stage received similar treatments for their disease. This reflects the PLCO study design policy of not mandating specific therapies

At seven years, 50 deaths were attributable to prostate cancer in the screening group and 44 deaths were attributable in the usual-care group. Through year 10, there were 92 prostate cancer deaths in the screening group and 82 in the usual-care group. The difference between the numbers of deaths in the two groups was not statistically significant. Thus there was no detectable mortality benefit for screening vs. usual-care.

Given the uncertainties about the mortality benefits of PSA testing, NCI has been pursuing many avenues to find new ways of screening for prostate cancer, including several sets of biomarkers that are being validated in its Early Detection Research Network (EDRN), some using specimens from PLCO's biorepository of tissue and blood. Some examples of the marker tests include using microstrands of RNA to detect disease, examining changes in genes such as GSTP1, and imaging of proteins in prostate cancer tissue.

"NCI wants to understand why some prostate cancers are lethal even when found early by annual screening, and what approaches can be used to identify these more aggressive cancers when they can be effectively treated," said Christine Berg, M.D., NCI leader of the PLCO trial and senior author of the study. "The PLCO biorepository is an invaluable resource for such research, with nearly three million biological samples collected from our participants. Our hope is that through all aspects of the PLCO, we will gather the information that tells us whom to treat aggressively and whom to avoid overtreating."

Another report in this same online publication of the NEJM is from the large European Randomized Study of Screening for Prostate Cancer (ERSPC), which shows a 20 percent reduction in the rate of death from prostate cancer but with a high risk of overdiagnosis. In the ERSPC, unlike the PLCO trial, men were referred for follow-up testing if their PSA level was 3.0 ng/mL or higher and were also screened, on average, every four years as opposed to annually in the PLCO.

"Approaches such as lowering the threshold for what is considered an abnormal PSA level to 3.0 ng/mL will diagnose more cases, but it is not at all clear that it will identify the prostate cancers that are more likely to lead to a man's death," said Berg.

The PLCO data are being made public now because the study's Data and Safety Monitoring Board (DSMB), an independent review committee that meets every six months, saw a continuing lack of evidence that screening reduces death due to prostate cancer as well as the suggestion that screening may cause men to be treated unnecessarily. The DSMB also supports continued follow up of all participants so that every participant is tracked for at least 13 years from entry onto the trial.

The PLCO is a large-scale clinical trial, sponsored and run by NCI's Division of Cancer Prevention, begun in 1992 to determine whether certain cancer screening tests can help reduce deaths from prostate, lung, colorectal and ovarian cancer. The underlying rationale for the trial is that screening for cancer may enable doctors to discover and treat the disease earlier.

Nearly 155,000 women and men between the ages of 55 and 74 have joined the PLCO trial. At entry, participants were assigned at random to one of two study groups: One group received routine health care from their health providers. The other received a series of exams to screen for prostate, lung, colorectal, and ovarian cancers. Screening of participants ended in late 2006. Follow-up of participants is anticipated to continue for several more years.

Folic Acid Supplements Raise Prostate Cancer Risk.

But 10-year study also showed having enough folate in diet might offer protection

A 10-year study has found that men who took folic acid supplements faced more than twice the risk of prostate cancer as those who didn't take the supplements.
But the incidence of prostate cancer in the study was slightly lower in men who simply got adequate amounts of folate in their diet, according to a report in the March 10 online issue of the Journal of the National Cancer Institute.

"What we think is that perhaps too much folate is not necessarily beneficial, whereas adequate levels may be," said study leader Jan Figueiredo, an assistant professor of preventive medicine at the University of Southern California.

Folic acid is a synthetic version of folate, a basic nutrient found in green, leafy vegetables. In the study, which followed 643 men for slightly more than a decade, the estimated prostate cancer risk was 9.7 percent for the men who took the daily 1-milligram supplements, and 3.3 percent for men who took a placebo.

"Folate plays an important role in cell growth and division, and cancer cells often uprate their folate receptors," Figueiredo noted. "Folic acid, the synthetic version, has more bioavailability, meaning that the effective dose in the cell is higher than what you get from natural sources."
Dietary sources of folic acid in the United States now include cereals and other grain products. The U.S. Food and Drug Administration has required folic acid enrichment of those foods since 1996, in part to reduce the incidence of birth defects affecting development of the central nervous system.

"Since we fortified, the amount of folate we consume from fortified foods is probably more than sufficient," Figueiredo said.

The newly reported results resemble those of a study done several years ago by Victoria Stevens, strategic director of laboratory services at the American Cancer Society, who specializes in research on folate metabolism.

That study of folate intake and prostate cancer "found that it really didn't have much effect," Stevens said. "Our study actually suggested that folate might be protective for men with advanced prostate cancer, a group that wasn't included in this study."

Overall, "it's a pretty complicated picture," Stevens said. "Previous epidemiological evidence suggests that not having enough folate can be bad, but having an excess might not be good. You need to have adequate folate nutrition. But it doesn't get better if you have more, and it may get worse."

The study is the latest to throw cold water on the hope that supplements can reduce the risk of cancer. Two studies reported late last year that supplements containing selenium, vitamin E and vitamin C had no effect on the incidence of prostate cancer.

One of those studies included more than 35,000 men aged 50 and over who were followed for more than five years, and the other included almost 15,000 male physicians aged 50 and over who were followed for an average of eight years.

"It is safe to conclude that cancer prevention is not going to be as simple as recommending high-dose micronutrient supplements for middle-aged and older adults," said an editorial accompanying the latest report.

Detailed studies to understand how diet and supplements affect biological mechanisms of cancer in humans are needed, as well as large-scale epidemiological studies looking for ways in which diet can reduce risk, according to the editorial by Alan Kristal of the Fred Hutchinson Cancer Research Center in Seattle and Dr. Scott Lippman of the M.D. Anderson Cancer Center in Houston.

"There is no evidence that supplements of any type reduce cancer risk, and increasing evidence that they may increase the risk for some cancers in some people," said Kristal, who is a professor of epidemiology and associate director of the cancer prevention program at Fred Hutchinson. "The only exception is calcium for recurrence of colorectal polyps, where there is solid evidence that calcium can reduce risk."

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