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Data reveal three risk factors for prostate ca.

ORLANDO, FLA. -- Three new risk factors for prostate cancer are associated with an increased likelihood of developing aggressive prostate cancer or dying of the disease, researchers reported at a symposium on prostate cancer sponsored by the American Society of Clinical Oncology.

Each report was based on analysis of data from the Physicians' Health Study, a prospective cohort of 22,071 U.S. male physicians originally designed to evaluate the primary prevention of cancer and cardiovascular disease.

High Body Mass Index

Overweight or obese men in the Physicians' Health Study had significantly increased prostate cancer mortality, said Jing Ma, M.D., an epidemiologist at Brigham and Women's Hospital, Boston.

Previous research has suggested that obesity "is linked more to dying of prostate cancer rather than getting it," Dr. Ma noted.

Between 1982 and 2003, 2, 144 men in the Physicians' Health Study developed prostate cancer, and 233 of them eventually died of it. Compared with men who were at a normal weight before their prostate cancer diagnosis, men who were overweight or obese prior to their diagnosis had a significantly increased risk of dying from prostate cancer. The risk became progressively higher as body mass index rose from overweight to obese levels, Dr. Ma reported.

Normal weight, overweight, and obese men had the same rate of locally advanced cancer at diagnosis (11%), but overweight or obese men were twice as likely to die from locally advanced prostate cancer as were normal weight men.

Obese men were more likely to have metastatic disease at diagnosis (19%) than were normal weight (8%) or overweight men (9%). Among men with metastatic prostate cancer, overweight or obese men had a greater than 50% increased likelihood of dying of prostate cancer, compared with normal weight men.

The fact that obese men were more likely to be diagnosed with metastatic disease suggests that obesity may delay the diagnosis of prostate cancer, Dr. Ma said, or that being overweight or obese may be associated with a biologically more aggressive form of prostate cancer.

Vitamin D Deficiency and Sensitivity

Low plasma levels of vitamin D appear to significantly increase the risk of aggressive prostate cancer, especially in patients with a particular polymorphism of the vitamin D receptor, said Haojie Li, M.D., a research fellow at Brigham and Women's Hospital.

Eight previous prospective studies of the possible association between vitamin D levels and the risk of prostate cancer yielded inconsistent results, she noted.

In a case-control study of 1,082 men with prostate cancer and 1,701 control men in the Physician's Health Study, men who had low levels of two vitamin D metabolites (1,25-dihydroxy D and 25-hydroxy D) at baseline were 80% more likely to have aggressive prostate cancer than were men with high levels of both metabolites.

Cases and controls were matched for age and had up to 18 years of follow-up. Dr. Li and her colleagues defined a high level of each vitamin D metabolite as a concentration above the median and a low level as the median concentration or less. Aggressive prostate cancers included those classified as stage C or D at diagnosis, those with a Gleason score of 7-10 at diagnosis, or those that caused death during follow-up.

The F allele of the FokI gene for the vitamin D receptor has been associated with a greater sensitivity to vitamin D and a higher transcriptional activity than the f allele, she said.

Men who had the FokI FF genotype in the vitamin D receptor were more sensitive to the status of vitamin D levels than were men with either Ff or ff genotypes, Dr. Li said at the symposium, cosponsored by the Society for Urologic Oncology and the American Society for Therapeutic Radiology and Oncology.

Among men with the FokI FF genotype, those who had low levels of 1,25-dihydroxy D alone were 80% more likely to have prostate cancer overall and nearly three times as likely to have aggressive prostate cancer as men who had high 1,25-dihydroxy D levels. In the same group of men, low levels of 1,25-dihydroxy D and 25-hydroxy D combined significantly increased the risk of prostate cancer overall by a factor of 2.2 and of aggressive prostate cancer by a factor of 3.8.

The vitamin D receptor mediates the function of the most active form of vitamin D--1,25-dihydroxy D--in the prostate by increasing cell differentiation and apoptosis and decreasing cell proliferation, growth, invasiveness, and metastatic potential, Dr. Li said.

Insulin-Like Growth Factor 1

People with high levels of the acid-labile subunit (ALS) glycoprotein that regulates the bioavailability of the hormone insulin-like growth factor 1 (IGF-1) may have an increased risk for prostate cancer and its aggressive forms, reported Lorelei Mucci, Sc.D., of the Harvard School of Public Health, Boston.

Epidemiologic evidence suggests that IGF-1 increases the risk of prostate cancer by stimulating cell growth and progression. Nearly 85% of IGF-1 is bound in a complex with IGF binding protein 3 (IGF-BP-3) and ALS. In this complex, IGF-1 is found only in the circulation and is restricted from affecting endothelial cells. The complex increases the half-life of IGF-1 from 10 minutes in its free form to up to 12 hours.

Epidemiologic studies have found that IGFBP-3 decreases prostate cancer risk through inhibition of cellular growth and proliferation. But no studies have yet been performed on the association between ALS and the risk of prostate cancer or any other cancer, Dr. Mucci noted.

She and her colleagues conducted a case-control study of 547 men diagnosed with prostate cancer between 1982 and 1995 and 547 control men in the Physicians' Health Study. The researchers adjusted the analyses for patient age, smoking status, height, body mass index, and total IGF-1 and IGFBP-3.

Men with higher levels of ALS had a 40%-60% increase in the risk of prostate cancer overall and a twofold increase in the risk of advanced disease or prostate cancer death independent of IGF-1 and IGF-BP-3, compared with men who had the lowest levels of ALS.

Higher ALS levels mitigated the effect of IGF-1 at all concentrations of IGF-1. Men with high IGF-1 levels and low ALS levels were more than nine times as likely to have advanced prostate cancer as men with low IGF-1 and low ALS levels.

At higher levels of ALS, the protective effects of IGFBP-3 can dominate, because less IGF-1 is bioavailable, Dr. Mucci said. Men with a high level of IGFBP-3 had an 80%-90% decline in the risk of advanced disease when they had high levels of ALS, compared with men who had low levels of ALS and IGFBP-3.

BY JEFF EVANS

Senior Writer
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Author:Evans, Jeff
Publication:Internal Medicine News
Date:Apr 15, 2005
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