Prostate Cancer: Our previous work from BLSA data suggests that PSA can stratify men at risk 20 years prior to prostate cancer diagnosis;a time when preventive strategies might decrease the risk for life threatening prostate cancer. A major concern with PSA is that diagnosed cancer will be low grade and never threaten the well-being or life of the individual man. The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial found no impact of randomization to screening on prostate cancer death rate after 7 to 10 years of follow-up. However, a major issue was the high screening rate in the control group. The European Randomized Study of Screening for Prostate Cancer (ERSPC) reported a 20% mortality reduction with PSA screening. However, the number-needed-to-screen (NNS) was 1410 and number-needed-to-treat (NNT) was 48 to prevent 1 prostate cancer death at 9 years. The difficulty is that the prostate cancer death rates were low at 9 years. Longer follow-up is needed to verify whether screening is reasonable in reducing mortality. To address this question, we used BLSA data to model the 10 to 15 years risk of prostate cancer by projecting the data presented in the ERSPC report. According to our model, the NNS decreased from 837 at year 10 to 503 at year 12, and NNT decreased from 29 to 18. If the data reported in ERSPC are correct, this would argue for the value of PSA screening to reduce prostate cancer mortality. Our recent work has focused on identifying men who develop life threatening prostate cancer at a time when the cancer should be curable. We found that PSA velocity was associated with a relative risk of 4.0 per ng/ml/yr for having a life-threatening prostate cancer and this risk is present 10-15 years prior to prostate cancer diagnosis. We have extended this concept using a simple additive approach called risk count where at each evaluation the health care provider sums the number of PSA evaluations that are higher than a certain level. For example, a man who never meets the rule of having a PSA velocity greater than 0.2 mg/year has less than a 2-4% probability of developing life-threatening prostate cancer, while a man who has met this rule on 5 consecutive evaluations has a risk of 19% (CI=8-35%), despite the likelihood that his PSA is still normal. We have extended the work on risk count by exploring a large PSA cohort study where 3 to 4 PSA levels had been collected over time. Further, we have developed simulations characterizing lethal prostate cancer risk using PSA velocity and risk count for the general USA male population. Such models demonstrate that a mans risk for dying of prostate cancer (approximately 3% in the male US population) can range from less than 1% to approximately 20-25%. Another concern is whether prostate cancer screening is appropriate and for which men and at what age. We find that men older than 75 years with a PSA less than 3 ng/ml have essentially zero risk of subsequently developing a life threatening prostate cancer. Thus, stopping PSA testing in the presence of low measurements is a low risk procedure in this older age group. In a number of studies, we and others have found that PSA velocity (PSAV) >0.35 ng/ml per year and >2.0ng/ml per year are associated with increased risk of prostate cancer death more than 10 years and 1 year prior to diagnosis. Since PSA and PSAV are highly correlated, the question is raised whether PSAV provides additional information to the simple PSA. In examining the distributional relationship between PSA and PSAV, we found the probability of life-threatening cancer could be stratified at a given PSA by PSAV. For example, the risk of life-threatening cancer was 3% (the same as the mortality rate observed in the US male population) at a PSA <3 ng/ml, but increased to 13.6% with PSAV >0.4 ng/ml/year. An unanswered question is to what degree this knowledge could improve the management of men with an elevated PSA. In another analysis, we compared 5 PSAV calculation techniques when PSA<10 ng/ml. We observed that the predictive ability of PSAV is dependent on the method of velocity calculation. Another consideration in the use of PSA is how it is modulated by genetic makeup. A number of single nucleotide polymorphisms (SNPs) on chromosomes 10 and 19 have been associated with PSA and prostate cancer. We found an interaction between having a minor allele in the selected SNPs and PSA level that altered the relationship with prostate cancer. Specifically prostate cancer risk per unit increase in PSA was different in carriers than in non-carriers of specific minor alleles. Men with a minor allele had a significantly higher risk of prostate cancer at PSA levels greater than 6 ng/ml, while at lower levels the risk was lower than men without a minor allele. The observation suggests that genotype influences the risk of prostate cancer per unit increase in PSA. Prostate cancer risk stratification using PSA and genotype could potentially improve PSA test performance. Another potential modulator of PSA that could impact diagnosis is body size. In men without prostate cancer, body mass index (as an indicator of body size) was not associated with prostate specific antigen after adjusting for age (p = 0.06). A 10-point increase in body mass index was associated with a prostate specific antigen difference of -0.03 ng/ml. Thus, adjusting prostate specific antigen for BMI does not appear warranted. A final study examined the association between bone (a common site of prostate cancer metastases) and life-threatening prostate cancer. We examined the association between BMC measurements from 1973 to 1984 with the development of overall and high-risk prostate cancer over the next 1 to 3 decades. The distribution of BMC across age was significantly higher among men diagnosed with prostate cancer than healthy controls, and tended to be higher in high-risk than non high-risk cases. The biology underlying the lesser decline in BMC among prostate cancer cases remains unclear, but suggests that host factors in the bony milieu may be associated with prostate cancer development and progression. Benign Prostatic Hyperplasia and Prostate Aging: A second area of interest is benign prostatic hyperplasia (BPH), which is a common problem affecting more than 90% of men by the age of 80 years. We are interested in the natural history of prostate growth, and in understanding the association between aging, prostate growth and the development of BPH and symptoms. Little information is published on the effect of differential prostate growth on PSA velocity. Our data suggest that volume increases alone do not cause a high prostate specific antigen velocity. Despite growth rates as high as 10 cc per year, prostate specific antigen velocity was less than 0.1 ng/ml per year in most men without prostate cancer. Thus, differential rates of prostatic growth should not confound the use of prostate specific antigen velocity for prostate cancer detection and prognostication. Our conception of the prostate as it ages is that it continues to grow. Little is known about the phenomenon of prostate atrophy. In an analysis of serial pelvic magnetic resonance imaging performed in men with 2 or more prostate volume measurements, we found at a median followup of 4.3 years prostate size actually was stable or decreased in 38.1% of men, while for the entire sample the median growth rate was 2.5% per year. The results suggest that changes in prostate size are highly variable among aging men, and a considerable proportion have a stable or decreasing prostate size. At present, we continue to examine factors contributing to prostate growth and cancer development.
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