Quantifying the role of PSA screening in the US prostate cancer mortality decline.

OBJECTIVE: To quantify the plausible contribution of prostate-specific antigen (PSA) screening to the nearly 30% decline in the US prostate cancer mortality rate observed during the 1990s. METHODS: Two mathematical modeling teams of the US National Cancer Institute's Cancer Intervention and Surveillance Modeling Network independently projected disease mortality in the absence and presence of PSA screening. Both teams relied on Surveillance, Epidemiology, and End Results (SEER) registry data for disease incidence, used common estimates of PSA screening rates, and assumed that screening, by shifting disease from distant to local-regional clinical stage, confers a corresponding improvement in disease-specific survival. RESULTS: The teams projected similar mortality increases in the absence of screening and decreases in the presence of screening after 1985. By 2000, the models projected that 45% (Fred Hutchinson Cancer Research Center) to 70% (University of Michigan) of the observed decline in prostate cancer mortality could be plausibly attributed to the stage shift induced by screening. CONCLUSIONS: PSA screening may account for much, but not all, of the observed drop in prostate cancer mortality. Other factors, such as changing treatment practices, may also have played a role in improving prostate cancer outcomes.

Endogenous sex hormones and prostate cancer risk: a case-control study nested within the Carotene and Retinol Efficacy Trial.

To examine whether endogenous androgens influence the occurrence of prostate cancer, we conducted a nested case-control study among participants enrolled in the Carotene and Retinol Efficacy Trial. We analyzed serum samples of 300 cases diagnosed between 1987 and 1998, and 300 matched controls. Higher concentrations of testosterone (T) were not associated with increased prostate cancer risk. Relative to men with levels in the lowest fourth of the distribution, men in the upper fourth of total T had a risk of 0.82 [95% confidence interval (CI), 0.52-1.29]. The corresponding relative risks for free T (0.72; 95% CI, 0.45-1.14), percentage of free T (0.74; 95% CI, 0.46-1.19), and total T:sex hormone binding globulin ratio (0.52; 95% CI, 0.32-0.83) similarly were not elevated. Higher concentrations of androstenedione, dehydroepiandrosterone sulfate, and 3 alpha-androstanediol glucuronide were weakly associated with risk. Relative risks associated with being in the highest fourth for androstenedione, dehydroepiandrosterone sulfate, and 3 alpha-androstanediol glucuronide were 1.20 (95% CI, 0.76-1.89), 1.38 (95% CI, 0.86-2.21), and 1.27 (95% CI, 0.80-2.00), respectively. Men in the upper fourth of total estradiol (E2), free E2 and percentage of free E2 had relative risks of 0.71 (95% CI, 0.42-1.13), 0.52 (95% CI, 0.33-0.82), and 0.65 (95% CI, 0.40-1.05), respectively. The inverse association between E2 and prostate cancer risk was largely restricted to men with blood collection within 3 years of diagnosis. Our results add to the evidence that serum testosterone is unrelated to prostate cancer incidence. The suggestions that intraprostatic androgen activity may increase risk and that serum estrogens may decrease risk, warrant additional study.

Polymorphic markers in the 5alpha-reductase type II gene and the incidence of prostate cancer.

In the prostate, the enzyme encoded by the SRD5A2 gene (5alpha-reductase) converts testosterone to dihydrotestosterone, a potent androgen that has been hypothesized to play a role in the genesis of prostate cancer. Several polymorphisms have been identified in the SRD5A2 gene, including a valine-to-leucine substitution (V89L) at codon 89, a variable number of TA dinucleotide repeats and a missense substitution at codon 49 resulting in an amino acid substitution of alanine with threonine (A49T). To investigate the influence of these polymorphisms on prostate cancer risk, we conducted a case-control study nested within the Beta-Carotene and Retinol Efficacy Trial. Genotypes were determined by PCR-based capillary electrophoresis using genomic DNA isolated from 300 cases and 300 controls matched on the basis of race, age at enrollment (within 5 years), enrollment study center and year of randomization. There was no association between V89L genotypes and prostate cancer risk. The age- and race-adjusted odds ratio (OR) associated with the VL and LL genotypes were 1.06 (95% confidence interval (CI) = 0.75-1.49) and 0.99 (95% CI = 0.57-1.73), respectively, as compared to the VV genotype. The age- and race-adjusted odds ratio for men having 1 TA(9) or TA(18) allele was 0.98 (95% CI = 0.64-1.48) when compared to men without TA repeats. The corresponding odds ratio for men without the TA(0) alleles was 0.68 (95% CI = 0.21-2.19). The age- and race-adjusted odds ratio associated with having at least 1 T allele at codon 49 was 1.11 (95% CI = 0.58-2.11), as compared to the AA genotype. Our results do not support the hypothesis that the V89L and A49T polymorphisms in the SRD5A2 gene are related to the risk of prostate cancer, but are compatible with the suggestion from earlier studies that men who are homozygous for the TA(9) or (18) alleles and men who have the TA(9)/TA(18) genotype are at a modestly reduced risk.

Androgen receptor polymorphisms and the incidence of prostate cancer.

The human androgen receptor gene contains polymorphic CAG and GGC repeats in exon 1. We investigated whether the number of CAG and/or GGC repeats is related to prostate cancer risk in a case-control study nested within the beta Carotene and Retinol Efficacy Trial. Among 300 cases and 300 controls, we did not observe any increase in risk associated with fewer CAG or GGC repeats. We observed a nonsignificant decrease in risk associated with each unit of decrease in CAG length [odds ratio (OR), 0.98; 95% confidence interval (CI), 0.93-1.03). Men with CAG <22 had a relative risk of prostate cancer of 0.89 (95% CI, 0.65-1.23) compared with men with CAG > or =22. There was no appreciable difference in the mean number of GGC repeats between cases and controls; the estimated change in the risk of prostate cancer associated with one fewer GGC repeat was 0.97 (95% CI, 0.88-1.06). The risk in men at or below the mean number of GGC repeats (17) was 0.80 (95% CI, 0.57-1.12). In contrast to prior reports, men with both short CAG (<22) and short GGC (< or =17) repeats were not at increased risk of prostate cancer (OR, 0.56; 95% CI, 0.32-0.98), compared with men with > or =22 CAG repeats and >17 GGC repeats. Our results do not support the hypothesis that a small number of CAG or GGC repeats in the androgen receptor gene increases a man's risk of prostate cancer.

A risk model derived from the National Registry of Myocardial Infarction 2 database for predicting mortality after coronary artery bypass grafting during acute myocardial infarction.

The mortality risk associated with coronary artery bypass grafting (CABG) after acute myocardial infarction (AMI) remains controversial. Although elective CABG is quite safe, the effects of recent myocardial infarction, gender, and other clinical factors on perioperative mortality rates are not completely understood. The objective of this study was to determine in-hospital mortality rates for patients with AMI receiving CABG and to generate a model to predict the risk for any individual patient with specific risk factors. Using the National Registry of Myocardial Infarction 2 database, we identified 71,774 subjects (21,270 women) with AMI who underwent CABG; we excluded those subjects who received immediate surgery as reperfusion therapy. Multivariate logistic regression was used to quantify the independent effects of age, recent myocardial infarction, gender, and other covariates on mortality. A risk score was then generated from the regression model to quantify the mortality risk. The results of logistic regression modeling determined that age was an independent predictor of in-hospital death (adjusted odds ratio [OR] 3.05, 95% confidence interval [CI] 2.76 to 3.37 for age >75), as were previous CABG (OR 2.84, 95% CI 2.55 to 3.16), heart failure on presentation (OR 1.73, 95% CI 1.57 to 1.91 for Killip class II), and female gender (OR 1.58, 95% CI 1.45 to 1.71). The mortality risk score showed that 55% of patients had risk scores of 2 to 5 and mortality rates of 4% to 13%. This moderate risk group experienced 76% of the total predicted mortality. Thus, in-hospital CABG mortality rates after AMI are high compared with elective surgery. Using the described risk score, clinicians can quantify the impact of patient risk factors in making decisions about referral for and timing of CABG.