Prostate-specific antigen

Prostate-specific antigen (PSA) has revolutionized the diagnosis and management of men with prostate cancer. Significant advances have been made since the early development of immunoassays. While PSA is useful for staging and monitoring of established disease, it has shown the greatest utility in the realm of early detection realm. PSA is the most important tumor marker; its importance in evaluating men for the possibility of prostate cancer is irrefutable. Enhancing specificity is a pressing need. In this regard, the recognition of the molecular forms of free PSA and complex PSA have shown the most promise and undoubtedly will result in fewer false-positive PSA test results. The salient literature is reviewed and commentary made on the current status of PSA with particular emphasis on methods to enhance its specificity in early detection and applications.     

Blood biomarkers for prostate cancer detection and prognosis

Prostate cancer is the most non-cutaneous malignancy diagnosed in men in the USA. The discovery of prostate-specific antigen (PSA) revolutionized prostate cancer diagnosis and management in the 1990s. Despite its remarkable performance as a marker for prostate cancer, PSA is not prostate cancer specific. PSA can be released by normal as well as hyperplastic prostate cells, which undermines the specificity of PSA for prostate cancer diagnosis. Hence, there is a need for new biomarkers that can detect prostate cancer and, in addition, distinguish indolent from biologically aggressive cancers. Moreover, the emergence of new therapeutic approaches for prostate cancer cannot flourish without a more reliable set of markers to serve as prognosticators, targets and surrogate end points of disease progression and response to treatment. As the most useful clinical biomarkers are likely to be those assayed from blood, there is an increasing interest in profiling blood proteins. With recent advances in biotechnology such as high-throughput molecular analyses, many potential blood biomarkers have been identified and are currently under investigation.     

Prostate-specific antigen levels in 1695 men without evidence of prostate cancer. Findings of the American Cancer Society National Prostate Cancer Detection Project.

The American Cancer Society National Prostate Cancer Detection Project is a prospective, multidisciplinary, and multicenter trial to assess the potential for early detection of prostate cancer by transrectal ultrasonography (TRUS), digital rectal examination (DRE), and serum prostate-specific antigen assay (PSA). By November 1990, 2805 men between the ages of 55 and 70 years with no known signs or symptoms of prostate cancer were enrolled in the study, which is planned to run for 5 years. Annual TRUS, DRE, and PSA tests were done on these subjects, and biopsies were recommended for suspicious lesions when detected. To study the performance of PSA testing in presumed normal subjects, all men were eliminated who had (1) prostate cancer detected on their initial examinations and proven by biopsy or (2) cancer detected during the year or subsequent examinations. Additionally, all men with TRUS or DRE findings that were interpreted as suspicious for cancer but who are being followed and have not yet had biopsies done were removed from this series. This left a unique, extensively screened group of 1695 men who were free of prostate cancer, as far as could be determined. Analyses of the PSA levels in this large population in the appropriate age range for increasing risk of prostate cancer revealed several important findings. First, there was a direct relationship between serum PSA levels and estimated prostate volume for both the currently available monoclonal and polyclonal PSA assays. Individuals with benign prostatic hyperplasia and larger gland volume have a higher normal limit of PSA than men with normal gland volume. Second, analyses showed no relationship between age and PSA levels or between symptoms of prostatism and PSA levels independent of gland enlargement. It was concluded that volume-adjusted upper limits of normal PSA can be determined for different levels of specificity desired. This information may be applicable to the use of PSA in men not already suspected of having prostate cancer and may increase its effectiveness as a tool for early detection.     

Population screening for prostate cancer and emerging concepts for young men

Prostate cancer is the most common malignancy in American men, accounting for > 29% of all diagnosed cancers and approximately 13% of all cancer deaths. Nearly 1 of every 6 men will be diagnosed with the disease at some time in their lives. In 2003 alone, an estimated 221000 men in the United States will be diagnosed with prostate cancer and > 28000 will die of the disease. An elevated level of prostate-specific antigen (PSA) is correlated with the presence of prostate cancer, and since 1989 we have been living in the "PSA era," in which the PSA screening test is widely used in clinical practice. This article summarizes what has been learned about the use of PSA screening, including the intricacies of free PSA, PSA doubling time, and various factors that may affect PSA and confound screening in young men. Although population-based screening for prostate cancer has yet to be definitively proven to affect disease-specific mortality, PSA testing is detecting cancers in younger men and at earlier stages of disease progression and, partly as a result, 5-year cancer-specific survival is increasing. Even though this lead-time effect may not translate into long-term improvement, these changes are very promising and are a necessary prerequisite to effective screening. For patients at high risk with a family history of the disease and for black men, a strategy consisting of an annual PSA blood test and digital rectal examination for men >or=40 years of age appears to be prudent. Use of age- and race-specific reference ranges for PSA based on sensitivity, or maximal cancer detection, is the most appropriate approach in this high-risk group. Specifically among black men 40-49 years of age, those with a PSA value > 2.0 ng/mL should consider further evaluation. Many men at low/average risk aged 40-49 years also request testing and it is reasonable to offer testing and risk assessment to these young men. The exact screening threshold for total PSA in these men is unknown, but 95% of these men will have a PSA < 2.5 ng/mL. Prostate-specific antigen velocity, percentage of free PSA, and perhaps complexed PSA may be used to help determine risk, but further study of young men is needed. In the future, a risk-stratified approach using molecular biomarkers and/or proteomics in young men is anticipated.     

Next-generation prostate-specific antigen test: precursor form of prostate-specific antigen

An urgent need exists to develop a more sophisticated screening system in order to improve diagnostic accuracy of clinically significant cancer and also to reduce the drawbacks of prostate-specific antigen (PSA) screening including overdetection and overtreatment. The most promising next-generation PSA test, which can improve the management of prostate cancer, may be proenzyme PSA (proPSA) or precursor PSA (pPSA). proPSA has pro-leader peptide sequences of seven or less amino acids and previous studies demonstrated that [?2]proPSA, which contains only a 2-amino-acid propeptide leader, could be more useful not only to distinguish between men with and without cancer, but also between tumors with aggressive features with performance exceeding other classical PSA-related indices including ratio of free PSA to total PSA (%f-PSA) and PSA density. Recently, it was demonstrated that baseline [?2]proPSA-related indices were independent factors to predict pathological reclassification at one year or several years after entering active surveillance. Furthermore, a retrospective study suggested that [?2]proPSA might be a useful predictive marker for future developing clinically manifested prostate cancer as well as aggressive tumors. ProPSA-related indices may have the potential for developing a more ideal risk classification for men at risk for prostate cancer, with a screening system maintaining the sensitivity of detecting clinically significant prostate cancer while saving cost, individualized treatment strategies, and follow-up procedures of active surveillance or active treatments. At a minimum, proPSA will be one of the most important new markers on the prostate cancer management in the near future.     

Prostate-specific antigen and detection of prostate cancer: What have we learned and what should we recommend for screening?

Opinion statement Prostate-specific antigen (PSA) has become one of the most commonly used cancer clinical tests, and routine PSA-based screening has led to a dramatic increase in prostate cancer detection. A significant downward stage migration has resulted, and a decrease in prostate cancer mortality has also been observed. However, PSA screening remains controversial because there is no definitive proof that it decreases prostate cancer death rates, and there is concern that it may detect a significant number of clinically insignificant cancers. Screening age and interval have been recently questioned, and the best threshold to recommend biopsy has been complicated by new data showing that prostate cancer exists at all PSA levels, even those thought to be “normal” in the past. It is hoped that ongoing prospective screening trials will determine the value of PSA screening. However, until these results are available the controversy will continue, and men will continue to be screened.     

Prostate specific antigen as a clinical biomarker for prostate cancer: what's the take home message?

Prostate specific antigen (PSA) continues to be challenged as a legitimate clinical biomarker in early detection of prostate cancer due to lack of specificity for malignant transformation. Skepticism surrounding the utility of serum PSA as a clinical marker is not new and many questioned its initial use in widespread prostate cancer screening due to non-specific expression and low predictive value for cancer detection. Despite these initial concerns, serum PSA measurement along with digital rectal examination (DRE) is currently the accepted practice for prostate cancer screening in the United States with hundreds of thousands of men undergoing serum PSA measurement annually. In contrast to its role for early detection, serum PSA measurement as a surrogate for prostate cancer recurrence (biochemical failure) following curative intent therapy has consummate clinical utility in post-treatment surveillance. As thousands of men each year are aggressively treated for potentially curable prostate cancer, development of simple and effective diagnostic tools for detecting treatment failures should be an important area of biomedical and clinical investigation. We have constructed and tested a home-based prostate cancer surveillance device for use by patients to detect PSA from blood obtained by finger stick. Our initial results suggest that home based PSA testing is feasible and may have clinical utility in management of men treated for prostate cancer.     

Percent free prostate-specific antigen (PSA) is an accurate predictor of prostate cancer risk in men with serum PSA 2.5 ng/mL and lower

BACKGROUND: Up to 17% of men with a prostate-specific antigen (PSA) level below the accepted prostate biopsy cutoff of 2.5 ng/mL may have prostate cancer. Because identification of these patients represents a difficult task, we assessed the ability of percent free PSA to discriminate between benign and malignant prostate biopsy outcomes in men with PSA < or =2.5 ng/mL. METHODS: Between 1999 and 2006, 543 men with a PSA < or =2.5 ng/mL were referred for initial prostate biopsy. Age, total PSA, percent free PSA, and digital rectal examination findings represented predictors of prostate cancer at biopsy in logistic regression models. The area under the receiver operating characteristics curve (AUC) quantified the discriminative ability of the predictors. The pathological characteristics of the detected cancers were assessed in individuals treated with radical prostatectomy. RESULTS: Of all, 23% had prostate cancer on biopsy, 16.5% of patients treated with radical prostatectomy had pT3 stage, and 35.6% had a pathological Gleason score of 3 + 4 or higher. The most accurate predictor of prostate cancer on biopsy was percent free PSA (0.68) versus age (0.50), total PSA (0.57), or rectal examination findings (0.58). Of patients with percent free PSA below 14%, 59% had prostate cancer. In multivariate models, percent free PSA (P < .001) and rectal examination findings (P = .001) were the only independent predictors of prostate cancer. The combined AUC of all predictors (0.69) was not significantly (P = .7) higher than that of percentage of free PSA alone (0.68). CONCLUSIONS: The risk of prostate cancer is clearly non-negligible in patients with PSA < or =2.5 ng/mL. The percent free PSA can accurately predict the prevalence of prostate cancer at prostate biopsy in these individuals.     

Prostate-specific antigen

Prostate specific antigen (PSA) is serine protease produced at high concentrations by normal and malignant prostatic epithelium. It is mainly secreted into seminal fluid, where it digests the gel forming after ejaculation. Only minor amounts of PSA leak out into circulation from the normal prostate, but the release of PSA is increased in prostatic disease. Thus PSA is a sensitive serum marker for prostate cancer but its specificity is limited by a high frequency of falsely elevated values in men with benign prostatic hyperplasia (BPH). Approximately two-thirds of all elevated values (>4 microg/l) in men over 50 years of age are due to BPH. In serum, most of the PSA immunoreactivity consists of a complex between PSA and alpha1-antichymotrypsin (PSA-ACT) whereas approximately 5-40% are free. The proportion of PSA-ACT is larger and the free fraction is smaller in prostate cancer than in benign prostatic hyperplasia (BPH). Determination of the proportion of free PSA has become widely used to improve the cancer specificity of PSA especially in men with PSA values in the 'grey zone' (4-10 microg/l). PSA also occurs in complexes with other protease inhibitors and determination of these and other markers may further improve the diagnostic accuracy for prostate cancer. Interpretation of the results for many different markers is complicated, but this can be simplified by using statistical methods. The diagnostic accuracy can be further improved by using logistic regression or neural networks to estimate the combined impact of marker results and other findings like digital rectal examination (DRE), transrectal ultrasound (TRUS) and heredity.     

Prostate-Specific Antigen Testing: Good or Bad?

Prostate-specific antigen (PSA) screening is not the panacea that enthusiasts hoped for, but it is not worthless. Men who have elevated PSA need to be aware that a prostate biopsy can identify both clinically significant and insignificant cancers and that intervention can affect quality of life. The oncologist can provide expert guidance, but once a patient understands the risks and benefits, only he can make the choice to be screened or not.The authors of the recent 13-year update of the European Randomised Study of Screening for Prostate Cancer (ERSPC) claim that testing for prostate-specific antigen (PSA) at least once every 4 years reduces prostate cancer mortality by as much as 27% among men aged 55–70 years [1]. This interpretation of the data is probably the most optimistic but is often quoted by the media or prostate cancer screening enthusiasts. The recent statement by the U.S. Preventive Services Task Force (USPSTF) takes the opposite position [2]. The USPSTF stated that the harms associated with PSA testing far outweigh the benefits and argued that PSA screening should not be done. What should patients be told regarding these seemingly contradictory statements concerning PSA screening? Several factors affect PSA testing outcomes including how the data are accrued and analyzed, the prevalence of prostate cancer among the men being tested, the natural history of prostate cancer progression, and the impact of treatment interventions. This commentary will review these factors with the goal of assisting the practicing oncologist in counseling patients appropriately.A careful review of the abstract of the ERSPC 13-year update reveals several numbers summarizing the trial results [1]. What do they all mean? The “rate ratio of prostate cancer incidence” between the intervention and control groups was 1.57 after 13 years. This means that one and a half times as many cancers were identified in the screening arm as in the control arm. Many people assume that it is good to find more cancers, but unfortunately, with prostate cancer, this may not be so. In the screening arm, more than half of the cancers identified were categorized as Gleason 6 tumors. In the control arm, less than one-third of the tumors were classified this way. Gleason 6 tumors are usually associated with an excellent prognosis; therefore, many men tested for PSA now carry the burden of a prostate cancer diagnosis without obvious benefit. Epidemiologists describe this problem as overdiagnosis. The ERSPC investigators estimate that almost half of the men diagnosed with screen-detected cancers have disease that will probably never cause morbidity.The abstract states that the “rate ratio of prostate cancer mortality” was 0.79 at 13 years [1]. What does this mean? This means that 21% fewer men died in the screening arm than in the control arm. Although this number may sound impressive, it is actually difficult to interpret in isolation because it is a relative rate. The percentage depends not on the number of men who died but simply on the ratio of deaths in the two arms of the trial. The next sentence states that the “absolute risk reduction” was 0.11 per 1,000 person-years or 1.28 per 1,000 men randomized. This means that the difference in prostate cancer deaths between the screening arm and the control arm was fairly modest. The authors note that for every 781 men invited for PSA testing, 1 prostate cancer death is averted. More important, for every 27 prostate cancers diagnosed by screening, 1 prostate cancer death is averted. Presenting the outcomes in relative terms versus absolute terms can influence how PSA testing is perceived. The editorial that accompanied the publication of the ERSPC update suggests that the absolute risk reduction will increase with longer follow-up [3]. This may or may not be true. The absolute risk reduction did not change when follow-up was extended from 11 to 13 years.The authors of the update end the abstract by stating that “after adjustment for nonparticipation,” the rate ratio of prostate cancer mortality in men screened was 0.73 [1]. What does this mean? This is an attempt to estimate the maximum possible impact of screening. Men participating in the screening arm of the ERSPC study, for example, were supposed to be screened every 4 years, to undergo a prostate biopsy if PSA was elevated, and to undergo treatment if they were found to have cancer. Conversely, men participating in the control arm should not have had any PSA screening. Unfortunately, in the real world, not every man actually does what he is supposed to do. To avoid selection biases that might occur by reclassifying men, researchers conducting a randomized trial usually perform an “intent-to-screen” analysis. Patients who do not complete their assigned intervention are considered not to have participated. By adjusting for nonparticipation, the authors are trying to calculate the maximum possible impact of PSA testing in a perfect world. As noted in the editorial, “such adjustments are not a precise science” [3]. Most epidemiologists usually quote the more conservative rate ratio derived from the unbiased intent-to-screen approach.A review of the entire paper reveals other important factors that have affected outcomes. Table 1 [1] lists all of the centers participating in the ERSPC trial. On quick inspection, one would assume that the trial was conducted in a similar fashion at each site, but this is not actually the case. Many epidemiologists look at this study as a series of seven separate screening trials, of which two are positive and the rest are negative. Each site had somewhat different accrual methods and used different screening criteria and different screening intervals. From an absolute perspective, the number of cases randomized differs significantly by center. Finland enrolled >80,000 men; the Netherlands enrolled 35,000; Italy enrolled almost 15,000; and Sweden enrolled almost 12,000. I mention these four sites because the trial showed no advantage for PSA testing in Finland or Italy but showed a statistically significant decline in prostate cancer mortality in the Netherlands and Sweden. Finland had the largest number of men randomized but did not show a positive outcome, whereas Sweden had the smallest number of men among these four centers but showed the most dramatic outcome. Why were findings so different among these sites? This question raises concerns about whether the results can be generalized to other nations and other populations. Sweden is unusual in that it has much higher mortality from clinically significant prostate cancer than the other participating European centers. Prostate cancer mortality among men aged 65–74 years is twice as high in Sweden compared with the U.S. Consequently, screening is likely to be much more effective in identifying clinically significant disease in Sweden and less effective in the U.S.A review of Table 4 [1] also raises concerns. This table lists prostate cancer mortality by age groups at the time of randomization. The results are statistically significant for the core age group of 55–69 years and for all ages from 54 to ≥70 years. A review by each age group, however, shows a more complex story. The results were dramatically positive for men aged 65–69 years at randomization but were not statistically significant for men aged 55–59 and 60–64 years despite comparable sample sizes and the fact that the men in the younger age groups were screened for a longer period of time. The positive findings of the entire trial are driven primarily by the older cohort of patients. Most screening advocates recommend that PSA testing start at age 50, but no evidence shows that more clinically significant cancers are found at this age.The paper does not address two other issues that affect the screening debate and that led the U.S. Preventive Services Task Force to recommend against PSA testing: treatment efficacy and associated treatment complications. Screening works only if there is an effective treatment that alters the outcome of the disease. Fortunately, two randomized trials address these issues. The Prostate Cancer Intervention Versus Observation Trial (PIVOT) trial was conducted by the U.S. Veterans Administration and enrolled 731 men with localized prostate cancer between 1994 and 2002 [4]. Men were randomly assigned to observation or radical prostatectomy and followed through January 2010. After a median follow-up of 10.0 years, 171 of 364 men assigned to radical prostatectomy died compared with 183 of 367 assigned to observation. Among men undergoing radical prostatectomy, 21 died of prostate cancer or treatment compared with 31 men assigned to observation. The authors concluded that radical prostatectomy did not provide a survival advantage for men identified with localized prostate cancer by PSA testing through 12 years of follow-up. Analysis by prostate cancer risk showed that observation was the preferred strategy for men with low-grade disease. There was a suggestion that surgery benefitted men with intermediate- or high-grade disease, but the sample size was too small to achieve statistical significance.The other key trial, the Scandinavian Prostate Cancer Group 4 study, was recently updated in March 2014 [5]. This trial was conducted in Sweden and accrued patients between 1989 and 1999 and followed them until December 31, 2012. Although most of the patients were not identified by PSA testing, this trial provides important data concerning the efficacy of surgery to treat prostate cancer. After a median follow-up of 13.4 years, 200 of 347 men assigned to radical prostatectomy had died compared with 247 of 348 men assigned to observation. Among men undergoing radical prostatectomy, 63 had died of prostate cancer or treatment compared with 99 men assigned to observation. In this case, radical prostatectomy provided a survival advantage, but the primary beneficiaries were men aged <65 years with intermediate-grade disease. Relatively few men with low-grade disease succumbed to prostate cancer (11 and 20, respectively, in the surgery and observation arms), and surgery appeared to have no impact among men with high-grade disease (28 and 29 prostate cancer deaths, respectively, in the surgery and observation arms). The data surrounding the efficacy of radiation therapy is much less robust.Unfortunately, whether effective or not, treatment can be associated with morbidity. This has been well documented for both surgery and radiation [6]. The USPSTF estimated that PSA testing will prevent 1 prostate cancer death for every 1,000 men tested [2]; however, to achieve this outcome, approximately 100–120 men will undergo a prostate biopsy, with the associated risks of bleeding and infection. Approximately 110 men will be diagnosed with prostate cancer. A majority of these men will undergo treatment. Treatment is associated with at least 2 serious cardiovascular events, 1 serious deep vein thrombosis, 29 cases of erectile dysfunction, and 18 cases of incontinence. From the USPSTF’s perspective, the ability to spare 1 prostate cancer death for every 1,000 men screened is not justified by the associated morbidity experienced by the 110 men undergoing treatment.Is PSA testing good or bad? It clearly is not the panacea that PSA screening enthusiasts hoped for, but it is not worthless. The significant overdiagnosis and the modest number of deaths prevented over 13 years of follow-up raise major concerns from a public health perspective. Many patients, however, still want to be tested. They believe that early diagnosis can protect them from prostate cancer progression, and in some cases, it can. From a practical standpoint, screening makes the most sense for men in their 50s and 60s. Obtaining a series of PSA levels drawn annually or biannually allows a physician to monitor the growth of the prostate over time. PSA levels often rise with age as a consequence of benign hypertrophy. Elevated PSA values should always be repeated after a few weeks before proposing a biopsy. Many will return to baseline within 1 month. An increase of up to 0.75 ng/mL over a 3-year period is normal.Those men who have elevated PSA need to be aware that a prostate biopsy can identify both clinically significant and insignificant cancers. Men found to have high-grade cancers will receive treatment, but this may improve outcomes for only a subset of patients. Men found to have low-grade cancers have a more difficult decision. Should they undergo treatment or active surveillance? Low-grade tumors usually do not progress for 10–20 years or longer. Patients must also recognize that intervention can have a serious impact on their quality of life, although not always. The oncologist can provide expert guidance, but once a patient understands the risks and benefits, only he can make the choice to be screened or not.     

Overdiagnosis due to prostate-specific antigen screening: lessons from U.S. prostate cancer incidence trends

BACKGROUND: Overdiagnosis of clinically insignificant prostate cancer is considered a major potential drawback of prostate-specific antigen (PSA) screening. Quantitative estimates of the magnitude of this problem are, however, lacking. We estimated rates of prostate cancer overdiagnosis due to PSA testing that are consistent with the observed incidence of prostate cancer in the United States from 1988 through 1998. Overdiagnosis was defined as the detection of prostate cancer through PSA testing that otherwise would not have been diagnosed within the patient's lifetime. METHODS: We developed a computer simulation model of PSA testing and subsequent prostate cancer diagnosis and death from prostate cancer among a hypothetical cohort of two million men who were 60-84 years old in 1988. Given values for the expected lead time--that is, the time by which the test advanced diagnosis--and the expected incidence of prostate cancer in the absence of PSA testing, the model projected the increase in population incidence of prostate cancer associated with PSA testing. By comparing the model-projected incidence with the observed incidence derived from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registry data, we determined the lead times and corresponding overdiagnosis rates that were consistent with the observed data. RESULTS: SEER data on prostate cancer incidence from 1988 through 1998 were consistent with overdiagnosis rates of approximately 29% for whites and 44% for blacks among men with prostate cancers detected by PSA screening. CONCLUSIONS: Among men with prostate cancer that would be detected only at autopsy, these rates correspond to overdiagnosis rates of, at most, 15% in whites and 37% in blacks. The observed trends in prostate cancer incidence are consistent with considerable overdiagnosis among PSA-detected cases. However, the results suggest that the majority of screen-detected cancers diagnosed between 1988 and 1998 would have presented clinically and that only a minority of cases found at autopsy would have been detected by PSA testing.     

Indications and timing for prostate biopsy, diagnosis of early stage prostate cancer and its definitive treatment: A clinical conundrum in the PSA era

The use of PSA for prostate cancer screening has led to a large increase in the number of men undergoing transrectal ultrasonography (TRUS) – guided biopsy of the prostate to determine the presence of prostate cancer. Recently, the indications for prostate biopsy based on PSA level have been questioned and new prostate cancer risk calculators that consider other factors related to prostate cancer have been proposed. Also, there have been significant changes over the years regarding the protocols used to sample the prostate. Most protocols recommend more extensive sampling of the prostate with more laterally directed biopsies of the peripheral zone for both initial and subsequent biopsies. There is still much controversy over the appropriate number and location of biopsy cores, and timing to optimize the diagnosis of prostate cancer on initial and repeat biopsy. Finally, discovery of a new molecular marker independent of the PSA level will be very important in the diagnosis and prognosis of prostate cancer.     

Prostate cancer diagnosis,staging and survival

Prostate cancer is the most common malignancy in men and the second most common cancer related death. Through research, we have found that African–American men and men with a family history of prostate cancer have a significantly higher risk of prostate cancer. In the 90's the mortality rate from prostate cancer decreased, presumably due to PSA testing. Patients with organ-confined tumors, particularly if they have a moderate Gleason score have an excellent chance of long-term survival with radical prostatectomy or external beam radiation therapy. Advances in detecting micrometastatic disease are needed to further impact on this disease.     

Uptake of prostate-specific antigen testing for early prostate cancer detection in Sweden

The aim of our study was to estimate uptake of prostate-specific antigen (PSA) testing in an entire country, including time trends and geographical differences. Data from the Swedish Cancer Register on prostate cancer incidence between 1980 and 2007 and published data from the Gothenburg branch of the European randomized study of screening for prostate cancer (ERSPC), a population-based PSA screening study, were used in two models of changes in incidence of prostate cancer as a proxy for uptake of PSA testing in all 24 Swedish counties. The estimated annual PSA testing, irrespective of previous years' exposure, reached a peak of 12% of all men in 2004 and decreased thereafter to 6% in 2007 and varied from less than 5 to 20% between counties. Under the assumption that men who underwent annual PSA testing were previously unexposed to PSA testing, the cumulated uptake of PSA testing in men aged 55-69 years in Sweden increased from zero in 1997 to 56% in 2007. Our study shows that it is possible to estimate uptake of PSA testing in the population from the prostate cancer incidence pattern. There were large geographical variations in uptake of PSA testing despite a uniform health care system in Sweden and there was a substantial increase in the uptake of PSA testing during the study period, despite that there were no national recommendations for PSA-based prostate cancer screening.     

Preoperative serum DNA GSTP1 CpG island hypermethylation and the risk of early prostate-specific antigen recurrence following radical prostatectomy.

PURPOSE: Hypermethylation of the CpG island at the promoter region of the pi-class glutathione S-transferase gene (GSTP1) is the most common somatic genome abnormality in human prostate cancer. We evaluated circulating cell-free DNA GSTP1 CpG island hypermethylation as a prognostic biomarker in the serum of men with prostate cancer. EXPERIMENTAL DESIGN: Prostate cancer DNA GSTP1 CpG island hypermethylation was detected using a restriction endonuclease quantitative PCR technique. We analyzed preoperative serum from 85 men with clinically localized prostate cancer treated with radical prostatectomy and from 35 men with a negative prostate biopsy. We then assayed preoperative serum from a data set of 55 pairs of men with clinically localized prostate cancer treated with radical prostatectomy, matched for Gleason score, comprising 55 men suffering prostate-specific antigen (PSA) recurrence (median, 2 years) and 55 men who were free of disease at last follow-up (median, 3 years). The association of serum GSTP1 CpG island hypermethylation and PSA recurrence was determined. RESULTS: Circulating cell-free DNA with GSTP1 CpG island hypermethylation was not detected in the serum of men with a negative prostate biopsy but was detected in 12% of men with clinically localized disease and 28% of men with metastatic cancer (P = 0.003). In the matched data set, eight men (15%) who developed PSA recurrence were positive for DNA with GSTP1 CpG hypermethylation, whereas no patient who was free of disease was positive for GSTP1 CpG island hypermethylation (McNemar test, chi(2) = 6.1, P = 0.01). In a multivariable analysis that accounted for recognized prognostic factors, the presence of serum DNA with GTSP1 CpG island hypermethylation was the most significant predictor of PSA recurrence (hazard ratio, 4.4; 95% confidence interval, 2.2, 8.8; P < 0.001). CONCLUSION: Our study suggests that GSTP1 CpG island hypermethylation may be an important DNA-based prognostic serum biomarker for prostate cancer.     

Changing relationship between socioeconomic status and prostate cancer incidence

BACKGROUND: Understanding the relationship between socioeconomic status (SES) and prostate cancer incidence could identify populations that should be targeted for intervention and prevention programs. We examined this relationship within the major racial/ethnic groups during the period 1972 through 1997, which spans the introduction of prostate-specific antigen (PSA) testing. METHODS: We used data from the population-based Los Angeles Cancer Surveillance Program to examine age-adjusted prostate cancer incidence rates in five SES groups over three specific calendar periods by racial/ethnic subpopulation (white, black, Asian, and Hispanic) and by stage of disease at diagnosis. Linear regression analysis was used to test for trends in the age-adjusted incidence rates that were associated with increasing levels of SES. All P values were two-sided. RESULTS: For men diagnosed with prostate cancer before 1987, when the test for PSA was not widely available, we found no association between SES and the incidence of prostate cancer in any of four racial/ethnic subpopulations or between SES and the stage of disease at diagnosis. In contrast, among men who were diagnosed with prostate cancer after 1987, SES was statistically significantly and positively associated with prostate cancer incidence in men from all racial/ethnic subpopulations except Asians (P =.01 for white men, P =.001 for black men, P =.02 for Hispanic men, P =.06 for Asian men, and P =.01 for all men combined). Higher SES was statistically significantly associated with cancers of earlier stage (P =.01 for localized cancer and P =.00 for regional cancer) for men who were diagnosed with prostate cancer after 1987. CONCLUSIONS: The association between SES and prostate cancer incidence after 1987 may reflect more prevalent PSA screening in populations with higher SES due to their greater access to health care. SES should, therefore, be considered an important factor in interpreting variations and time trends in prostate cancer incidence.     

p300 regulates androgen receptor-independent expression of prostate-specific antigen in prostate cancer cells treated chronically with interleukin-6

Prostate cancer is the most frequent non-skin cancer in men. Although the mechanisms involved in the progression of prostate cancer are not entirely understood, androgen receptor has been shown to play an important role. Androgen receptor is expressed in both early and late-stage prostate cancer. Also, androgen-regulated pathways are thought to be active as evidenced by elevated levels of prostate-specific antigen (PSA). In addition, several androgen receptor coactivators and cytokines are involved in prostate cancer progression. In this regard, we have shown previously that the coactivator p300 plays a major role in the androgen-independent activation of PSA by interleukin 6 (IL-6), a cytokine involved in late-stage prostate cancer. In this study, we investigated the role of p300 and its homologue CREB-binding protein in prostate cancer cells treated chronically with IL-6. We found that p300 but not CREB-binding protein induced activation of PSA in these cells and that the histone acetyltransferase activity of p300 was critical. This effect was independent of the presence of androgens or antiandrogens. Moreover, we found markedly reduced levels of androgen receptor in these cells and p300 transfection did not affect those levels, suggesting that the p300 effect on PSA could be bypassing the androgen receptor. Transfection with exogenous androgen receptor showed minimal response of PSA to androgens but higher response to p300. We found similar effects of p300 on the androgen response element III, which mediates the androgen receptor-dependent activation of PSA. Finally, we showed that p300 alone regulates expression of the endogenous PSA gene in the IL-6-treated cells. These findings reveal a new insight in the progression of prostate cancer, suggesting that coactivators, such as p300, play more important roles in late-stage prostate cancer, and could regulate androgen-dependent genes in the absence or with very low levels of androgen receptor.     

Family history, perceived risk, and prostate cancer screening among African American men.

BACKGROUND: Many African American men have two major risk factors for prostate cancer. By ethnicity alone, they have twice the risk of Euro-American men of developing prostate cancer. Having a family history (brother or father with prostate cancer) also doubles their risk. The major hypotheses tested in this study are that men with a family history perceive their risk to be higher, are more worried about getting prostate cancer, and are more likely to have used cancer screening tests than men without such a history. METHODS: A sample of 208 African American men, ages 40 to 74 years, were recruited through relatives or friends whose prostate cancer diagnosis was reported to the California Cancer Registry during the years 1997 to 2001 and from churches and African American social groups. Following a screening interview to determine eligibility, 88 men with self-reported, first-degree family history of prostate cancer and 120 without such history were interviewed by telephone. Logistic regression was used to create models of perceived risk, prostate cancer worries, receipt of a digital rectal exam, and/or prostate-specific antigen (PSA) testing. RESULTS: Men with a self-reported family history of prostate cancer did not perceive their risk as higher than men without a family history, nor did they report more cancer worries. They were more likely to report having a recent PSA test, but not a digital rectal exam. Having a higher than average perceived risk was associated with younger age, a college education, and lower mental well-being, and reporting more prostate cancer worries and being more likely to have had a recent PSA test. CONCLUSIONS: Although there continues to be controversy about PSA testing, these data suggest that African American men at above-average risk are inclined to be screened.     

Use of the prostate-specific antigen test among U.S. men: findings from the 2005 National Health Interview Survey.

BACKGROUND: Although evidence that prostate cancer deaths are reduced by screening for elevated prostate-specific antigen (PSA) concentration coupled with early diagnosis and treatment is insufficient to advocate routine screening for prostate cancer, PSA testing has become more common in the past decade. We examined characteristics that might influence testing and compared test use between men ages 40 to 49 and 50 to 79 years. METHODS: We used data from 7,669 participants with no history of prostate cancer in the 2005 National Health Interview Survey. RESULTS: Among men reporting about PSA testing, an estimated 16% of 40- to 49-year-old men and 49% of 50- to 79-year-old men had a PSA test in the past 2 years. In multivariate analyses, among men ages 40 to 49 years, non-Hispanic Black men were more likely (P < 0.05) to have had a PSA test than non-Hispanic White men. We found no significant difference by race/ethnicity in men ages 50 to 79 years. Higher education, higher poverty threshold, usual source of medical care, family history of prostate cancer, and comorbid conditions were associated with increased PSA test use in both age groups. Additionally, men ages 50 to 79 years born in the United States, who were married, had private or military health insurance, and had been diagnosed with another cancer type were more likely to be tested. CONCLUSIONS: Findings from the multivariate analyses indicated significantly higher PSA test use among younger non-Hispanic Black men than among non-Hispanic White men. These findings may indicate that healthcare providers are getting and conveying the message of increased risk of prostate cancer among African American men.