Prostate cancer association studies: pitfalls and solutions to cancer misclassification in the PSA era

Widespread screening of American men for elevated PSA has changed the characteristics of prostate cancer cases in the U.S. The influence of the changed nature of prostate cancer cases in the PSA era and the need for careful consideration of who is a "case" and who is a "control" on the ability to detect associations of risk factors with prostate cancer in etiologic epidemiologic studies merits discussion. Issue 1: prostate cancer cases diagnosed in the PSA era are enriched with a pool of early lesions, which may differ in etiology, and are deficient in advanced lesions, which are the most likely to be the product of promotion and progression events. By admixing the two types of cases (i.e., imperfect specificity), the associations previously detected using epidemiologic designs when the majority of cases were clinically detected may no longer be apparent in the PSA era when the majority of cases are now detected in the pre-clinical phase. Researchers must now tailor hypotheses such that they are testable using early stage cases or specifically augment the number of advanced cases when testing hypotheses related to extraprostatic growth and progression. Issue 2: even when controls are screened for elevated PSA to rule out the presence of prostate cancer, some proportion of those controls currently will have one or more foci of prostate cancer. The imperfect sensitivity of the PSA test coupled with diagnostic work-up may in part result from (a) lack of PSA elevation in some men with prostate cancer or (b) failure of biopsy to sample the tumor focus in men with elevated PSA. Misclassification of men with undetected prostate cancer as controls usually produces a bias that tends to deflate associations. Given this type of disease misclassification, whether an association still can be statistically detected depends on the extent of misclassification, the magnitude of the true association, the prevalence of the exposure in the true controls, and the sample size, although in general moderate nondifferential misclassification does not lead to profound attenuation. However, under the same scenario attenuation does not occur in cohort or case-cohort studies in which the rate or risk ratio (RR) is calculated. That prostate cancer cases diagnosed in the PSA era are enriched with early stage, minimally invasive disease in our opinion is likely to pose a far more serious obstacle to epidemiologic research on the etiology of clinically important prostate cancer than the issue of inclusion as controls some men who have undiagnosed prostate cancer because of imperfect sensitivity of PSA screening and biopsy sampling error.     

Prostate cancer in elderly men

Due to increasing life expectancy and the introduction of prostate-specific antigen (PSA) screening, a rising number of elderly men are diagnosed with prostate cancer. Besides PSA serum levels and Gleason score, age is considered to be a key prognostic factor in terms of treatment decisions. In men older than 70 years, treatment without curative intent may deprive the frail patient of years of life. Modern radical prostatectomy techniques are associated with low perioperative morbidity, excellent clinical outcome, and documented long-term disease control. Thus, radical prostatectomy should be considered because local treatment of organ-confined prostate cancer potentially cures disease. The huge extent of PSA screening programs may lead to overdiagnosis of prostate cancer. Not every man who is diagnosed with prostate cancer will develop clinically significant disease. This has led to the concept of expectant management for screen-detected, small-volume, low-grade disease, with the intention of providing therapy for those men with disease progression.     

Genetic epidemiology of prostate cancer

A family history of prostate cancer is a consistent risk factor for prostate cancer, and can also be used to predict the presence of prostate cancer among asymptomatic men who undergo PSA screening. Approximately 5% of cases of prostate cancer have a familial component. The genetic epidemiology of prostate cancer is complex, and genes on chromosome 1 and X chromosome contribute to familial aggregation. Neither of these prostate cancer susceptibility genes have been identified, but are the subject of an active search. Hereditary prostate cancer resembles non-hereditary prostate cancer in terms of age of onset, pathologic appearance and grade.     

Current and projected annual direct costs of screening asymptomatic men for prostate cancer using prostate-specific antigen

BACKGROUND: Concern over the cost of screening for asymptomatic prostate cancer by means of prostate-specific antigen (PSA) testing has played an important role in PSA screening policy. However, little is known about the true costs of current PSA screening in Canada and how costs may change in the future. METHODS: The authors performed a cost identification study from the perspective of provincial ministries of health. They used data from published reports, hospital discharge data, claims data from several provinces, a laboratory survey, a national survey of knowledge, attitudes and beliefs about screening, a provincial cancer registry and expert opinion to estimate current first-year screening costs. Using demographic data from Statistics Canada and various scenarios regarding changes in screening patterns, the authors derived estimates of the future costs of PSA screening. RESULTS: In 1995 PSA screening cost an estimated $45 million (range $40 million to $84 million). Treatment accounted for over 61% of total costs, whereas screening, diagnosis and staging accounted for 35%. Screening all eligible men in Canada in 1995 would have cost $317 million (range $356 million to $691 million), more than the costs of all prostate cancer care in that year. Annual recurrent screening for all eligible men in 2005 would cost $219 million (range $208 million to $412 million). Projections from existing trends suggest that annual costs of PSA screening in 2000 are likely to increase from the estimated $45 million to approximately $66 million (range $59 million to $126 million). INTERPRETATION: PSA screening is costly, but even universal screening would consume a smaller share of national health expenditures than previous studies have suggested. Costs attributable to PSA screening may increase in the future owing to changes in utilization patterns and demographic shifts.     

Newer potential biomarkers in prostate cancer

Prostate-specific antigen (PSA) screening has led to a significant rise in the number of men diagnosed with prostate cancer and an associated increase in biopsies performed. Despite its limitations, including a positive predictive value of only 25%-40%, PSA remains the only generally accepted biomarker for prostate cancer. There is a need for better tools to not only identify men with prostate cancer, but also to recognize those with potentially lethal disease who will benefit from intervention. A great deal of work has been done worldwide to improve our knowledge of the genetics behind prostate cancer and the specificity of PSA by developing assays for different PSA isoforms. Common genetic alterations in prostate cancer patients have been identified, including CpG hypermethylation of GSPT1 and TMPRSS2:ERG gene fusion. Serum and urine detection of RNA biomarkers (eg, PCA3) and prostate cancer tissue protein antibodies (eg, EPCA) are being evaluated for detection and prognostic tools. This article reviews some of the promising developments in biomarkers.     

Management of clinically localized prostate cancer

Critics of screening have stated that early detection of prostate cancer does not necessarily reflect a diminishing death rate from the disease. However, several recent reports have demonstrated that the death rate from prostate cancer is decreasing, representing the most compelling validation for aggressive screening. Prostate cancer can be halted only if there is no evidence of systemic or regional metastases and the disease is confined to the surgical field or the radiation template. Surgeons and radiation oncologists must make a concerted effort to exclude men with regional and systemic metastases who are unlikely to benefit from treatment. With the widespread acceptance of prostate-specific antigen screening, a greater proportion of men are being diagnosed with clinically localized prostate cancer. Both radical prostatectomy and radiation therapy are able to halt disease spread in this significant subset of men, but survival outcomes indicate that radical prostatectomy is a more reliable treatment than radiation therapy for clinically localized prostate cancer. Overall, the immediate treatment-related morbidity of radical prostatectomy and radiation therapy in the modern era is quite low. Radical prostatectomy and radiation therapy appear to have a similar impact on continence and erectile function. There is a need for neoadjuvant and adjuvant therapies that can be utilized in those cases where radical prostatectomy and radiation are less likely to completely eradicate or destroy the cancer.     

UNINFORMED CONSENT: MASS SCREENING FOR PROSTATE CANCER

While medicine may agree in principle that cancer screening requires informed consent, such consent is not, in fact, common practice. In the case of prostate‐cancer screening this means that men in large numbers undergo PSA testing with little understanding of its liabilities – in particular, that it may or may not decrease mortality, often detects cancer of questionable significance, and may lead to unnecessary surgery. Given that prostate cancer is known to be overtreated and that family history is a risk factor, it follows that a man diagnosed with prostate cancer, even if it is of no clinical significance, automatically promotes his son into the high‐risk category; and given that those so categorized are subject to heightened medical surveillance and that the more diligently medicine searches for prostate cancer the more likely it is to find it, it follows that the sons of men diagnosed as a result of PSA testing are at risk of being overdiagnosed (and overtreated) precisely because their father was. Twenty years into the PSA revolution, its generational consequences have not been discussed in the medical literature.     

The 4Kscore? Test Reduces Prostate Biopsy Rates in Community and Academic Urology Practices

There is significant concern regarding prostate cancer screening because of the potential for overdiagnosis and overtreatment of men who are discovered to have abnormal prostate specific antigen (PSA) levels and/or digital rectal examination (DRE) results. The 4Kscore® Test (OPKO Diagnostics, LLC) is a blood test that utilizes four kallikrein levels plus clinical information in an algorithm to calculate an individual’s percentage risk (< 1% to > 95%) for aggressive prostate cancer (Gleason score ≥ 7) on prostate biopsy. The 4Kscore Test, as a follow-up test after abnormal PSA and/or DRE test results, has been shown to improve the specificity for predicting the risk of aggressive prostate cancer and reduce unnecessary prostate biopsies. A clinical utility study was conducted to assess the influence of the 4Kscore Test on the decision to perform prostate biopsies in men referred to urologists for abnormal PSA and/or DRE results. The study population included 611 patients seen by 35 academic and community urologists in the United States. Urologists ordered the 4Kscore Test as part of their assessment of men referred for abnormal PSA and/or DRE test results. Results for the patients were stratified into low risk (< 7.5%), intermediate risk (7.5%–19.9%), and high risk (≥ 20%) for aggressive prostate cancer. The 4Kscore Test results influenced biopsy decisions in 88.7% of the men. Performing the 4Kscore Test resulted in a 64.6% reduction in prostate biopsies in patients; the actual percentage of cases not proceeding to biopsy were 94.0%, 52.9%, and 19.0% for men who had low-, intermediate-, and high-risk 4Kscore Test results, respectively. A higher 4Kscore Test was associated with greater likelihood of having a prostate biopsy (P < 0.001). Among the 171 patients who had a biopsy, the 4Kscore risk category is strongly associated with biopsy pathology. The 4Kscore Test, as a follow-up test for an abnormal PSA and/or DRE results, significantly influenced the physician and patient shared decision in clinical practice, which led to a reduction in prostate biopsies while increasing the probability of detecting aggressive cancer.Key Words: Prostate cancer, Prostate-specific antigen, Digital rectal examination, Biopsy rate, Gleason score, 4Kscore Test, Prostate cancer prognosisWidespread screening for prostate cancer with serum prostate-specific antigen (PSA) began in 1991, and subsequently a 45% decline in prostate cancer mortality has been observed.¹ A recent large European randomized clinical trial also reported a 29% reduction in death from prostate cancer in men undergoing routine screening.² However, because of a US study that showed no mortality benefits to organized PSA screening,³ and the net physical and psychologic burden of secondary adverse events triggered by PSA testing versus the number of lives saved, the United States Preventative Services Task Force (USPSTF) recently advised against routine PSA screening for prostate cancer.⁴ The concern of the USPSTF is based on the fact that most men diagnosed with prostate cancer have a tumor that is unlikely to pose a threat to life expectancy. A recent systematic analysis suggested that up to 60% of prostate cancers diagnosed in contemporary studies might be safely observed without a need for immediate intervention.⁵One of the primary challenges for urologists is the potential for under-grading of Gleason 6 prostate cancer due to biopsy sampling error; as a result, up to 90% of men with a Gleason 6 prostate cancer still proceed to prostate cancer treatment despite the advent of active surveillance programs. Approximately 66% of patients who are diagnosed with Gleason 6 disease at biopsy will be confirmed to have Gleason 6 cancer after radical prostatectomy.⁶ Some of these men are considered to have undergone overtreatment, because Gleason 6 cancer is not considered life threatening.⁷ This subset of men has the potential for developing complications following surgery, including erectile dysfunction, urinary incontinence, and changes in health-related quality of life with disruption of psychologic, sexual, and urinary function.^8–12The prostate biopsy procedure is invasive, and has significant costs and complications such as bleeding, urinary retention, and life-threatening infection. A recent population-based study from Ontario, Canada, revealed a fourfold increase to 4.1% for the rate of hospital admissions after prostate biopsy from 1996 to 2005, with 72% of admissions due to infection.¹³ These risks, combined with the anxiety involved in undergoing the procedure, present a significant burden to any man considering prostate cancer screening.The impact of the USPSTF has been a decrease in overall biopsy rates with a subsequent decline in the detection rate of Gleason 7 to 10 high-grade prostate cancers.¹⁴ The elimination of PSA screening means that the 20% to 30% of men who would have presented with an abnormal PSA level and been found to have high-grade prostate cancer may lose an opportunity for a possible cure.¹⁵ Clearly, there is a need for better risk-stratification tools for men presenting with an abnormal PSA level and/or digital rectal examination (DRE) result in order to both reduce the number of prostate biopsies performed and decrease the rate of Gleason 6 diagnosis and treatment.⁶The 4Kscore® Test (OPKO Diagnostics, LLC) incorporates measured blood levels of four kallikrein proteins: total PSA, free PSA, intact PSA, and human kallikrein 2 plus clinical information (age, DRE findings, and a history of prior negative biopsy result) into a proprietary algorithm to calculate an individual man’s percentage risk (< 1% to > 95%) of having Gleason score ≥ 7 if a prostate biopsy were to be performed. The 4Kscore Test has been extensively validated through a total of 12 prospective and retrospective studies published in peer-reviewed journals involving over 22,000 patients from both the United States and Europe.^16–23 These studies of men with elevated PSA levels involved cohorts of unscreened and screened men, and those with negative prior prostate biopsy results. Based on analyses published in these studies, the 4Kscore Test would have theoretically resulted in a 45% reduction in prostate biopsies while delaying the diagnosis of aggressive prostate cancer in only a few men (1.3%–4.7%).The 4Kscore Test is used to accurately determine percentage risk for aggressive prostate cancer (Gleason score ≥ 7) and provide additional information for men being considered for prostate biopsy because of abnormal PSA levels and/or DRE results. This allows urologists to better risk stratify men for biopsy and ultimately results in more selective treatment of those men with aggressive disease. Conversely, those men not harboring life-threatening disease are able to safely avoid prostate biopsy and overtreatment of indolent disease.With the introduction of any new diagnostic test such as the 4Kscore Test into clinical practice, it is important to assess whether its implementation, in this case as a follow-up test for an abnormal PSA and/or DRE result, influences and changes the physician-patient shared decision-making process and leads to an actual reduction in prostate biopsies. Herein we evaluated the influence of the 4Kscore Test on urologist-patient decisions about proceeding with biopsy in men who have an abnormal PSA and/or DRE result from multiple academic and community urology clinical practices in the United States.     

Pathological and molecular mechanisms of prostate carcinogenesis: implications for diagnosis, detection, prevention, and treatment

Prostate cancer is an increasing threat throughout the world. As a result of a demographic shift in population, the number of men at risk for developing prostate cancer is growing rapidly. For 2002, an estimated 189,000 prostate cancer cases were diagnosed in the U.S., accompanied by an estimated 30,200 prostate cancer deaths [Jemal et al., 2002]. Most prostate cancer is now diagnosed in men who were biopsied as a result of an elevated serum PSA (>4 ng/ml) level detected following routine screening. Autopsy studies [Breslow et al., 1977; Yatani et al., 1982; Sakr et al., 1993], and the recent results of the Prostate Cancer Prevention Trial (PCPT) [Thompson et al., 2003], a large scale clinical trial where all men entered the trial without an elevated PSA (<3 ng/ml) were subsequently biopsied, indicate the prevalence of histologic prostate cancer is much higher than anticipated by PSA screening. Environmental factors, such as diet and lifestyle, have long been recognized contributors to the development of prostate cancer. Recent studies of the molecular alterations in prostate cancer cells have begun to provide clues as to how prostate cancer may arise and progress. For example, while inflammation in the prostate has been suggested previously as a contributor to prostate cancer development [Gardner and Bennett, 1992; Platz, 1998; De Marzo et al., 1999; Nelson et al., 2003], research regarding the genetic and pathological aspects of prostate inflammation has only recently begun to receive attention. Here, we review the subject of inflammation and prostate cancer as part of a "chronic epithelial injury" hypothesis of prostate carcinogenesis, and the somatic genome and phenotypic changes characteristic of prostate cancer cells. We also present the implications of these changes for prostate cancer diagnosis, detection, prevention, and treatment.     

Épidémiologie du cancer de la prostate: Article de revue

Prostate cancer is the first cancer in incidence and the second in mortality for men in France. In 2000, the estimated number of newly diagnosed cases was 40,309. Crude and standardised on world population yearly incidence rates were 141.4/100,000 and 75.3/100,000, respectively. The French Society of Urology recommends individual screening for prostate cancer. Information and consent is required before screening. The Haute Autorité de Santé has published an information for men seeking for screening. Mass screening is not recommended. Screening tests consist of prostate specific antigen (PSA) dosage, rectal examination, yearly for men aged 50 to 75 or starting from 45 in case of risk factors. Currently, large studies are ongoing to estimate the benefit of mass screening on morbidity and mortality. France participates to a European study (ERSPC). Results will be available in years 2008–2010.     

Finding the Wolf in Sheep’s Clothing: The 4Kscore Is a Novel Blood Test That Can Accurately Identify the Risk of Aggressive Prostate Cancer

Better biomarkers that can discriminate between aggressive and indolent phenotypes of prostate cancer are urgently needed. In the first 20 years of the prostate-specific antigen (PSA) era, screening for prostate cancer has successfully reduced prostate cancer mortality, but has led to significant problems with overdiagnosis and overtreatment. As a result, many men are subjected to unnecessary prostate biopsies and overtreatment of indolent cancer in order to save one man from dying of prostate cancer. A novel blood test known as the 4Kscore® Test (OPKO Lab, Nashville, TN) incorporates a panel of four kallikrein protein biomarkers (total PSA, free PSA, intact PSA, and human kallikrein-related peptidase 2) and other clinical information in an algorithm that provides a percent risk for a high-grade (Gleason score ≥ 7) cancer on biopsy. In 10 peer-reviewed publications, the four kallikrein biomarkers and algorithm of the 4Kscore Test have been shown to improve the prediction not only of biopsy histopathology, but also surgical pathology and occurrence of aggressive, metastatic disease. Recently, a blinded prospective trial of the 4Kscore Test was conducted across the United States among 1012 men. The 4Kscore Test replicated previous European results showing accuracy in predicting biopsy outcome of Gleason score ≥ 7. In a recent case-control study nested within a population-based cohort from Västerbotten, Sweden, the four kallikrein biomarkers of the 4Kscore Test also predicted the risk for aggressive prostate cancer that metastasized within 20 years after the test was administered. These results indicate that men with an abnormal PSA or digital rectal examination result, and for whom an initial or repeat prostate biopsy is being considered, would benefit from a reflex 4Kscore Test to add important information to the clinical decision-making process. A high-risk 4Kscore Test result may be used to select men with a high probability of aggressive prostate cancer who would benefit from a biopsy of the prostate to prevent an adverse and potentially lethal outcome from prostate cancer. Men with a low 4Kscore Test result may safely defer biopsy.Key words: Prostate cancer, Biomarker, High-grade prostate cancer, ScreeningProstate cancer is the most common cancer in men in the United States, accounting for an estimated 27% of all newly diagnosed cancers in 2014.¹ Since the advent of screening for prostate cancer with serum prostate-specific antigen (PSA), we have seen a significant decline in prostate cancer mortality.¹ Randomized clinical trials have reported a 20% to 40% reduction in death from prostate cancer in men undergoing routine screening compared with those who are not screened.^2,3 However, these trials, and a trial showing little difference between opportunistic and systematic screening,⁴ have raised the concern for overdiagnosis and overtreatment of indolent prostate cancer. The fundamental concern is that an overwhelming number of men are subjected to interventions such as prostate biopsy in order to prevent one man’s death from prostate cancer.^2,3Prostate biopsy is an invasive procedure with significant complications, such as bleeding, urinary retention, and life-threatening infection. A recent population-based study from Ontario, Canada, revealed a fourfold increase to 4.1% for the rate of hospital admissions after prostate biopsy from 1996 to 2005, with 72% of admissions being due to infection.⁵ These risks, combined with the enormous anxiety involved in undergoing the procedure, present a significant burden to any man considering prostate cancer screening.Today, most men diagnosed with prostate cancer have a tumor that is unlikely to pose a threat to their life expectancies. A recent systematic analysis suggested that up to 60% of prostate cancers diagnosed in contemporary studies can be safely observed without a need for immediate intervention.⁶ However, in the United States, because of the concern for possible undergrading of prostate cancer due to biopsy sampling error, 90% of men diagnosed with prostate cancer undergo treatment and approximately 66% will be confirmed to have indolent Gleason score 6 prostate cancer,⁷ suggesting a significant problem with overtreatment. Although treatment for localized prostate cancer provides excellent cancer control,^8,9 it comes at a significant detriment to health-related quality of life (HRQoL). Previous studies have reported significant changes in HRQoL after primary treatment for prostate cancer, primarily in the domains of sexual and urinary function and bother.^10–12 Given the physical and psychological burden of these secondary adverse events, many government agencies and patients are beginning to question the risks and benefits of prostate cancer screening and treatment.¹³The United States Preventive Services Task Force recently advised against routine screening for prostate cancer, claiming that the risks of screening outweigh the benefits.¹³ However, 20% to 30% of men who are diagnosed with prostate cancer are found to have high-grade disease at presentation¹⁴; without screening, these men would lose their opportunity for cure. It is clear that new biomarkers or tests that promote the detection of both indolent and aggressive prostate cancer are unlikely to be helpful. We need tests that focus on the detection of aggressive tumors, not the indolent ones that are better left alone. Aggressive prostate cancer, for purposes of this review, is defined as cancer with a Gleason score ≥ 7 and tumors that are most likely to progress to metastatic disease and death. Targeted detection of aggressive prostate cancer would allow urologists to diagnose and treat those men most likely to benefit from aggressive intervention to avoid premature death. Conversely, those men harboring non-life-threatening disease would be able to avoid unnecessary interventions. The 4Kscore® Test (OPKO Lab, Nashville, TN) is a new blood test that accurately identifies the risk of aggressive prostate cancer. The 4Kscore Test plays an important clinical role as a reflex test prior to proceeding with initial prostate biopsy in men with an elevated PSA level or abnormal digital rectal examination (DRE) results, or after a prior negative biopsy and persistently abnormal PSA levels.     

Comparison of digital rectal examination and prostate specific antigen in early detection of prostate cancer

This study compares the value of digital rectal examination (DRE) and prostate specific antigen (PSA) determination in the detection of prostate cancer. 1,000 men aged > or = 50 from the Osijek surroundings were examined. The subjects with prostatitis were excluded from the study. The subjects with elevated concentration of total prostate specific antigen and/or digital rectal examination suspect of carcinoma underwent prostate biopsy. The rate of prostate cancer detection showed to be 3.3% for PSA > 4 ng/ml, 2% for abnormal finding of DRE, and 3.7% for combination of the two methods. Out of 35 patients with prostate cancer detected, 19 had suspect DRE finding and 32 had PSA exceeding 4 ng/ml. Thus, PSA pointed to the diagnosis of prostate cancer in 91.4%, and abnormal finding of DRE in 54.2% of cases, the difference being statistically significant. The positive predictive value was 48.7% for abnormal finding of DRE, 47% for PSA > 4 ng/ml, and 80.0% for the combination of both. Although PSA determination detected a considerable proportion of tumors missed on DRE, the former alone was found to be insufficient as a screening method because of its inadequate sensitivity. When combined with digital rectal examination, the probability of prostate cancer detection increased considerably.     

Incorporating Known Genetic Variants Does Not Improve the Accuracy of PSA Testing to Identify High Risk Prostate Cancer on Biopsy

Introduction

Prostate-specific antigen (PSA) testing is a widely accepted screening method for prostate cancer, but with low specificity at thresholds giving good sensitivity. Previous research identified four single nucleotide polymorphisms (SNPs) principally associated with circulating PSA levels rather than with prostate cancer risk (TERT rs2736098, FGFR2 rs10788160, TBX3 rs11067228, KLK3 rs17632542). Removing the genetic contribution to PSA levels may improve the ability of the remaining biologically-determined variation in PSA to discriminate between high and low risk of progression within men with identified prostate cancer. We investigate whether incorporating information on the PSA-SNPs improves the discrimination achieved by a single PSA threshold in men with raised PSA levels.

Materials and Methods

Men with PSA between 3-10ng/mL and histologically-confirmed prostate cancer were categorised as high or low risk of progression (Low risk: Gleason score≤6 and stage T1-T2a; High risk: Gleason score 7–10 or stage T2C). We used the combined genetic effect of the four PSA-SNPs to calculate a genetically corrected PSA risk score. We calculated the Area under the Curve (AUC) to determine how well genetically corrected PSA risk scores distinguished men at high risk of progression from low risk men.

Results

The analysis includes 868 men with prostate cancer (Low risk: 684 (78.8%); High risk: 184 (21.2%)). Receiver operating characteristic (ROC) curves indicate that including the 4 PSA-SNPs does not improve the performance of measured PSA as a screening tool for high/low risk prostate cancer (measured PSA level AU C = 59.5% (95% CI: 54.7,64.2) vs additionally including information from the 4 PSA-SNPs AUC = 59.8% (95% CI: 55.2,64.5) (p-value = 0.40)).

Conclusion

We demonstrate that genetically correcting PSA for the combined genetic effect of four PSA-SNPs, did not improve discrimination between high and low risk prostate cancer in men with raised PSA levels (3-10ng/mL). Replication and gaining more accurate estimates of the effects of the 4 PSA-SNPs and additional variants associated with PSA levels and not prostate cancer could be obtained from subsequent GWAS from larger prospective studies.     

Screening for Prostate Cancer: A Review of the ERSPC and PLCO Trials

The advent of prostate-specific antigen (PSA) testing in the early 1980s revolutionized the diagnosis of prostate cancer. As a result of PSA testing, there has been a surge in the number of prostate cancer diagnoses. This review examines the results of 2 recent landmark trials that studied the effect of screening on prostate cancer mortality: the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the US-based Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial.Key words: PSA screening, European Randomized Study of Screening for Prostate Cancer (ERSPC), Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening TrialProstate cancer poses a significant problem for men’s health; it has become the most common malignancy and the second most common cause of cancer death in American men. It is estimated that 1 in 6 men will be diagnosed with prostate cancer at some time in their lives, and more than 30,000 men died of the disease in 2002.¹ The advent of prostate-specific antigen (PSA) testing in the early 1980s revolutionized the diagnosis of prostate cancer, and, as a result, there has been a surge in the number of prostate cancer diagnoses.Similar to other common malignancies, such as breast and cervical cancer, population screening with this effective tumor marker appears enticing, and the American health care model has advocated PSA screening since the early 1990s. This review examines the results of 2 recent landmark trials: the European Randomized Study of Screening for Prostate Cancer (ERSPC)¹ and the US-based Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial.² The results of these trials have contributed significantly to our understanding of the effects and efficacy of prostate cancer screening, and its difficulties. Both trials examined mortality as the endpoint, and both found little effect on mortality from screening.     

Contribution of Genetic Variation rs266882 to Prostate-Specific Antigen Levels in Healthy Controls with Serum PSA Below 2.0 ng/ml

We evaluated the impact of genetic variation in the prostate-specific antigen (PSA) gene (rs266882) on serum PSA levels in healthy men as well as risk factors for benign prostate hypertrophy (BPH) and prostate cancer. The study population comprised 91 men with PSA levels below 2.0 ng/ml as healthy controls, 78 men with PSA 2–10 ng/ml as a BPH group, and 128 prostate cancer patients, all in Korea. DNA was amplified by polymerase chain reaction and the product was sequenced. We found that PSA levels were associated with a G/A polymorphism only in healthy controls. The transition, however, was not associated with PSA levels of BPH and cancer patients, nor was it a risk factor. In conclusion, this genetic factor is important for determining serum PSA levels in the naive group, whereas the disruption of prostatic architecture in BPH or prostate cancer may be a major determining factor for PSA levels.     

Involving a Citizens’ Jury in Decisions on Individual Screening for Prostate Cancer

Aims

Most public health agencies and learned societies agree that the prostate-specific antigen (PSA) test in asymptomatic men should not be recommended, on account of its potential for harm. Yet PSA is still widely used as a screening test and is not being abandoned. This remains a significant public health issue, and citizens’ engagement is needed. This study was designed to produce a deliberation on the PSA screening test by a citizens’ jury.

Methods

Fifteen citizens were selected and balanced for sex, age, and education. They received an information booklet and participated in a two-day meeting with experts to reach a deliberation on the question “Should the National Health Service discourage or recommend PSA as an individual screening test for prostate cancer in men 55–69 years old?”. A facilitator ran the jurors’ discussion.

Results

All except three of the jurors decided that the National Health Service should discourage the use of PSA as an individual screening test for prostate cancer in 55–69 year-old men. The jury was particularly convinced by the uncertainty of the test outcomes, the utility of the test, and its cost/benefit ratio. Before the meeting 60% of jurors would have recommended the test to a relative, and all the male jurors would have done so. After the meeting these percentages fell to 15% and 12%.

Conclusions

This experience confirms the feasibility and effectiveness of delegating to a group of citizens the responsibility to decide on public health issues on behalf of the community. Public health authorities should invest in information campaigns aimed at the public and in educational initiatives for physicians. This also provided an opportunity to disseminate information on screening, over-diagnosis, and over-treatment.     

Effect of CYP17 and PSA gene polymorphisms on prostate cancer risk and circulating PSA levels in the Slovak population

Cytochrome P-450c17α (CYP17) and prostate-specific antigen (PSA) genes, which are involved in the androgen metabolism cascade, have been studied as possible candidates for genetic influences on prostate cancer development. Contradictory results prompted us to evaluate the frequencies of polymorphisms in the CYP17 and PSA genes as well as the association between these genetic variants and serum PSA levels in prostate cancer patients and men routinely screened for prostate cancer with PSA in the Slovak male population. The CYP17 and PSA polymorphisms were determined by the PCR-RFLP analysis in 197 Caucasian prostate cancer patients and 256 Caucasian controls. We did not find any association between the CYP17 and PSA genotypes and prostate cancer risk overall, or by grade. Also the total serum PSA levels in the cases with the AG or AA genotype were not significantly higher than in the men with the GG genotype (P > 0.05). Our study did not provide support for the hypothesized relationship between CYP17 and PSA gene polymorphisms and prostate cancer in the Slovak male population.     

Evaluation and treatment of men with biochemical prostate-specific antigen recurrence following definitive therapy for clinically localized prostate cancer

Early detection and monitoring by serum prostate-specific antigen (PSA) measurement has increased the number of men presenting with potentially curable prostate cancer. Most will choose radical prostatectomy or some form of radiation therapy for treatment, but some will have evidence of biochemical disease recurrence following therapy, shown by a rising PSA level without other clinical evidence of disease. Radical prostatectomy involves the removal of all prostate tissue, causing the serum PSA to decline to undetectable levels within four to six weeks following surgery; a subsequent rise in the serum PSA to a detectable level indicates disease recurrence. Patients should be evaluated to assess whether rising PSA levels indicate local recurrence or early metastatic disease. The advantages of salvage radiation, endocrine therapy, and other treatment modalities in local disease recurrence must be weighed against potential side effects and the resulting decrease in quality of life. Radiation therapy does not immediately eradicate all PSA-producing cells; therefore the persistence of a detectable PSA does not necessarily imply residual cancer, but rising PSA levels indicate treatment failure. Salvage surgery can be performed after radiotherapy for the purpose of removing all viable cancer cells, but should be weighed against a higher incidence of surgical complications; cryoablation offers a less invasive therapeutic modality.     

Prostate Cancer Specificity of PCA3 Gene Testing: Examples from Clinical Practice

A specific marker for early prostate cancer would fill an important void. In initial evaluations of the prostate cancer antigen 3 (PCA3) gene vis-à-vis serum prostate-specific antigen (PSA) levels, the gene offers great promise. At the cellular level, PCA3 specificity for cancer is nearly perfect because of the gross overexpression of the gene by cancer cells. As a clinical test for early prostate cancer, heightened specificity is also seen in urine containing prostate cells from men with the disease. PCA3 gene testing holds valuable potential in PSA quandary situations: (1) men with elevated PSA levels but no cancer on initial biopsy; (2) men found to have cancer despite normal levels of PSA; (3) men with PSA elevations associated with varying degrees of prostatitis; and (4) men undergoing active surveillance for presumed microfocal disease.     

Advances in proteomic prostate cancer biomarker discovery

Prostate cancer is the most common non-cutaneous cancer in men in the United States. For reasons largely unknown, the incidence of prostate cancer has increased in the last two decades, in spite or perhaps because of a concomitant increase in serum prostate-specific antigen (PSA) screening. While PSA is acknowledged not to be an ideal biomarker for prostate cancer detection, it is however widely used by physicians due to lack of an alternative. Thus, the identification of a biomarker(s) that can complement or replace PSA represents a major goal for prostate cancer research. Screening complex biological specimens such as blood, urine, and tissue to identify protein biomarkers has become increasingly popular over the last decade thanks to advances in proteomic discovery methods. The completion of human genome sequence together with new development in mass spectrometry instrumentation and bioinformatics has been a major driving force in biomarker discovery research. Here we review the current state of proteomic applications as applied to various sample sources including blood, urine, tissue, and “secretome” for the purpose of prostate cancer biomarker discovery. Additionally, we review recent developments in validation of putative markers, efforts at systems biology approach, and current challenges of proteomics in biomarker discovery.