Molecular diagnosis of prostate cancer

The diagnosis, staging, and management of prostate cancer as we know it today is greatly dependent on our ability to measure serum prostate-specific antigen (PSA) concentration. Nevertheless, because serum PSA concentration, particularly when less than 10 ng/mL, reflects the presence of benign prostatic hyperplasia more often than cancer, there is a clear need for more specific prostate cancer markers. The most promising new markers for prostate cancer are the various molecular forms of free PSA. Mass spectrometry also is emerging as a potential tool in prostate cancer screening. Because it is unlikely that any one marker will have 100% sensitivity and specificity, as new serum markers are tested, nomograms that incorporate multiple independently predictive parameters for the detection of prostate cancer will become indispensable in our efforts to improve prostate cancer screening.     

Prognostic value of serum markers for prostate cancer

The incidence of prostate cancer has increased dramatically during the last 10-15 years and it is now the commonest cancer in males in developed countries. The increase is mainly caused by the increasing use of opportunistic screening or case-finding based on the use of prostate-specific antigen (PSA) testing in serum. With this approach, prostate cancer is detected 5-10 years before giving rise to symptoms and on average 17 years before causing the death of the patient. While this has led to detection of prostate cancer at a potentially curable stage, it has also led to substantial overdiagnosis, i.e. detection of cancers that would not surface clinically in the absence of screening. A major challenge is thus to identify the cases that need to be treated while avoiding diagnosing patients who will not benefit from being diagnosed and who will only suffer from the stigma of being a cancer patient. It would be useful to have prognostic markers that could predict which patients need to be diagnosed and which do not. Ideally, it should be possible to measure these markers using non-invasive techniques, i.e. by means of serum or urine tests. As it is very useful for both early diagnosis and monitoring of prostate cancer, PSA is considered the most valuable marker available for any tumor. Although the prognostic value of PSA is limited, measurement of the proportion of free PSA has improved the identification of patients with aggressive disease. Furthermore, the rate of increase in serum PSA reflects tumor growth rate and prognosis but, due to substantial physiological variation in serum PSA, reliable estimation of the rate of PSA increase requires follow-up for at least 2 years. Algorithms based on the combined use of free and total PSA and prostate volume in logistic regression and neural networks can improve the diagnostic accuracy for prostate cancer, and assays for minor subfractions of PSA and other new markers may provide additional prognostic information. Markers of neuroendocrine differentiation are useful for the monitoring of androgen-independent disease and various bone markers are useful in patients with metastatic disease.     

Detection of prostate cancer: the impact of the European Randomized Study of Screening for Prostate Cancer (ERSPC)

The European Randomized Study of Screening for Prostate Cancer (ERSPC) is a large, randomized controlled trial of screening versus control, conducted in eight European countries (Belgium, Finland, France, Italy, the Netherlands, Spain, Sweden, and Switzerland). This article focuses on important aspects relating to recent findings from the ERSPC about two topics: first, leadtime and overdiagnosis, and second, prostate-specific antigen (PSA) as a test for repeated screening. The ERSPC together with the prostate cancer arm of the Prostate, Lung, Colon and Ovary (PLCO) screening trial of the National Cancer Institute in the United States are set to show or exclude an effect of screening on prostate cancer mortality. Both studies are progressing according to plan. Definitive endpoint-related data can be expected between 2005 and 2010 depending on the difference in prostate cancer mortality that may be shown between the screening and control arms. The ERSPC will allow a risk-to-benefit analysis including parameters of quality of life and cost. Overdiagnosis with present prostate cancer screening regimens is high. This amount of overdiagnosis is likely to be unacceptable for most healthcare policy makers and providers. Addressing overdiagnosis will be a major research task for urologists for the years to come. Present screening needs to be more "selective" for cases that have aggressive patterns and are likely to lead to clinical diagnosis of prostate cancer and/or death. The test characteristics of prostate-specific antigen (PSA) change after one use. The positive relation between PSA levels and positive predictive value (PPV) and detection rates in first screening rounds are lost. This may be compatible with the observation that tumor volumes in second round screening are smaller, and larger tumors are harvested. Tumor volume becomes a negative predictor in round 2, indicating that a large proportion of elevated PSA values are caused by benign prostatic hyperplasia (BPH) rather than by prostate cancer. While the outcome of the ongoing randomized studies is uncertain, screening tests cannot be refused to men who are well-informed and accept to take the risk of experiencing more harm than benefit as a result of a positive screening test result.     

Prostate specific antigen: clinical use in the diagnosis and management of prostate cancer.

Prostate specific antigen (PSA) has replaced prostatic acid phosphatase as the preeminent clinical tumor marker in the management of patients with prostate cancer. Serum PSA levels have been shown to be proportional to clinical and pathologic stage of prostate cancer and in particular to correlate closely with prostate cancer volume. Serum levels of PSA thus serve as a useful adjunct in the initial clinical staging of men with prostate cancer. Serum PSA values provide a unique and valuable tool in monitoring prostate cancer progression over time and its response to surgical, radiation, and/or hormonal therapies. Unfortunately, its lack of specificity for prostate cancer leaves many questions unanswered as to the efficacy and advisability of using PSA as a screening test for this cancer.     

UPM3: review of a new molecular diagnostic urine test for prostate cancer

PSA elevation is the most common indication for urologic referral to rule out the presence of prostate cancer. Recently PSA screening and its usefulness in suggesting the presence of clinically significant prostate cancer has been put into doubt. PSA has limitations in detecting significant cancers even when elevated and on the other hand significant cancers are found in the presence of low PSA levels. In order to better predict patients at risk of harboring prostate cancer new diagnostic tests are required. A promising novel approach is based on the molecular detection of prostate cancer cells in urine. The uPM3 assay is based on the amplification of specific target RNA using the nucleic acid sequence-based amplification (NASBA) technology. In a large multi-center study of 517 cases the overall sensitivity was 66% with a specificity of 89%. The positive (PPV) predictive values for the uPM3 test were 75% compared to 38% for a serum PSA cutoff of 4. The negative predictive value (NPV) was equivalent between the tests, but due to the higher PPV for uPM3, the accuracy of uPM3 was nearly two-fold greater than PSA (81% versus 43% and 47% for PSA cutoffs of 2.5 and 4 ng/ml, respectively). This test may become one of the first molecular diagnostic tools to aid in prostate cancer detection.     

A retrospective and prospective overview of prostate-specific antigen

Since the identification of prostate-specific antigen (PSA), continued technological advances have provided highly sensitive assays for its quantification. Given its lack of disease specificity, and its recent detection at low levels in an increasing number of non-prostatic tissues, PSA is far from being the perfect “tumour” marker (biological marker). However, the positive predictive value of PSA for assessing cancer risk makes PSA the most useful “tumour” marker for monitoring progression and response to treatment among patients with prostate cancer. Earlier detection through screening for elevated levels of PSA, while controversial, has been proposed as a way to decrease prostate cancer mortality. Haematogenous identification of PSA mRNA may provide stage-related prognostic information, and the use of ultrasensitive assays for PSA may permit earlier identification of residual or recurrent cancer, following treatment and the initiation of adjuvant therapy. Various PSA-related concepts, including the ratio of “free” PSA and complexes of PSA with the protease inhibitor, α₁-antichymotrypsin, to total PSA, have been proposed and placed within diagnostic and management algorithms. Elevations of PSA in other irregularities of the prostate, notably in benign prostatic hyperplasia, and the increasing frequency and number of non-prostatic tissues, including those in women, expressing PSA, have implications for future immunoassays for PSA and strategies for immunotherapy using PSA-based monoclonal antibodies or vaccines, as well as for the molecular basis for its anomalous expression and physiological function(s).     

Prostate cancer: measuring PSA

Population screening with prostate‐specific antigen (PSA) for detection of prostate cancer is a topic associated with ongoing dissent and confusion within the oncology and wider medical community. The PSA blood test has been used in various stages of prostate cancer management, including screening and the assessment of future risk of prostate cancer development, detection of recurrent disease after local therapy and in the management of advanced disease. However, PSA‐based decision‐making in prostate cancer has significant shortcomings. This review will summarise the evidence and current recommendations for the use of PSA in detection and management of prostate cancer.     

Prostate cancer detection strategies

Prostate cancer is the most common malignancy in men and, as a result, there has been a nationwide emphasis on screening and detection. With the widespread use of the prostate-specific antigen (PSA), prostate cancer screening effectively detects localized prostate cancer. However, recent reports have identified a significant proportion of prostate cancer in men with low PSA levels. Many of these cancers are higher-grade malignancies. Consequently, PSA may function more effectively as a screening tool when applied over a continuum that is associated with degree of risk, rather than a binary measure. Other markers are currently being investigated. Ideally, a marker will identify the malignancy that is a clinical threat, thereby avoiding intervention for indolent disease. Prevention strategies may be employed for higher-risk patients, and these strategies eventually may be tailored to genetic or other risks.     

Assessment of indirect hemagglutination and zymography procedures in evaluation of gelatinase a in patients with benign and malignant prostate hyperplasia

There are increasing data on novel tumor markers such as gelatinase A, which play a key role in tissue invasion and metastasis. Since prostate cancer is one of the common malignancies, we designed a simple and applicable Indirect Hemagglutination (IHA) test for determination of total gelatinase A in serum samples. In this study, we have analyzed the circulating form of gelatinase A (MMP-2) in patients suffering from either benign prostate hyperplasia (n= 54) or prostate cancer (n= 26) and normal individuals as control (n= 26). The gelatinolytic activity was determined by zymography followed by densitometric analysis. PSA was quantified by using a standard ELISA technique. Correlation of densitometric analysis of gelatinase A activity and IHA titer was significant at 0.01 level (p< 0.01, r = 0.916). Correlation of PSA and IHA titer was significant at 0.01 level (p< 0.01, r = 0.746). Border line IHA titer in patients with prostate cancer was 512 +/- 1 tube titer, in benign prostate hyperplasia patients was 128 +/- 1 tube titer, and the titer in normal individuals was 8 +/- 1 tube titer. These results demonstrate that IHA compared to zymography may be a better and simpler procedure in monitoring and screening patients with prostate cancer.     

Evaluation of Plasma Interleukin-8 Concentration in Patients with Prostate Cancer and Benign Prostate Hyperplasia

Background: Prostate specific antigen (PSA) has been used as a screening test for the early detection of prostate cancer (PC) for many years. Although the introduction of PSA test led to a considerable increase in reported prostate cancer cases, there is still some controversy over the sensitivity and specificity of this marker in distinguishing PC patients from those with benign prostate hyperplasia (BPH), the most common benign prostate condition. Objective: An attempt is made to elucidate if the plasma level of Interleukin 8 (IL-8) could be used effectively as a marker for the detection of prostate cancer. Methods: Plasma levels of IL-8 and PSA were measured in two groups of 40 BPH and PC patients using enzyme-linked immunosorbent (ELISA) and radioimmunoassay (RIA) techniques, respectively. In addition IL-8 levels in PC3 and DU145 cell line supernatants were measured by ELISA technique. Results: The concentration of IL-8 in the plasma of PC patients was not significantly higher than the BPH subjects. Although, a correlation between plasma IL-8 concentration and the Gleason score of PC patients was found, no indicated correlation was detected between the concentration of IL-8 or PSA and age of the patients in both groups. DU145 and PC3 cell lines produced and secreted IL-8 in the media. Conclusion: Data of this investigation collectively conclude no correlation between IL-8 concentration in PC and BPH patients.     

The importance of patient preference in the decision to screen for prostate cancer

OBJECTIVE: Routine screening for prostate cancer is controversial because of frequent false-positive results, the potential for slow, non-life-threatening growth of untreated cancer, the uncertainty regarding whether treatment can extend life, and the potential for treatment complications. This study examines how information about prostate-specific antigen (PSA) testing and the uncertain benefits of treating prostate cancer affects patients’ desire for PSA testing. DESIGN: An educational videotape designed to inform men about the uncertainty surrounding PSA screening and the treatment of early-stage prostate cancer was presented to two groups of male patients 50 years of age or older. SETTING: Dartmouth-Hitchcock Medical Center. PATIENTS/PARTICIPANTS: For study 1, men seeking a free prostate cancer screening were preassigned to view the educational videotape (N=184) or another videotape (N=188). For study 2, men scheduled to visit a general internal medicine clinic viewed either the educational videotape (N=103) or no videotape (N=93). MEASUREMENTS AND MAIN RESULTS: The men’s information and preferences about prostate cancer screening and treatment and actual choice of PSA test at the next test opportunity were measured. Men who viewed the educational videotape were: better informed about PSA tests, prostate cancer, and its treatment; preferred no active treatment if cancer were found; and preferred not to be screened (all significant atp≤.002 in both studies). Men viewing the educational video were less likely to have a PSA test (p=.041, study 2). This tendency was not significant at the free-PSA clinic (p=.079). CONCLUSIONS: Preference regarding cancer screening and treatment is greatly affected by information about medical uncertainties. Because informed patient choices vary, PSA screening decisions should incorporate individual preferences.     

The effectiveness of screening for prostate cancer: a nested case-control study

BACKGROUND: Screening for prostate cancer is done commonly in clinical practice, using prostate-specific antigen (PSA) tests or digital rectal examination (DRE). Evidence is lacking, however, to confirm a survival benefit among screened patients. We evaluated the effectiveness of PSA, with or without DRE, in reducing mortality. METHODS: We conducted a multicenter nested case-control study at 10 Veterans Affairs medical centers in New England. Among 71 661 patients receiving ambulatory care between 1989 and 1990, 501 case patients were identified as men who were diagnosed as having adenocarcinoma of the prostate from 1991 through 1995 and who died sometime between 1991 and 1999. Control patients were men who were alive at the time the corresponding case patient had died, matched (1:1 ratio) for age and Veterans Affairs facility. The exposure variable (determined blind to case-control status) was whether PSA testing or DRE was performed for screening prior to the diagnosis of prostate cancer among case patients, with the same time interval for control patients. The association of screening and overall or cause-specific (prostate cancer) mortality was adjusted for race and comorbidity. RESULTS: A benefit of screening was not found in our primary analysis assessing PSA screening and all-cause mortality (adjusted odds ratio, 1.08; 95% confidence interval, 0.71-1.64; P=.72), nor in a secondary analysis of PSA and/or DRE screening and cause-specific mortality (adjusted odds ratio, 1.13; 95% confidence interval, 0.63-2.06; P=.68). CONCLUSIONS: These results do not suggest that screening with PSA or DRE is effective in reducing mortality. Recommendations for obtaining "verbal informed consent" from men regarding such screening should continue.     

Circulating free insulin-like growth factor (IGF)-I, total IGF-I, and IGF binding protein-3 levels do not predict the future risk to develop prostate cancer: results of a case-control study involving 201 patients within a population-based screening with a 4-year interval

Recent studies have reported that serum IGF-I levels in the highest quartile of the normal range and IGF binding protein-3 (IGFBP-3) in the lowest quartile of the normal range are associated with an increased risk of future prostate cancer and/or presence of prostate cancer. It has also been suggested that the measurement of circulating total IGF-I concentrations might be a useful tool for the early detection of prostate cancer in men with moderately increased prostate-specific antigen (PSA) levels.To determine whether circulating free IGF-I, total IGF-I, and IGFBP-3 levels can predict future prostate cancer risk, we prospectively studied prostate cancer characteristics in a cohort of men during two rounds (mean interval, 4 yr) of a population-based screening study for prostate cancer. Two hundred one prostate cancer cases were detected at the second-round screening (aged 55-70 yr), and all these subjects were enrolled in the case group for the present study. Prostate cancer had been confirmed by biopsy in all cases. These 201 subjects were matched with the 201 nonprostate cancer cases by age, serum PSA range at the first-round screening (PSA < 2 ng/ml, n = 67; PSA = 2-3 ng/ml, n = 67; and PSA = 3-4 ng/ml, n = 67), and residence area.At baseline, total IGF-I, free IGF-I, and IGFBP-3 levels and prostate volume of cases with prostate cancer were not different from those of healthy controls. PSA velocity was significantly different between cases and controls (P < 0.001).Stepwise forward logistic regression analysis showed that only PSA levels at baseline and PSA at round 2 after 4 yr are good predictors of prostate cancer, whereas total IGF-I, free IGF-I, and IGFBP-3 did not predict the development of prostate cancer.Only one of the 201 subjects with prostate cancer had metastases. Within the subjects with prostate cancer, there were no differences of IGF-I parameters with different tumor node metastasis categories and/or Gleason scores.Our study suggests that the measurement of serum IGF-I and/or IGFBP-3 concentrations in addition to PSA does not improve the identification of men at high risk to develop early stages of prostate cancer. In addition, our results indicate that the endocrine IGF-I system is not directly involved in the growth of the early stages of prostate cancer.     

Prostate-specific antigen screening for prostate cancer in older men in the United States of America

Prostate cancer, like many diseases, is more common in older men. Although an estimated 1 in 7 men will be diagnosed with it, the majority of these men will not die from prostate cancer. The latent nature of this disease, the use of screening with prostate-specific antigen (PSA) testing and the greater risk of dying from causes other than prostate cancer contribute to this disparity. As the US population continues to age, prostate cancer screening and disease management presents an increasingly important public health issue. We discuss the current PSA screening recommendations and practices in the USA and the benefits and harms of screening older populations.     

Racial differences in screening for prostate cancer in the elderly

BACKGROUND: Black men are more likely than white men to be diagnosed as having advanced prostate cancer, and their prostate cancer mortality rates are more than twice as high. Low screening rates among black men may contribute to these disparities, but there are few data on racial differences in prostate cancer screening. OBJECTIVES: To present a case-control study of racial differences in the use of prostate-specific antigen (PSA) as a screening test among Medicare beneficiaries in New Jersey and to assess the degree to which race is associated with prostate cancer screening. METHODS: The study used a statewide database of claims data from Medicare Parts A and B, Medicaid, and the state's Pharmaceutical Assistance for the Aged and Disabled program. Prevalent cases of prostate cancer were excluded using the state's cancer registry. Of 139 672 men who underwent PSA screening, 34 984 were randomly selected along with an identical number of controls matched by month and year of birth. After men with International Classification of Diseases, Ninth Revision, Clinical Modification,or Current Procedural Terminology codes indicative of prostate cancer were excluded, 33 463 case patients and 33 782 control subjects remained. RESULTS: The use of PSA screening was strongly and inversely associated with black race (odds ratio [OR] = 0.50; P<.001), poverty (OR = 0.33; P<.001), and near poverty (OR = 0.69; P<.001). Multivariate logistic regression analysis after age, socioeconomic status, comorbidity, and use of health care services were controlled for revealed that black race remained a strong predictor of not undergoing PSA screening (OR = 0.65; 95% confidence interval, 0.60-0.70). CONCLUSIONS: Elderly blacks are substantially less likely to undergo PSA screening than elderly whites. Differences in socioeconomic status and comorbid conditions explain only a small part of the racial differences in screening rates.     

Identification of clinically significant prostate cancer by prostate-specific antigen screening

BACKGROUND: The importance of screening for early-stage prostate cancer has been debated in the literature. However, there are well-established prognostic factors (Gleason score [GS], pretreatment prostate-specific antigen [PSA], and percent positive biopsy findings [%+Bx]) that predict biologically aggressive disease. These factors, together with a patient's age and general state of health, will permit physicians to project the effect of a prostate tumor over the patient's expected lifetime. This study was performed to determine the proportion of clinically significant prostate cancers diagnosed in a screened population. METHODS: From 1991 through 2002, 977 patients with nonpalpable (T1c) prostate cancer were seen for evaluation and comprise the study group. Patients were classified according to pretreatment PSA level, GS, %+Bx, and age. RESULTS: Based on tumor characteristics alone, 130 patients were noted to be at high risk (GS = 8-10 or PSA level >20 ng/mL; or GS = 7 or PSA level >10-< or =20 ng/mL and >50%+Bx), with a historical 4-year PSA control of 10% to 30% after definitive therapy. An additional 45 patients were at intermediate risk (GS = 7, PSA level >10-< or =20 ng/mL, and 34%-50%+Bx), with a historical 4-year PSA control of 50% to 60% after definitive therapy. Additional patients were identified who had a cumulative anticipated prostate cancer mortality greater than 30% to 50% based on age and GS (GS = 7, age < or =70 years [n = 89]; GS = 6, age < or =65 years [n = 337]). The total at risk for clinically significant tumors was 601 (61.5%) of 977 patients. CONCLUSIONS: A significant proportion of patients with nonpalpable disease diagnosed as having prostate cancer by PSA screening have clinically significant cancers. This supports the continued use of PSA screening.     

Current status and prospects of androgen depletion therapy for prostate cancer

The old concept of androgen depletion therapy (ADT) for prostate cancer, which had been established on the basis of clinical experiences essentially on the far advanced disease, should be changed. The recent major increase in the diagnosis of localized and locally advanced prostate cancer due to prostate-specific antigen (PSA) screening prompts us to make clear the role of ADT for such an early stage of prostate cancer. Recent literature has proved that combination therapy of castration (medical or surgical) and non-steroidal anti-androgens (maximal androgen blockade, MAB, or combined androgen blockade, CAB) is markedly effective on non-metastatic prostate cancer. It is important to promote basic and clinical research based on the understanding that cure of prostate cancer is almost always possible with ADT if progression to the hormone-independent prostate cancer which accompanies metastatic disease can be avoided.     

A test of knowledge about prostate cancer screening

BACKGROUND: Although the benefits of prostate cancer screening are uncertain and guidelines recommend that physicians share the screening decision with their patients, most U.S. men over age 50 are routinely screened, often without counseling. OBJECTIVE: To develop an instrument for assessing physicians' knowledge related to the U.S. Preventive Services Task Force recommendations on prostate cancer screening. PARTICIPANTS: Seventy internists, family physicians, and general practitioners in the Los Angeles area who deliver primary care to adult men. MEASUREMENTS: We assessed knowledge related to prostate cancer screening (natural history, test characteristics, treatment effects, and guideline recommendations), beliefs about the net benefits of screening, and prostate cancer screening practices for men in different age groups, using an online survey. We constructed a knowledge scale having 15 multiple-choice items. RESULTS: Participants' mean knowledge score was 7.4 (range 3 to 12) of 15 (Cronbach's alpha=0.71). Higher knowledge scores were associated with less belief in a mortality benefit from prostate-specific antigen (PSA) testing (r=-.49, P<.001). Participants could be categorized as low, age-selective, and high users of routine PSA screening. High users had lower knowledge scores than age-selective or low users, and they believed much more in mortality benefits from PSA screening. CONCLUSIONS: Based on its internal consistency and its correlations with measures of physicians' net beliefs and self-reported practices, the knowledge scale developed in this study holds promise for measuring the effects of professional education on prostate cancer screening. The scale deserves further evaluation in broader populations.     

Update on the diagnosis and management of prostate cancer

Early detection of prostate adenocarcinoma (prostate cancer) through screening tests such as a serum prostate-specific antigen (PSA) test and a digital rectal examination (DRE) enables primary care physicians and urologists to offer patients a broader choice of treatments that are also more likely to provide a cure. Whether men are being over treated or over diagnosed through the widespread use of screening tests remains controversial. This review aims to provide general practitioners with a better understanding of different prostate cancer tests that can be performed and to help them decide which patients should be referred to a urologist for an ultrasound-guided biopsy.     

Brief Report: Free prostate-specific antigen test utilization

BACKGROUND: The American Cancer Society and American Urologic Association recommend prostate cancer screening for average-risk men between the ages of 50 and 75 years using digital rectal examination and prostate-specific antigen (PSA) testing. Measuring the percent free PSA may improve test specificity for detecting prostate cancer when the total PSA is between 2.5 and 10 ng/mL. OBJECTIVE: To assess whether free PSA testing practices are consistent with published screening guidelines. DESIGN: Retrospective analysis of free PSA testing performed by a national reference laboratory between October 1, 2003 and September 30, 2004. MEASUREMENTS: Free PSA and total PSA results and the age of the patient at testing. RESULTS: Over 24% of free PSA tests were performed on patients greater than 75 years of age, and 38% were performed on patients with a total PSA either less than 2.5 ng/mL or greater than 10.0 ng/mL. CONCLUSIONS: A substantial proportion of free PSA tests performed in a national reference laboratory appeared to be inconsistent with existing screening guidelines. This raises concern that some of these patients may have received inappropriate diagnostic workup and/or therapy, resulting in excess medical costs and potential harms.