Molecular targeted therapies, omics, and AI based theranostics approaches for the treatment of prostate cancer.

Critical Appraisal of Prostate-specific Antigen in Prostate Cancer Screening: 20 Years Later

Prostate Specific Antigen and Human Glandular Kallikrein 2 in Early Detection of Prostate Cancer

At present, increased early detection of prostate cancer appears to be the most feasible way to reduce cancer-related mortality. As a result significant efforts have been made to identify more men with curable cancer. This article reviews the role of serum prostate-specific antigen in an early detection or screening strategy and describes efforts to enhance the specificity of prostate-specific antigen testing.

OPTIMAL PREDICTORS OF PROSTATE CANCER ON REPEAT PROSTATE BIOPSY: A PROSPECTIVE STUDY OF 1,051 MEN

Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

High Prevalence of Screen Detected Prostate Cancer in West Africans: Implications for Racial Disparity of Prostate Cancer

Comparison of Digital Rectal Examination and Serum Prostate Specific Antigen in the Early Detection of Prostate Cancer: Results of a Multicenter Clinical Trial of 6,630 Men.

With more than 230,000 new cases each year in the United States, prostate cancer is the most common cancer diagnosed among American men [(1)][1] . Prostate cancer is expected to account for nearly 30,000 deaths in the United States in 2004 and consequently represents the second most common cause of

The purpose of this study was to examine the diagnostic efficiency of prostate-specific antigen (PSA) and digital rectal examination (DRE) testing when using either 4.0 ng/ml or an age-specific reference range (ASRR) as an abnormal cutoff PSA value. Between 1992-1995, 116,073 men, aged 40-79 years, were screened during Prostate Cancer Awareness Week. When using a 4.0-ng/ml cutoff PSA value, 22,014 had either an abnormal PSA, an abnormal DRE, or both. When using an ASRR cutoff PSA value, 17,561 had either an abnormal PSA, an abnormal DRE, or both. The positive predictive value (PPV), sensitivity, and specificity of PSA, DRE, and combined PSA and DRE tests were evaluated. When using a 4.0-ng/ml cutoff PSA value, the PPVs of abnormal PSA alone, abnormal DRE alone, and combined abnormal PSA and DRE tests were 27.7%, 17.7%, and 56.0%, respectively. Sensitivities were 34.9%, 27.1%, and 38.0%, respectively. Specificities were 63.1%, 49.0%, and 87.9%, respectively. When using an ASRR cutoff PSA value, the PPVs of each category were 31.8%, 20.8%, and 63.7%, respectively. Sensitivities were 27.1%, 41.0%, and 31.8%, respectively. Specificities were 75.0%, 32.8%, and 92.2%, respectively. The PPVs of the PSA test were higher than those of the DRE. The PPVs of combined tests were highest when using either a 4.0-ng/ml cutoff PSA value or an ASRR cutoff PSA value (all P < 0.001). When using an ASRR, the PPVs of PSA, DRE, and combined tests were higher than those when using a 4.0-ng/ml without statistical significance (all P > 0.05). Sensitivity of PSA when using an ASRR was lower than when using 4.0 ng/ml. Significantly higher PPVs indicated that utilizing both a PSA test and a DRE is most effective in screening for the early detection of prostate cancer. Although higher PPVs when using an ASRR cutoff PSA value suggested fewer unnecessary biopsies, lower sensitivities resulted in fewer cancers detected. Thus, we recommend that the combination of a PSA test with a cutoff value of 4.0 ng/ml and a DRE should continue to be utilized in the screening programs.

BACKGROUND The purpose of this study was to examine the diagnostic efficiency of prostate-specific antigen (PSA) and digital rectal examination (DRE) testing when using either 4.0 ng/ml or an age-specific reference range (ASRR) as an abnormal cutoff PSA value. METHODS Between 1992–1995, 116,073 men, aged 40–79 years, were screened during Prostate Cancer Awareness Week. When using a 4.0-ng/ml cutoff PSA value, 22,014 had either an abnormal PSA, an abnormal DRE, or both. When using an ASRR cutoff PSA value, 17,561 had either an abnormal PSA, an abnormal DRE, or both. The positive predictive value (PPV), sensitivity, and specificity of PSA, DRE, and combined PSA and DRE tests were evaluated. RESULTS When using a 4.0-ng/ml cutoff PSA value, the PPVs of abnormal PSA alone, abnormal DRE alone, and combined abnormal PSA and DRE tests were 27.7%, 17.7%, and 56.0%, respectively. Sensitivities were 34.9%, 27.1%, and 38.0%, respectively. Specificities were 63.1%, 49.0%, and 87.9%, respectively. When using an ASRR cutoff PSA value, the PPVs of each category were 31.8%, 20.8%, and 63.7%, respectively. Sensitivities were 27.1%, 41.0%, and 31.8%, respectively. Specificities were 75.0%, 32.8%, and 92.2%, respectively. The PPVs of the PSA test were higher than those of the DRE. The PPVs of combined tests were highest when using either a 4.0-ng/ml cutoff PSA value or an ASRR cutoff PSA value (all P < 0.001). When using an ASRR, the PPVs of PSA, DRE, and combined tests were higher than those when using a 4.0-ng/ml without statistical significance (all P > 0.05). Sensitivity of PSA when using an ASRR was lower than when using 4.0 ng/ml. CONCLUSIONS Significantly higher PPVs indicated that utilizing both a PSA test and a DRE is most effective in screening for the early detection of prostate cancer. Although higher PPVs when using an ASRR cutoff PSA value suggested fewer unnecessary biopsies, lower sensitivities resulted in fewer cancers detected. Thus, we recommend that the combination of a PSA test with a cutoff value of 4.0 ng/ml and a DRE should continue to be utilized in the screening programs. Prostate 38:296–302, 1999. © 1999 Wiley-Liss, Inc.

-2]Proenzyme Prostate Specific Antigen is More Accurate Than Total and Free Prostate Specific Antigen in Differentiating Prostate Cancer From Benign Disease in a Prospective Prostate Cancer Screening Study

Prostate specific antigen (PSA) is an androgen regulated serine protease produced by secretory epithelial cells lining of normal prostatic glands as well as in the majority of prostatic cancer1,2. PSA expression has been the most extensively used marker for prostate cancer screening and gauging the therapeutic response following an intervention1,2. The serum PSA concentration greater than 4 ng/ml is generally considered as an indicator of a potential prostatic abnormality which warrants a further screening by means of prostate needle biopsy3. However, PSA testing has been plagued by numerous controversies and a low sensitivity and specificity for detecting prostate cancer due to numerous factors such as presence of non-cancerous prostatic diseases (i.e. prostatitis or benign prostatic hyperplasia) which are very common in India and its variation among different ages and races4. To negate the effect of age and race to serum PSA levels there are age- and race-specific cut-off values for serum PSA testing5,6. However, there still remains substantial controversy regarding the use of such cut-offs as these are weighed down by further decreased sensitivity for detection of prostate cancer7. The PSA gene contains a 6-kb promoter in the 5′ region that contributes to tissue and hormone specificity of PSA expression8,9,10. This promoter contains androgen-responsive elements (AREs) that regulate promoter activity by binding to androgen receptors. ARE I and II are located in the proximal region of the PSA promoter centered at -170 base pairs (bp) and -394 bp, respectively while ARE III is located in the 5′ upstream enhancer region, centered at -4200 bp with respect to the transcription start site8,9,10,11. ARE I and ARE III are both found to have high affinities for the androgen receptor, whereas ARE II has a low affinity for the androgen receptor11,12,13,14. Further research into these promoter regions has demonstrated the presence of additional high, medium, and low-affinity AREs within the 5′ upstream enhancer region of the PSA promoter located between -3870 bp and -4366 bp with respect to the transcription start site14. Chavan et al15 in their study in this issue have calculated the influence of genetic variants exhibited by PSA and androgen receptor (AR) genes towards the variable expression of PSA in prostate cancer. PSA genotype analysis in promoter region and AR gene microsatellite Cytosine / Adenine / Guanine (CAG) repeat analysis in exon 1 region was studied. They found SNPs 158G/A in the proximal promoter region and -3845G/A in enhancer region to be significantly (P<0.001) associated with serum PSA levels15. The carriers of homozygous GG genotype showed higher expression of PSA whereas homozygous AA genotype carriers demonstrated lower PSA levels. The authors also found that homozygous GG genotype along with AR long CAG repeats and homozygous AA genotype along with AR short CAG repeats at position -3845 and -158 showed strong interaction and thus synergistically influenced serum PSA levels. Xue et al16 in their study of 420 healthy men from a multiethnic cohort found that men with PSA AA genotype and short AR CAG alleles have higher PSA levels. Cramer et al17 found -4643 /A SNP (G allele) is associated with higher mean PSA levels. These studies have further emphasised the enigma of the cut-off level for PSA16,17,18,19. The role of PSA as a screening marker for prostate cancer has been severely questioned following the Prostate, lung, colorectal and ovarian (PLCO) cancer screening trial19. To incorporate SNP in the promoter region of PSA gene into the genetic model for prostate cancer may help in improving the sensitivity and specificity of PSA as a screening tool but these studies need to be taken on a larger scale preferably on a prospective multicentric and multiethnic group to validate these findings.

Prostate specific antigen (PSA) testing of asymptomatic men enables the diagnosis of localised prostate cancer which in potentially curable, but it also poses certain risks. Doctors run the risk of litigation for failure to diagnose cancer at a curable stage, while patients run the risk of being diagnosed with non-significant cancer, incurring costs and possible complications without any survival benefit. PSA reflects a ‘range of risk’ for prostate cancer: the higher the PSA, the greater the risk. There in no ‘normal’ PSA, because even with a PSA below 4 ng/ml cancer can be detected on biopsy in up to 20% of men. However, the prevalence of high-grade (life- threatening) cancer in relatively low at low PSA values. The following recommendations appear reasonable: • PSA testing should be offered to all men aged 50 years or more (45 years in those with a family history of prostate cancer and—possibly—African men); • Alternatively, PSA testing should be done at 40, 45 and 50 years and then every two to four years (the lower the baseline value, the lower the risk of ever developing prostate cancer); • PSA testing should be repeated annually if it is more than 2 ng/ml and every two years if less than 2 ng/ml; • Stop PSA testing in asymptomatic men over 75 years or with less than 10 years' life expectancy, and in those aged over 65 years with PSA less than 0.5 to 1 ng/ml. The free-to-total PSA ratio and PSA density (PSA divided by prostate volume) can be used to decide which patients need prostatic biopsy. PSA velocity (increase of PSA per year) can predict which men are likely to develop prostate cancer or to die of it (the higher the PSA velocity, the greater the risk). PSA doubling time (the period it takes for the PSA to double) correlates with the prognosis both before and after treatment (the shorter the doubling time, the worse the prognosis). An internet Prostate Cancer Risk Calculator is available which calculates a man's risk by taking into account his age, race, family history, PSA level, findings on rectal examination and prior negative biopsy. Although this in a very convenient tool, it should be used with caution, especially at low PSA values, because there is a real risk of overdiagnosis.

BackgroundThe role of Prostate Specific Antigen (PSA) testing in the early detection of prostate cancer is controversial. Current UK policy stipulates that any man who wishes to have a PSA test should have access to the test, provided he has been given full information about the benefits and limitations of testing. This study aimed to determine UK GPs' current reported practice regarding PSA testing, and their views towards informed decision-making and PSA testing.MethodOnline questionnaire survey, with a sample of 421 GPs randomly selected from a database of GPs across the UK.Results95% (400/421) of GPs responded. 76% of GPs reported having performed a PSA test for an asymptomatic man at least once in the previous three months, with 13% reported having tested more than five men in this period. A majority of GPs reported they would do a PSA test for men presenting with a family history and requesting a test, for asymptomatic men requesting a test and also for men presenting with lower urinary tract symptoms. Reported testing rates were highest for men with a family history. Amongst men with lower urinary tract symptoms and men with no symptoms, reported testing rates were significantly higher for older than younger men.The majority of GPs expressed support for the current policy (67%), and favoured both the general practitioner and the man being involved in the decision making process (83%). 90% of GPs indicated that they would discuss the benefits and limitation of testing with the man, with most (61%) preferring to ask the man to make a further appointment if he decides to be tested.ConclusionThis study indicates that PSA testing in asymptomatic men is a regular occurrence in the UK, and that there is general support from GPs for the current policy of making PSA tests available to 'informed' men who are concerned about prostate cancer. While most GPs indicated they would discuss the benefits and limitations prior to PSA testing, and most GPs favoured a shared approach to decision making, it is not known to what extent men are actually being informed. Research is needed to evaluate the most effective approach to assisting men in making an informed decision about whether or not to have a PSA test.

Objective: Prostate cancer is common and prostate cancer screening is controversial; this retrospective observational study was conducted to determine the prevalence of digital rectal examination (DRE) in those in whom a prostate-specific antigen (PSA) test was performed. Methods: A manual review was performed of the electronic medical record for male veterans in the VA Connecticut Healthcare System without a history of known prostate cancer aged between 50 and 74 years who underwent PSA testing. Main Outcomes: Documentation of DRE (or refusal) within 12 months before or after the performance of a PSA test. Results: Less than half (47.6%) of patients underwent DRE. An additional 6.9% were offered DRE and refused. Although the provider gender was not associated with DRE, resident physicians were less likely to perform DRE than nonresidents; P = 0.01. Patients whose PSA was > 4.0 ng/mL were more likely to undergo DRE than those whose PSA was ≤ 4.0 ng/mL; P = 0.002. Those with body mass index (BMI) > 40 kg/m2 were less likely to undergo DRE than those with BMI < 30 kg/m2; P = 0.04. Conclusions: Screening for prostate cancer remains controversial. We found a low rate of DRE among veterans in whom prostate cancer screening was entertained. Although the provider gender does not seem to influence DRE, resident physicians were less likely to perform DRE than other providers. Our finding that BMI > 40 kg/m2 is associated with a lower rate of DRE than those with BMI < 30 kg/m2 is consistent with screening for other cancers and should be explored further.