February 6, 2009

New Screening Tests for Prostate Cancer

What are screening tests?

The term screening refers to the regular use of certain examinations or tests in persons who do not have any symptoms of a cancer but are at risk for developing a specific cancer.

Who is at risk for prostate cancer?

All men are at risk for prostate cancer. Prostate cancer is the second leading cause of cancer in the United States . With most cancers, early detection increases the chance of a cure; however, it is unclear whether current screening tests for prostate cancer reduce the number of deaths from this disease. Often, after a diagnosis of prostate cancer, physicians and patients will choose a course of “watchful waiting” rather than beginning treatment.

What are the current screening tests for prostate cancer?

Despite the controversy over survival benefits of screening, it is recommended that men undergo annual screening for this disease utilizing digital rectal examination (DRE) and prostate specific antigen (PSA) blood test. Currently, it is recommended that Caucasian men begin annual screening with PSA and DRE at age 50 and that African-American men and men with a strong family history of prostate cancer begin annual screening at age 45.

What is a Digital Rectal Exam (DRE)?

During a digital rectal exam (DRE), a physician inserts a gloved finger into the rectum to assess the texture and size of the prostate. The DRE is the most common prostate screening procedure and has been used for many years; however, whether the test is effective in decreasing the number of deaths from prostate cancer has yet to be determined.

What is a PSA Blood Test ?

A simple blood test allows laboratory technicians to determine PSA levels. Prostate-specific antigen (PSA) is a protein that is normally secreted and disposed of by the prostate gland. High PSA levels (more thatn 4.0 ng/ml) may indicate the presence of prostate cancer cells or other non-cancerous prostate conditions. However, in approximately 10% of prostate cancer cases, there is no rise in PSA above this threshold level, which creates a diagnostic problem for this group of individuals.

What happens after an elevated PSA or positive DRE?

Patients usually undergo transrectal ultrasonography to determine if a cancer can be located. During transrectal ultrasonography, a small probe is inserted into the rectum. The probe emits high frequency sound waves that bounce off of the prostate and produce echoes. A computer uses these echoes to create a picture called a sonogram that can show abnormal areas. The ultimate test for prostate cancer is a prostate biopsy or series of biopsies that sample the entire prostate. If a suspicious area can be detected by transrectal ultrasound, it is biopsied. More often, various areas of the prostate are sampled by multiple biopsies.

What is being done to improve screening tests for prostate cancer?

There are several new approaches to screening for prostate cancer, including:

  • Screening at an earlier age
  • Performing biopsies at lower PSA levels
  • Measuring different forms of PSA
  • Improving the accuracy of biopsies
  • Utilizing the EPCA test
  • Improving ultrasound testing

Screening at an Earlier Age

While the current recommendations for PSA screening described above are the standard, some research indicates that beginning screening earlier in life may be more effective. Researchers conducted a study using a computer program to estimate the number of lives that would be saved by giving the PSA test in each of seven different patterns. The researchers found that the most effective strategy was to begin PSA testing at 40 years of age, repeat the test at 45 and 50, and then test every two years thereafter. These recommendations are of particular importance for individuals with increased risk due to a family history or being African-American.

Biopsies at Lower PSA Levels

The standard PSA level that prompts physicians to perform prostate biopsies is 4.1 ng/ml. One study was carried out in Caucasian men over the age of 50 and African-American men over the age of 40 to determine if a lower threshold was more effective in detecting prostate cancer. [1] The researchers performed prostate biopsies in men with a PSA level of 2.6 ng/ml or above. They found a significant number of prostate cancers in men with PSA levels between 2.6 ng/ml and 4.1 ng/ml. In this trial, 82% of prostate cancers would have been missed with the standard PSA threshold of 4.1 ng/ml in men younger than 60 years. For the group of men 60 years or older, 65% of prostate cancers would have been missed with the PSA threshold of 4.1 ng/ml. In the group of men under 60 years of age, unnecessary biopsies occurred in 6% with the PSA threshold of 2.6 ng/ml, and would have occurred in 2% of men using the standard threshold of 4.1 ng/ml. In the group of men aged 60 or older, unnecessary biopsies occurred in 40% of men with the PSA threshold of 2.6 ng/ml and would have occurred in 12% of men using the threshold of 4.1 ng/ml. These researchers concluded that lowering the threshold of PSA levels in recommending prostate biopsies may significantly improve the early detection of prostate cancer, particularly in men under 60 years of age. Moreover, this could be achieved without significantly increasing the number of unnecessary biopsies performed. However, the question still remains as to whether this increase in detection will confer a survival benefit, which can only be answered with longer follow-up and future clinical trials.

Measuring Different Forms of PSA

Total versus Complexed PSA: Prostate specific antigen may be found in various forms in the blood. The usual measurement for PSA is called total PSA or tPSA. PSA can also be complexed with other molecules and this is called cPSA. Recently, researchers conducted a clinical trial to compare tPSA to cPSA for the detection of prostate cancer. [2] This trial included 831 men who had their blood drawn for PSA levels prior to undergoing a biopsy. Of these men, 37.5% had prostate cancer according to biopsy results. Using a cutoff of 2.2 ng/ml for cPSA and 2.5 ng/ml for tPSA, both tests correctly identified 85% of patients with cancer. However, at this level, cPSA measurement would have reduced the need of unnecessary biopsies in 14% of men. These researchers concluded that cPSA levels may provide a more accurate indication of the presence of cancer and reduce unnecessary biopsies when used for the detection of prostate cancer, compared to the standard tPSA.

PSA Complexed to Alpha 1-protease Inhibitor: PSA also can be complexed with specific molecules that can also be measured. Alpha 1-protease inhibitor is one of the specific proteins that is commonly bound to PSA in the blood. Previous studies have shown that the ratio of free PSA to total PSA (all different forms of PSA) improves the accuracy of the detection of prostate cancer. In order to further derive specificity of PSA testing, scientists have recently developed a blood test that can detect the presence of alpha 1-protease inhibitor bound to PSA. In this clinical trial, 3 different forms of PSA were evaluated for accuracy in determining prostate cancer. [3] The patients involved in this trial were divided into 2 groups: those who had confirmed prostate cancer and those who did not have prostate cancer. Blood samples from these individuals were tested for free PSA levels, PSA-alpha-1-protease inhibitor levels and tPSA levels. The proportion of PSA-alpha-1-protease inhibitor levels compared to total PSA levels was shown to be lower in patients with cancer. This test alone improved the accuracy of determining prostate cancer. Moreover, when the results of PSA-alpha-1-protease inhibitor levels were combined with free PSA results, the accuracy of determining prostate cancer was improved to approximately 90%.

Improved Accuracy of Biopsies

In some instances, biopsies do not detect cancer even when the PSA is elevated. Some research has been directed at more sensitive methods of detecting cancer than looking at tissue under the microscope.

Researchers at the Johns Hopkins University Medical Center have studied the link between the GSTP1 gene and prostate cancer since 1994. [4] Researchers also have looked at the efficacy of GSTP1 methylation measurement to diagnose prostate cancer in small biopsy samples. For this clinical study, the ratio of methalyated GSTP1 to the reference gene was measured in small biopsy samples taken from 21 patients with high levels of PSA. Of the 21 patients, 10 were correctly diagnosed as not having prostate cancer and 10 out of 11 were correctly diagnosed with prostate cancer using the GSTP1 ratio. These results are encouraging and indicate that the measurement of GSTP1 methylation may be used to improve the accuracy for detecting early-stage prostate cancer. Study results also indicate that small biopsy tissues samples may be sufficient in methylated GSTP1 testing, further enhancing the practicality of the test. Improvement in the accuracy of determining prostate cancer with practical testing may spare patients with elevated PSA levels due to a benign medical condition from undergoing unnecessary procedures. Future studies will further define the role of this promising research in testing for prostate cancer.

Researchers at the Universtiy of Michigan have determined that the over-expressed gene,-methylacyl coenzyme A racemase (AMACR) is associated with prostate cancer and not benign hypertrophy. [5] AMACR was evaluated by reverse transcriptase polymerase chain reaction (RT-PCR) and by immuno-blot and immuno-histochemical analysis. AMACR levels were examined using prostate cancer tissue representing different stages of prostate cancer progression. Three of 4 independent DNA microarray analyses (n = 128 specimens) revealed significant over-expression of AMACR in prostate cancer (P<.001). AMACR up-regulation in prostate cancer was confirmed by both RT-PCR and immuno-blot analysis. Immunohistochemical analysis demonstrated an increased expression of AMACR in malignant prostate epithelia relative to benign epithelia. They demonstrated significant differences in staining intensity between clinically localized prostate cancer compared with benign prostate tissue, with mean expression scores of 3.2 and 1.3, respectively. Using moderate or strong staining intensity as positive (score = 3 or 4), evaluation of AMACR protein expression in 94 prostate needle biopsy specimens demonstrated 97% sensitivity and 100% specificity for detecting prostate cancer. These researchers concluded that AMACR was over-expressed in prostate cancer using independent experimental methods and prostate cancer specimens. AMACR may be useful in the interpretation of prostate needle biopsy specimens that are diagnostically challenging.


Men with elevated PSA levels sometimes have negative biopsies, but ultimately go on to develop prostate cancer. The usual approach to such patients is to repeat the series of biopsies at periodic intervals in attempts to detect cancer. EPCA is a marker protein that may represent an early change that occurs in cells during the development of prostate cancer.

Researchers from the University of Pittsburgh have reported that staining of prostate tissue for a prostate cancer marker called EPCA can detect prostate cancer earlier than by histology. In this study, researchers performed an immuno-histochemistry test for EPCA on biopsy material from 27 men who did not develop cancer and on 29 tissue samples from patients with prostate cancer who had initial negative biopsies. [6] They found that the samples from the negative biopsies of those patients who were eventually diagnosed with prostate cancer expressed EPCA. Furthermore, EPCA was not expressed in tissue samples from individuals without disease. Sensitivity of the test was estimated to be 84% and specificity is 85%. The researchers also found that EPCA was not only expressed in the tumor, but throughout the prostate in men with prostate cancer indicating its usefulness as a prognostic marker for prostate cancer. Some of the patients in this study did not develop proven prostate cancer until 5 years after the initial biopsy, which was negative by histology and positive by EPCA.

Improving Ultrasound Testing

A new development in ultrasound involves the use of color Doppler imaging with microbubble contrast so that physicians are better able to determine the presence and exact location of a mass within the prostate. Doppler imaging can sense differences in velocity (i.e. blood flow versus solid tissue) and transmits these differences through different color pixels to create a picture on a screen. Microbubbles are tiny bubbles of gas that can permeate through small blood vessels without creating any harm. The microbubbles further enhance imaging by increasing the intensity of backscatter signal. Since blood vessels and blood flow are more prevalent in cancerous tissues than regular tissues, microbubbles tend to concentrate in the cancer, which is revealed on the created picture. This allows physicians to more accurately locate where biopsies should be taken.

Researchers recently compared the use of the contrast-enhanced Doppler ultrasonography with a microbubble contrast agent to conventionally used grey-scale ultrasonography. [7] Eighty-four men involved in this study first underwent the Doppler ultrasonography and 5 biopsies. Patients then underwent grey-scale ultrasonography and 10 biopsies. The accuracy of the biopsies could then be compared in the same patient. The detection rate of prostate cancer was 27% with Doppler-guided biopsies compared with 20% with conventional ultrasonography. The overall core biopsy detection rate was 13% for Doppler-guided biopsies, compared with only 4.9% for conventional ultrasonography. These results indicate that Doppler-guided biopsies with microbubble contrast may enable physicians to more accurately determine the optimal location for a biopsy. This will allow fewer biopsies than conventional ultrasonography, with an improved rate of cancer detection. Biopsies are associated with pain, infection, blood in the urine, and/or blood in the sperm. In addition, cost could be reduced by approximately 50%.


Researchers continue to investigate ways of diagnosing prostate cancer earlier without an increase in the number of negative biopsies performed. None of the tests outlined in this review can be considered “standard” at the present time. Currently, the most useful advice would be to possibly initiate PSA testing earlier in higher risk individuals and to be aware of the fact that prostate cancer can occur at PSA levels less than 4.1 ng/ml. Men are also encouraged to participate in clinical trials evaluating new methods of screening for prostate cancer.


[1] Punglia R, D’Amico A, Catalona W, et al. Effect of verification bias on screening for prostate cancer by measurement of prostate-specific antigen. The New England Journal of Medicine. 2003;349:335-342.
[2] (Partin A, Brawer M, Bartsch G, et al. Complexed prostate specific antigen improves specificity for prostate cancer detection: results of a prospective multicenter clinical trial. The Journal of Urology. 2003; 170:1787-1791.
[3] Patrik F, Wan-Ming Z, Anssi A. et al. Use of the complex between prostate specific antigen and alfa 1-protease inhibitor for screening prostate cancer The Journal of Urology,2000; 164:1956-1960, 2000)
[4] Jeronimo C, Usadel H, Henrique R, et al. Quantitation of GSTP1 methylation in non-neoplastic prostatic tissue and organ-confined prostate adenocarcinoma. Journal of the National Cancer Institute 2001; 93:1747-1752, 2001
[5] Rubin MA, Zhou M, Dhanasekaran SM, et al, Methylacyl Coenzyme A Racemase as a Tissue Biomarker for Prostate Cancer. JAMA. 2002;287:1662-1670.
[6] Dhir R, Vietmeier BN, Arlotti J, et al. Early Identification of Individuals with Prostate Cancer in Negative Biopsies. Journal of Urology 2004;171:1419-1423
[7] Roy C, Buy X, Lang H, et al. Contrast enhances color Doppler endorectal sonography of the prostate: efficiency for detecting peripheral zone tumors and role for biopsy procedure. The Journal of Urology. 2003;170:69-72.

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Tags: Prostate Cancer, Uncategorized