Medical Journal of Dr. D.Y. Patil Vidyapeeth

SHORT REVIEW
Year
: 2016  |  Volume : 9  |  Issue : 4  |  Page : 438--442

Moving ahead of prostate-specific antigen


Banyameen Mohamad Iqbal1, Mushtaq Ahmed Peer2,  
1 Department of Pathology, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Pune, Maharashtra, India
2 Department of Computer Sciences, University of Kashmir, Srinagar, Jammu and Kashmir, India

Correspondence Address:
Banyameen Mohamad Iqbal
Department of Pathology, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Pimpri, Pune - 411 018, Maharashtra
India

Abstract

Prostate gland is the second most leading site of cancer among males in Indian cities and it is the second most common site of cancer among US men. Prostate cancer (PCa) is the sixth leading cause of cancer death among men worldwide. The worldwide PCa burden is expected to grow to 1.7 million new cases and 499,000 new deaths by 2030. Prostate specific antigen (PSA) is a protein made by the prostate. Biochemically, it belongs to the protease family of kallikrein and is also known as human kallikrein 3. PSA test was originally approved by the Food and Drug Administration in 1986 to monitor the progression of PCa in men who had already been diagnosed with the disease. PSA test is a nonspecific test for PCa. It can be raised in a number of benign conditions of the prostate as well. The most frequent benign prostate conditions that cause an elevation in PSA level is prostatitis and benign prostatic hyperplasia. Moreover, PSA test may give false-positive or false-negative results. Scientists and researchers are experimenting new ways to improve the PSA test to give us the ability to distinguish cancerous from benign conditions. Some new methods/genetic studies such as PCa gene 3, TMPRSS2-ERG fusion gene, micro ribonucleic acid patterns, proteo-imaging, etc., are being developed to detect PCa in its earliest form. These new tests are much more sensitive and specific than the age old PSA test. It is only a matter of time when these new tests will be fully functional and will either augment or fully replace the age old PSA test.



How to cite this article:
Iqbal BM, Peer MA. Moving ahead of prostate-specific antigen.Med J DY Patil Univ 2016;9:438-442


How to cite this URL:
Iqbal BM, Peer MA. Moving ahead of prostate-specific antigen. Med J DY Patil Univ [serial online] 2016 [cited 2022 Nov 28 ];9:438-442
Available from: https://www.mjdrdypu.org/text.asp?2016/9/4/438/186079


Full Text



 Introduction



While browsing the internet on a lazy Sunday morning, we came across a recently developed technique to detect prostate cancer (PCa) in urine through smell. We were amazed as well as curious to learn about it more. We wandered through the literature and the internet for a couple of days to find that it is really high time to think beyond prostate specific antigen (PSA).

The prostate gland is the second most leading site of cancer among males in Indian cities such as Delhi, Kolkata, Pune, and Thiruvananthapuram. It is the third leading site of cancer in cities such as Bengaluru and Mumbai. The prostate is among the top 10 leading sites of cancers in the rest of the population based on cancer registries of India.[1] It is the second most common cancer among US men. PCa is the sixth leading cause of cancer death among men worldwide. The worldwide PCa burden is expected to grow to 1.7 million new cases and 499,000 new deaths by 2030.[2] Incidence rates of PCa are higher in Australia/New Zealand (104.2/100,000), Western and Northern Europe and North America. Although incidence rates of PCa are considered low in Asian and North African countries (1-9/100,000) but demographic and epidemiological transitions in developing countries like India have shown an increasing trend in various cancer cases including PCa. Recent data have shown that we are not very far behind the rate from Western countries. The cancer registries are reporting some new information, and we can see that we are going to face a major increase in cancer incidences in the coming years.[3] This increase in the incidence of PCa is largely because the practice of PSA has become widespread in these regions.

PSA is a protein made by the prostate. Biochemically, it belongs to the protease family of kallikrein and is also known as human kallikrein 3. Flock in 1960 was the first to experiment with antigens in the prostate, and 10 years later, Ablin reported the presence of precipitation antigens in the prostate. In 1978, Sensabaugh identified semen-specific protein p30 and described its source to be from the prostate. In 1979, Wang purified a tissue-specific antigen from the prostate (“prostate antigen”). PSA was first measured quantitatively in the blood by Papsidero in 1980, but Stamey carried out the initial work on the clinical use of PSA as a marker of PCa. Although the credit for purifying PSA goes to Wang, other eminent scientists also published their research on this antigen.[4]

Since long the PSA test has been used as a marker for the presence of PCa in men. PSA test was originally approved by the Food and Drug Administration (FDA) in 1986 to monitor the progression of PCa in men who had already been diagnosed with the disease. In 1994, FDA approved the use of the PSA test in conjunction with a digital rectal examination (DRE) to test asymptomatic men for PCa. Men who report prostate symptoms often undergo PSA testing (along with a DRE) to help doctors determine the nature of the problem.[4] The principle underlying PSA estimation is a two-site immunoenzymatic “sandwich” assay and/or a chemiluminiscent assay which is done for the estimation for PSA. Men with a PSA level between 4 ng/mL and 10 ng/mL have a >40% chance of having PCa detected. PSA above 10-20 ng/mL indicate a strong probability of cancer, and almost always result in a recommendation for prostate biopsy. A cutoff of 2.5 ng/mL for prostate biopsy has been recommended by several investigators and recently was recommended in guidelines established by The American Cancer Society.[5]

The PSA test is a nonspecific test for PCa. It can be raised in a number of benign conditions of the prostate as well. The most frequent benign prostate conditions that cause an elevation in PSA level is prostatitis and benign prostatic hyperplasia (BPH). Moreover, PSA test may give false-positive or false-negative results. A false-positive test result occurs when the PSA level is elevated, but cancer is actually not present. A false-positive test result may create a lot of anxiety for the patient as well as his family and lead to additional medical procedures, such as prostate biopsy and its complications including serious infections, pain, and bleeding. Most men with an elevated PSA level turn out not to have PCa. Not more than 25% of men who have had a prostate biopsy done because of an elevated PSA level actually have PCa.[6] A false-negative test result occurs when a man's PSA level is low even though he actually has pica. False-negative test results, on the other hand, may give a man, his family, and his doctor's false assurance that he does not have cancer when he may, in fact, have a cancer that requires treatment.

Since PSA is the only approved screening test for PCa (besides DRE) scientists and researchers are experimenting new ways to improve on the PSA test to give us the ability to distinguish cancerous from benign conditions. Some of the methods being studied and some of them even in use, include:

Free versus total PSA: The amount of PSA in the blood that is “free,” means the PSA, which is not bound to any other protein, divided by the total amount of PSA, which is the free plus bound PSA. Some researchers believe that the lower the proportion of free PSA, more aggressive the tumor can be. PSA density of the transition zone: It can be calculated by dividing the blood level of PSA by the volume of the transition zone of the prostate. The transition zone is the interior part of the prostate that surrounds the urethra. Some studies suggest that this criterion may be more accurate at detecting PCa than the standard PSA test Age-specific PSA reference ranges: It is well known that a man's PSA level tends to increase with increasing age, it has been suggested by some studies that the use of age-specific PSA levels may increase the sensitivity of PSA tests. PSA velocity and PSA doubling time: PSA velocity is the rate of change of PSA in a patient over time, given as ng/mL/year. PSA doubling time is the period over which a patient's PSA level doubles. Some evidence suggests that the rate of increase in a patient's PSA level may be helpful in predicting whether he has PCa. Pro-PSA: It refers to several different inactive precursors of PSA. There are some researches showing that pro-PSA is more strongly associated with PCa than with BPH. One recently approved test combines measurement of a form of pro-PSA called [-2] pro-PSA with measurements of PSA and free PSA. The resulting “prostate health index” can be used to help a man with a PSA level of between 4 and 10 ng/mL decide whether he should have a biopsy or not.[7]

 Improving on the Prostate Specific Antigen Test



The lack of reliability of the PSA test, and its limited specificity for PCa has led to sharp criticism over the use of the PSA test as a routine health screening test for men of increasing age. What everyone does accept is the need for better markers of PCa. Till date, there are no perfect biomarkers to identify PCa specifically. Each year some progress is definitely being made toward such a goal. University of Michigan's Department of Pathology has brought up a new test called Mi-Prostate score (MiPS) urine test. This test is ultra-specific for PCa. The MiPS test scans urine samples for two molecular markers that are distinct to PCa.[7]

One marker is a morsel of ribonucleic acid (RNA) which is made from a gene called the PCa gene 3 (PCA3), which is overactive in 95% of all PCa. PCA3 assay is a gene-based test. It is not a replacement for PSA but an additional tool to help decide if in men suspected of having PCa, (those with a PSA between 2.5 and 10 ng/mL) prostate biopsy is really needed or not to diagnose PCa. PCA3 is PCa specific, unlike PSA. This means that it is only produced by PCa cells and not affected by prostate size at all. It discriminates better than PSA between PCa and benign prostate diseases such as BPH or prostatitis. Therefore, PCA3 gives very useful information, in addition to PSA, in deciding if biopsy is really needed. A recent study suggests that the PCA3 score can also differentiate between nonsignificant and significant PCa. In PCA3 assay, following a DRE, cancerous cells with high PCA3 levels are shed from prostate into the urine. A urine sample is then collected and tested to determine the PCA3 score. A high PCA3 score indicates an increased chance of a positive prostate biopsy (positive for malignancy). Likewise, a low PCA3 score indicates a decreased likelihood of a positive prostatic biopsy. Therefore, if the PCA3 score is low, the biopsy may be delayed or eventually avoided. In this way, the PCA3 assay may help to avoid many unnecessary first biopsies and the potential discomfort and complications associated with biopsies. The PCA3 assay can also be used in men with one or more previous negative biopsies to assess the need for a next biopsy.[8]

The second marker to detect PCa is an RNA that is made only when two genes (TMPRSS2 and ERG) abnormally fuse. The presence of this fusion RNA in patient's urine is ultra-specific for PCa.

A researcher from University of Michigan Dr. Tomlins co-discovered what is now commonly known as the TMPRSS2-ERG fusion. Evidence shows that if TMPRSS2-ERG RNA is detectable at high levels in urine, a man likely has PCa, whether or not his biopsy is positive for cancer. Biopsies typically samples <1% of the prostate gland, cancers can be missed if it is not from the representative area, even high-grade cancers.[9]

A commercial urine test for PCA3, developed and marketed by the California-based biotech company, gained FDA approval in 2012 for use in men who are considering repeat biopsy after an initially negative result. Researchers have shown that the test MiPS that measures both PCA3 and TMPRSS2-ERG should improve a doctor's ability to triage men suspected of having PCa. In a study published in Science Translational Medicine, Tomlins et al. found the highest rates of cancer in men with the highest levels of TMPRSS2-ERG and PCA3 in their urine. The men in this study were placed into three groups based on the levels of TMPRSS2-ERG and PCA3 in their urine. The groups were classified as low, intermediate, and high-level groups, or scores. Cancer was diagnosed in each of the groups 21%, 43%, and 69%, respectively. High-grade PCa was defined in the study as a Gleason score >6, also occurred at different frequencies in the three groups with 7%, 20%, and 40% diagnosed in each group, respectively.[9]

It has been seen that dogs can smell out urologic cancers with high accuracy. Depending on these findings a research team led by Probert, at the University of Liverpool and Ratcliffe, at UWE, Bristol, developed an OdoReader, a gas chromatography (GC) sensor system, which they called the electronic nose. When a urine sample is inserted into the OdoReader, after some time it separates the volatile organic compounds (VOC) present in urine into readable patterns, which are then analyzed and read by computer algorithms, which are also developed by the same research team.[10]

The results of their pilot study, published in the Journal of Breath Research, suggest that the GC-sensor algorithm system is able to successfully identify and read urologic cancers based on VOC patterns. Their research consisted of 155 men attending urology clinics in Bristol. Of those patients, 58 were diagnosed with PCa, 24 with bladder cancer, and 73 with symptoms such as hematuria (not presenting with cancer). Results varied depending on the statistical model used: “For bladder cancer, the test was >96% sensitive/specific, for PCa about 90%.”[10]

These results hold promise that a noninvasive PCa screening test yielding both high sensitivity and specificity, better than the age old PSA, may soon make its way into health care practices.

Researchers are investigating several other ways that could be used alone or in combination with the PSA test and DRE to detect PCa. Some of these include:

MicroRNA patterns: MicroRNAs are tiny, single-stranded molecules of RNA that regulate important cellular functions. Scientists have found that the pattern of microRNAs arrangement in a particular cell can differ depending on the type of cell and also between healthy cells and abnormal cells. Some research also suggests that the microRNA patterns in early-stage PCa and late-stage PCa may also be different.[11] Hence by being able to read the arrangements of microRNAs we can not only predict the cell abnormalities, but we can also predict the stage of the cancer. Nonmutation gene alterations: In this field, the activity of a gene can be altered in a way that it does not involve a change (mutation) to its DNA code. This can be done by modifying the gene's DNA through a method known as methylation or by modifying the proteins that bind to the gene and help control how it is configured in the chromosome on which it is located. These types of gene alterations are known as epigenetic alterations. Research has already shown that certain genes become hypermethylated and inactivated during the development and progression of PCa. Scientists hope to identify DNA methylation changes and protein modifications that will be able to identify PCa early and help predict tumor behavior.[11] Gene fusions: Sometimes different genes on different chromosomes can come together haphazardly and fuse to form hybrid genes. These hybrid genes have been found in several types of cancer, including PCa, and may play a role in cancer development. The gene fusions found in PCa involve members of the ETS family of oncogenes, which are genes that cause cancer when mutated or expressed at higher than normal levels. Researchers are investigating whether diagnostic or prognostic tests based on gene fusions can be developed.[11] Significant amount of work has been carried out in this field and we are hopeful to get some quantifiable tests in the near future which will help in cancer detection, especially PCa. Differential detection of metabolites: Molecules produced by the body's metabolic processes, or metabolites, may be able to help distinguish between benign prostate tissue, localized PCa, and metastatic PCa. One such molecule, known as sarcosine, has been identified and may be associated with PCa's invasiveness and aggressiveness. On-going research is investigating whether a test based on sarcosine can be developed.[11] Proteo-imaging: Proteo-imaging is the ability to localize and follow changes at the molecular level, through imaging, of the protein distributions in specific tissues. Being able to see different patterns of protein expression in healthy prostate tissue versus abnormal prostate tissue may help classify early prostate changes that may 1 day lead to cancer.[11] Protein patterns in the blood: Res earchers are also studying patterns of proteins in the blood to see if they can identify one or more unique patterns that indicate the presence of PCa and allow more aggressive cancers to be distinguished from less aggressive ones.[11]

PSA testing although not so specific for detecting PCa and after more than two decades of being approved by FDA as a screening test for PCa has still not lost its importance and is still being used as a first-line investigation for screening PCa. Recent times have seen a surge of new techniques and methods which are far more specific and sensitive in detecting PCa when used in conjunction with or without PSA. Techniques such as genetic studies, RNA studies, chromatographic studies and all the others as described above, although much more sensitive and specific than PSA in detecting PCa, but because of their complexities, cost factors, time taken and awaiting human trial experimental results, PSA, of course with certain modifications is still the first line of investigation in PCa.

The above-mentioned factors are a serious impediment in its progress, but it is just a matter of time when these hurdles will be overcome, and a whole new era in PCa testing will open, which will be far more superior and more specific than the conventional PSA testing.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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