Introduction
orldwide
and in Asia, Prostate cancer is the most
common urological malignancy affecting men. The countries in North America,
Oceania, Europe and, Latin America and Caribbean
have the highest incidence of PC. Whereas Asian and African countries reported
the lowest rates of PC1,2. In India, following lung and oral
cavity, prostate is the third most common site for cancer. PC incidence begins
to rise after the age of 50 years, with a noticeable acceleration in incidence
after 64 years of age and the mean age at the time of diagnosis over 70 years. Among
other factors, improved access to health care facilities including imaging,
urological, biochemical and biomarker investigations has resulted in more cases
of PC cases being reported in India3. However, more than 40.0% of PC
cases are diagnosed at an advanced stage and younger patients below 50 years of
age are more likely to have advanced PC at the time of presentation. Biomarkers
which facilitate early diagnosis help mitigate this problem. Biomarkers also
help identify patients who require active intervention, they also reduce
over-diagnosis and over-treatment, minimize mortality and morbidity and have
become an invaluable tool in management of PC4,5. PSA was the first FDA
approved PC biomarker that was made available. Currently FDA has approved three
serum based biomarkers for PC namely PSA, Prostate Health Index (PHI) and 4k-score.
The only FDA approved urinary biomarker is Prostate Cancer Antigen 3 (PCA3) assay6,7,8,9.
Methods
We
undertook an electronic literature search using PubMed database and Google
Scholar. Literature search was carried on till 20th of May 2024. For
the PubMed search, the following MeSH Terms combined with the Boolean Operators
were used “prostate or prostatic” and “cancer or neoplasm or carcinoma or tumor
or cancers or neoplasms or tumors” and “marker or markers or biomarker or
biomarkers”. These keyword searches were limited to the articles title and
abstract.
1.
*Dr Naveen Ravi, Senior Resident,
Department of Physiology, AIIMS, Bibinagar, India; E-mail: [email protected]
2.
Professor Nitin Ashok John,
Professor and Head, Department of Physiology, AIIMS, Bibinagar, India
3.
Professor Madhuri Taranikanti,
Additional Professor, Department of Physiology, AIIMS, Bibinagar, India
*for correspondence
Titles
and abstracts of the extracted articles were quickly screened by the authors.
Only articles written in English language were included in this review. As FDA
approved the last PC biomarker, namely 4k-score in 2021, article search were
limited to those published in the previous 5 years. Articles that were mostly
about PC without much information on biomarkers were excluded. The authors then
analyzed the entire texts of filtered articles.
Prostate Specific Antigen (PSA):
The Cornerstone in Prostate Cancer Biomarker
Diagnosis
and management of PC was completely revolutionized with the discovery of PSA10.
PSA is currently the most widely used PC biomarker worldwide. In the year 1986,
it was US FDA approved for monitoring progression of men previously diagnosed
with PC and in 1994 FDA approved PSA for PC screening in conjunction with DRE.
PSA level of 4ng/ml was defined as the upper normal limit7,8.
PSA
also known as human kallikrein (hk) 3 is a glycoprotein that can be detected in
circulating blood6. PSA is secreted by the prostate in its inactive
form proPSA, which is then processed into PSA. In health, proPSA does not enter
circulation. However, in PC, there is disruption of basement membrane and loss
of normal histological architecture resulting in diminished processing of PSA
consequently resulting in an increase in PSA, proPSA and other PSA isoforms in
blood11. Of the total PSA (tPSA) majority is bound to serum protease
inhibitors, such as α2-macroglobulin and α1-antichymotrypsin and only
a tiny fraction of the tPSA is unbound and free, referred to as free PSA (fPSA)6.
Normally,
fPSA accounts for 5.0 to 35.0% of the tPSA7. The fPSA has been
identified to be constituted of three isoforms namely benign PSA (bPSA), intact
PSA (iPSA) and proPSA6. Native proPSA has a leading 7 amino acid
peptide sequence [-7]proPSA. This 7 amino acid leader peptide chain is then
cleaved off by hk-2 and hk-4, ultimately resulting in the formation of PSA7,9.
Approximately one third of fPSA exists as proPSA. ProPSA is much more likely to
be associated with PC compared to the other isoforms. Depending on the length
of the leader amino acid pro-peptide, numerous isoforms of pro-PSA was been
identified in serum such as [-5]proPSA
(with 5 amino acid pro-peptide), [-4]proPSA
(with 4 amino acid pro-peptide), [-2]proPSA
(with two amino acid pro-peptide), among others9. The [-2]proPSA,
has a serine-arginine pro-leader peptide and is the most stable isoform of
proPSA and can be measured using immunoassays. It is very strongly correlated
with PC rather than benign prostatic hypertrophy (BPH), and hence is of immense
use not only for the early detection of PC but also for determining the
aggressiveness of PC6,7. Studies have shown [-2]proPSA to be a superior predictor of clinically
significant PC compared to tPSA11. In patients diagnosed with PC, PSA
has a sensitivity of 93.0% and specificity of 20.0%12.
Although
PSA is specific to the prostate organ, it is not cancer specific. Elevated
levels of PSA can be found in several benign conditions such as BPH,
prostatitis, following prostate biopsy or surgery. This limitation results in a
clinical conundrum. Because ~20.0% of men with PSA levels <4ng/ml have PC
and several men with much higher PSA levels do not have PC. Consequently,
resulting in over-diagnosis and over-treatment of PC. This shortcoming has
necessitated the need for novel and improved PC biomarkers7.
The prostate health index (PHI)
Following
FDA approval of PSA, in the year 2021, FDA approved PHI7. PHI is a derived
number that combines the values of tPSA, fPSA and [-2]proPSA. It is calculated
using the formula {[-2] proPSA/free PSA) × √ total serum PSA}10.
PHI is not only useful for early detection of PC but also for differentiating
between benign and malignant lesions in patients over 50 years of age with
normal prostate on DRE and with PSA between 4 and 10ng/mL. In patients whose tPSA
levels are between 4 to 10ng/mL, PHI test is a stronger predictor of PC positive
biopsy compared to serum PSA or its individual components10. By
determining the need for prostate biopsy, in cases with tPSA levels between 4
and 10ng/ml, it helps in mitigating unnecessary biopsies7. A PHI
score of 27.0 shows 90.0% sensitivity and 30.0% specificity for predicting
prostate cancer at biopsy8.
Prostate cancer antigen 3 (PCA3) assay
The
PCA3 gene expresses a non-coding mRNA that is specific to prostate and can be detected
in urine. This gene is over-expressed by 10 to 100 times in >95% of PC. This
over-expression of PCA gene is independent of serum PSA levels and prostate
volume. By modulating androgen receptor signaling, PCA3 mRNA plays a vital role
in cancerous cell survival10. PCA3 gene expression in healthy
prostate is undetectable7. With the help of quantitative RT-PCR test,
levels of mRNA PCA3 and mRNA PSA is measured in the first void urine sample
following a DRE. A score ranging from 0 to >100 is calculated using the
formula; urinary mRNA PCA3/ mRNA PSA × 1000. Apart from improving the diagnosis
of PC, PCA3 score also helps clinicians determine which patients should undergo
a biopsy and who should avoid a repeat biopsy. In 2012, the FDA approved the
use of PCA3 assay for making informed decision on re-biopsy among patients with
suspicious PSA values and normal DRE10. Optimal threshold levels for
PCA3 is still a subject a lot of lot of debate. Some studies consider utilizing
a threshold of ≥35, while others favor a threshold of 35, and few studies
suggest a threshold level <25 to be suggestive of an indolent PC7.
The sensitivity of PCA3 assay at a score of 35 ranges between 58.0% to 76.0%
and specificity between 58.0% to 76.0% respectively8,9,13.
The 4kScore
The
4kScore was developed based on data from European Randomized Study of Screening
for Prostate Cancer (ERSPC) studies and the Prostate Testing for Cancer and
Treatment (ProtecT) study11. The four-kallikrein (4K) Score uses the
levels of 4 prostate kallikrein biomarkers and combines them with 3 clinical
parameters using an algorithm. The 4 kallikreins are tPSA, fPSA, intact PSA,
and human kallikrein protein 2 while the three clinical parameters include age
of the individual, prior biopsy status, and findings on digital rectal
examination (presence or absence of nodules). For each individual, the 4kscore
gives a personalized risk prediction score that ranges from 1 to 100 for the
probability of detecting aggressive PC. Scores ranging from 1 to 7.5 are low
risk, whereas score >20 are indicative of clinically significant PC. The
4KScore test was approved by US FDA in 2021 for use in men over 45 years of age
who are biopsy negative or have not had a prior biopsy with abnormal tPSA and
or with an abnormal DRE. 4kScore is a good diagnostic indicator for detecting
significant PC. By providing clinicians with the probability of significant PC,
it helps them decide whether or not to perform a prostate biopsy10. The
test has a sensitivity of 96.0% and specificity of 45.0%14.
The
use of the discussed biomarkers has been recommended by the National
Comprehensive Cancer Network (NCCN) guidelines15, American
Urological Association (AUA) guidelines16, European Association of
Urology (UAU) guidelines17, among others. The urological society of India however, advocates
the use of PSA and DRE on case by case basis in men above 50 years of age when
life expectancy is >10-15 years and in men at risk for PC. Moreover, the use
of biomarkers based on PSA derivates should only be considered when PSA levels
are between 4-10ng/mL18.
Studies
from Western countries that evaluate cost-effectiveness, show that compared to
PSA, newer PC biomarkers were cost saving. PC biomarkers also helped in
reducing unnecessary biopsies. Additionally, PC biomarkers helped reduce over
treatment19. Combining PC biomarkers with radiological
investigations can further help in reducing costs20. However, In India, PSA and
its derivatives are still the most widely used PC biomarker. Furthermore, India specific
cost effectiveness studies on PC biomarkers are still lacking18. Besides
the US FDA, the Clinical Laboratory Improvement Amendments (CLIA) has also
approved blood and urine based biomarkers in PC. Apart from the serum based
4k-score, CLIA has approved PCA3, SelectMDx and ExoDx prostate Intelliscore urinary
biomarkers. Select MDx assay is a urine based CLIA approved PC biomarker that
is performed on post DRE urine specimens. The test measures the mRNA levels of
the Distal-less Homeobox 1 (DLX1) and Homeobox C6 (HOXC6) genes. ExoDx prostate
Intelliscore is also a urine based assay that measures assays ERG (v-ets
erythroiblastosis virus E26 oncogene homolog) and PCA3 genes along with SAM
pointed domain containing ETS transcription factor (SPDEF) gene, with the
latter acting as a control. The advantage of this test over the other urine PC
biomarkers is that there is no need for DRE prior to urine specimen collection.
Mi-prostate score (MiPS), is a multiplex biomarker for PC that uses an
algorithm which includes serum PSA, urinary PCA3 and TMPRSS2-ERG (fusion of
Transmembrane protease, serine 2 (TMPRSS2) and ERG) genes. This gene fusion is
the most common gene alteration associated with PC. However the racial
variations in the expression of this fused gene needs to considered prior to
clinical use. It has been suggested that this fusion to be present in about 15.0%
of Japanese, 30.0% of African Americans and 50.0% of Caucasians PC patients4,5,6,7,8,9.
Apart from serum and blood based PC biomarkers, there are also tissue based
biomarkers, which are in focus and a lot of research is being directed towards them
to improve the diagnostic accuracy of PC from prostate biopsy samples.
Conclusion
Over
the years biomarkers for early detection of PC has come a long way. PSA, is the
oldest and most widely employed biomarker for PC that was approved by FDA more
than a couple of decades ago. It was initially approved for monitoring
progression of PC and later on approved for screening PC. In 2012, FDA made two
new additions namely the serum based PHI and urine based PCA3 assay. PHI
combines the values of tPSA, fPSA and [-2]proPSA. PCA3 gene codes for an mRNA that
can be detected in first void urine specimen post DRE in patients with PC. In
the last few years, the FDA approved the 4k score which combines biochemical
and clinical parameters to help in diagnosis of PC. The use of these biomarkers
has been recommended by NCCN, AUA, UAU guidelines. In western countries these
biomarkers are proving to a cost effective strategy in addressing PC. In India, PSA is
still the most widely used PC biomarker and PSA derivatives are recommended
only when PSA levels are between 4-10ng/mL. Apart from FDA, CLIA also has
approved urinary and serum biomarkers. Biomarkers in clinical practice facilitate
early detection, alleviate the burden of over diagnosis and assist clinicians in
making informed decision of whether or not to subject the patient to a prostate
biopsy.
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