Update on Noninvasive Biomarkers in Prostate Cancer
The PSA is the standard initial screening test to detect prostate cancer, but if the PSA is equivocal and symptoms and history also suggest possible cancer, a diagnostic biopsy is often recommended.
Biopsy can provide significant information based on the Gleason scoring system, which, if cancer is present, grades cancer cells based on their degree of abnormality compared to normal cells, ranging from 2 to 10, with higher scores indicating more aggressive cancer. This Score is used as a guide for treatment decisions concerning the necessity and intensity of therapy.
PSA
The epithelial cells of the prostate gland secrete a specific antigen, which is distinctive only to this gland, called the prostate-specific antigen (PSA). It is a protein-digesting enzyme that is made by the epithelial periurethral gland cells of the prostate gland, and its function is primarily to liquefy the fluid mass occurring during ejaculation that is needed for sperm motility.
PSA also activates Insulin-Like Growth Factor (IGF-1), which stimulates prostate growth, whether in benign enlargement, hyperplasia (BPH), prostate cancer, urinary or prostate infection, or recent ejaculation.
Free PSA
The free PSA can provide additional data by measuring the % of unbound PSA in blood. If it is >25%, it adds a level of reassurance that there is a lower risk of disease, but it is not 100% definitive. If, however, the free PSA is <10%, a biopsy is often indicated, especially if the PSA itself is high.
However, if the digital rectal exam is abnormal and/or there is a strong family history of prostate cancer, even with lower PSA/free PSA measurements, biopsy may be indicated for a definitive tissue diagnosis.
Modernization of the Prostate Biopsy
Prostate biopsy is traditionally performed using transrectal ultrasound imaging to guide the procedure, but currently, MRI is also being used as the guide or can be combined with ultrasound.
Biopsy is not a single specimen but involves multiple small samples using hollow needles passed through the rectum and into the prostate to obtain tissue. This is the standard for diagnosis, with samples taken based on a grid pattern commonly associated with 12 different areas. The cells are then examined microscopically, and cancer cells are described based on their degree of abnormality, called the grade of disease.
MRIs are indirect, not being capable of a cancer diagnosis alone, but offer a much more detailed image of the gland and, importantly, can discern areas that visually appear abnormal for
localizing an area to biopsy, as well as potentially preventing unnecessary biopsies. This way, when an abnormal area is seen, it allows more precision in obtaining a sample.
An MRI can also be used if there is a positive biopsy, which, when combined with ultrasound, can provide a more detailed view of the location and the extent of the disease.
In 2025, a study in 678 men that were randomized to a more sophisticated modern technology called microultrasonography-guided biopsy was compared to MRI fusion-guided biopsy, MRI, and ultrasound, to detect lower risk or minimally elevated Gleason scores. The results showed that the microultrasound technique was essentially equal to MRI image-guided biopsy.
Imaging for Suspected Prostate Cancer Spread
Computerized Tomography, CT Scans,
They are utilized for cross-sectional viewing of body areas, primarily the abdomen and pelvis. They are useful for evaluating spread local lymph nodes and determining if recurrence has occurred in other organs and tissues.
Bone Scans
Prostate cancer commonly metastasizes to bone. This test uses a low level of radionucleotide material that travels to the bones throughout the body and can be viewed with a camera that detects radioactivity, creating a skeletal image of the bones. It is not a stand-alone test, and confirmation with another type of imaging is needed, whether x-ray, CT, or MRI.
Abnormal areas show "hot spots," but false positives occur due to infection, arthritis, fractures, other cancers, and Paget's disease, which is a chronic geriatric deterioration of bone tissue that causes intense pain.
MRI
Can image tissues adjacent to the prostate to which the cancer may have spread, and also determine if residual prostate tissue may be present after a prostatectomy
The MRI can be enhanced with magnetic particles 24 hours prior to the scan, and this allows the detection of lymph node metastasis, which can be difficult to detect. This appears to be still primarily being studied to validate its usefulness.
PET Scans
Require the injection of a sugar solution that actively growing cancer cells will take up and "light up" when imaged. It is often combined with CT scans for evaluations.
AI Techniques Using Machine Learning or Deep Learning
They are now beginning to be utilized for the improvement of the diagnostic accuracy of MRI interpretation of prostate lesions.
Research suggests a potential to enhance diagnosis, especially in situations where a second opinion is considered. With further validation, there is a belief that it can be integrated into standard practice.
Genetic Prostate Biomarkers
Advanced Testing is using cutting-edge genetic technology to delve more deeply into markers that offer more definitive information about prostate tumor behavior related to growth and progression.
Some of the signaling pathways include:
P53, which regulates cell replication
PI3K is associated with tumor survival and growth
Mutations in androgen hormone receptors, which allow resistance to hormone treatment
CENPA, KIF20A, and CDCA8 genes, which interact with signaling pathways that regulate genetic expression and prognosis.
Gathering genetic and epigenetic information helps differentiate levels of risk potential for progression and metastasis, and can offer direction for treatments that will be needed to hopefully achieve the best outcome. Stratification of risk to define the potential level of cancer's aggressiveness helps those at higher risk by matching them to a higher level of intervention while avoiding excessive therapies in those who are at lower risk.
Blood Tests
Testing does not suggest cancer, continued follow-up may be indicated with frequent assessments.
The cost is $750, but it is covered by Medicare when deemed medically necessary.
Molecular or Genomic Testing
Provides a high level of evaluation that has changed treatment patterns in prostate cancer. Through these advancements, individual personalized information is available that makes decisions focused on the individual rather than a more generalized approach based on just the PSA and Gleason score.
Decipher/Oncotype Dx and ProMark are similar.
Decipher Testing
Decipher testing uses prostate tissue to assess 22 RNA markers that predict how likely recurrent cancer metastasis is in patients with biochemical recurrence, or a rising PSA, after radical prostatectomy. It also provides information on the likelihood of metastasis within 5-10 years when there is high-risk pathology after the surgery.
In cases of recurrence after radical prostatectomy, treatment is generally radiation or radiation in combination with hormone therapy. Deciding to add hormone therapy, with its side effects, makes the decision more difficult.
Deciphering data from clinical trials has shown that higher scores from Testing suggest the likelihood of metastasis is much greater, and adding hormone therapy helps people live longer.
Its data is the most validated from a number of studies, with high levels of accuracy.
It is covered by Medicare and many other insurance carriers.
Promark
Testing is designed for the evaluation of low to intermediate Gleason scoring, 3/3 or 3/4 on prostate biopsy. It is a biomarker that uses eight proteins to provide a score. It is used to predict the risk of high-risk disease at the time of radical prostatectomy surgery.
Oncotype Dx GenomicProstate Score, GPS
GPS is a genomic score that measures the expression of 17 cancer-related genes from prostate tissue biopsy. It provides an independent risk level prediction of aggressive prostate cancer in men with unfavorable intermediate or high-risk disease at the time of diagnosis. The criteria used are for grade 2 disease, a PSA of 10-20 ng/ml, or >50% of the initial biopsies positive. Grade 2 cancer indicates the cells still resemble normal cells, but the PSA and biopsies suggest a higher risk of being more aggressive.
Testing can identify those who need immediate radiation or surgical intervention, or who can choose active surveillance.
The GPS has been clinically validated as a test that can predict the likelihood of biochemical recurrence, measured by rising PSA levels, with 3 years of radical prostatectomy, and an individual's risk of metastasis and death with 10 years of treatment.
The cost is covered for qualified medicare patients.
Polaris Prognostic Test
This is another genetic test based on prostate tissue from biopsy that is used to predict the level of aggressiveness of localized prostate cancer, the likelihood of progression, and an estimate of prostate-specific risk of death. It analyses 46 genes to generate a ten-point score. In addition, clinical information from the PSA, Gleason score, age, and extent of progression are all factored in to offer risk stratification based on a point score. So that every additional point in the 10-point Score doubles the increased risk of disease progression
This test is being used to guide patients and their doctors in decisions as to whether active surveillance or treatment should be utilized.
The cost is $3400, but it is covered by Medicare.
ConfirmMDx
This is for men with a negative prostate cancer biopsy, no cancer, which uses tissue from this initial biopsy to evaluate the possibility that there is prostate cancer in other areas. Testing looks for epigenetic changes, changes that affect DNA actions without changing the DNA itself. In this test, they are looking at hypermethylation of the genes GSPT1, APC, and RSS1. Methyl groups help regulate DNA actions, and in the case of these genes being hypermethylated, their tumor suppression function is reduced, with the implication that other areas of the prostate may have this alteration and an associated higher risk of cancer and potentially localized cancer. Therefore, if the biopsy shows hypermethylation, more biopsies may be warranted, as well as close follow-up and PSA testing.
Medicare does cover Testing.
Urine Testing
Select MDx
Select MDx was recently approved by the National Comprehensive Cancer Network.
In situations of an abnormal digital rectal exam or PSA, it can help determine the benefit of biopsy for early detection, or that biopsy is unnecessary as long as there is appropriate continued follow-up. It has a predictive value of 95%.
This is a noninvasive urine-based liquid biopsy that can determine a high (Gleason score>7) or low risk of prostate cancer by measuring two mRNA cancer biomarkers. HOXC6 is overexpressed in aggressive prostate cancer, and DLX1 regulates factors that are important in the development of prostate cancer progression.
Exo Dx
It is another urine-based liquid biopsy that is available for men >50 years old with PSA values from 2-10 who want more information to consider an initial prostate biopsy.
It measures PCA3, ERG, and SPDEF. PCA3 is a prostate antigen expressed particularly in prostate cancer. ERG is a gene that is associated with prostate growth, and when epigenetically changed, it promotes increased prostate cancer growth. SPDEF modulates gene expression and acts as a tumor suppressor, and when expression is changed, it is associated with prostate cancer progression.
It provides a risk score that, when greater than 15.6, is associated with a Gleason score that is >7, a level which indicates significant prostate cancer risk. Its sensitivity and specificity are both in the low 90%.
MyProstateScore 2.0 (MPS2)
It is a urine-based test developed at the University of Michigan that analyzes 18 genes that are associated with high-grade prostate cancer, offering discrimination between aggressive cancers needing treatment and those that appear to be slower growing and can be considered for surveillance. It can also help reduce unnecessary biopsies and imaging.
A recent study, published in 2024 in JAMA Oncology, shows validation for this Testing.
IsoPSA Test
This is a blood-based test developed by Cleveland Diagnostics that evaluates variants in the structure of the PSA protein for men over 50 with elevated PSA levels. It is designed to indicate only high-grade prostate cancer and has a high sensitivity of 90.2%. Its value is unaffected by other conditions that elevate the PSA.
AR-ctDECTECT
It is a liquid biopsy blood test developed by the Duke Cancer Institute in collaboration with the University of Minnesota Medical School, which focuses on 69 genes relevant to prostate cancer and resistance to hormone treatment. It detects circulating tumor DNA(ctDNA) to identify mutations to predict survival in advanced prostate cancer, and can provide information to focus individual treatment based on the profile.