Originally published 9/20/2018
In September, 2018 we posted a blog on this promising news of the IsoPSA blood test for prostate cancer (PCa). Then, in October 2019, the FDA granted breakthrough device designation to the test, in order to work closely with the manufacturer to expedite approval. This move sprang from results of a 2019 validation study[i], which closely matched the first. This was good news for the IsoPSA test.
The bad news is, there is no sign yet that the FDA has actually approved the test for market distribution. There are several widely used biomarker tests that enlarge upon information from blood or biopsy tissues, such as the PHI (Prostate Health Index), the 4K score, Prolaris, OncotypeDX, Decipher, etc. One of the leading PCa experts, Dr. Stacy Loeb (NYU Langone Medical Center), considers the PHI and 4K score to be “most useful second-line tests in screening since they are like new and improved versions of PSA itself.”[ii] Regarding the 2017 initial results of IsoPSA research, Dr. Loeb expressed caution: “Additional studies are needed to compare IsoPSA to other commercially available prostate cancer markers in this space,” before its potential use as a second-line test to help men decide on a biopsy.[iii]
Dr. Loeb herself is a proponent of multiparametric MRI in the PCa diagnostic space:
Overall, multiparametric MRI is probably the most transformative development in the context of prostate cancer detection. Not only does it show which patients are at greater risk of harboring clinically significant prostate cancer, but it can also be used to target the biopsy itself and increase diagnostic yield.[iv]
I want to underscore that Artificial Intelligence (AI) is ramping up diagnostic speed and accuracy. When AI is integrated with mpMRI, patients obtain two key advantages over PSA-triggered conventional TRUS biopsy. First, when the accuracy of MRI’s visual information is enhanced by AI, it can eliminate the need for a biopsy (no significant PCa detected). Second, if a biopsy proves necessary, real-time MRI precision targeting means maximum diagnostic results using only minimum needles. An overview article in Nature (2020) discusses the rapidly increasing benefits of integrating MRI and AI for several different cancers, including prostate cancer. Today, MRI + AI are combining to provide swift, accurate information on the state of a man’s prostate. When genomic or molecular biomarkers join forces with that team, doctors and patients have the best that medical science can offer today.
“Build a better mousetrap, and the world will beat a path to your door.”
Ralph Waldo Emerson
The entire world of prostate cancer is eagerly waiting for a better prostate cancer (PCa) blood test. Before the development of the Prostate Specific Antigen (PSA) blood test, countless patients were diagnosed only after symptoms appeared, and by then their cancer had generally left the gland. This meant a high prostate cancer mortality rate.
When the PSA blood test was introduced in the mid-1990s as a way to screen for possible PCa, the death rate dropped dramatically over the following decade. However, that reduction came with a price. Most men who were found to have a high (or rising) PSA were promptly sent for an ultrasound-guided biopsy (TRUS biopsy). In turn, this often had one of two general outcomes:
- If the biopsy picked up PCa, they were quickly sent for surgery or radiation – even if they had a low risk Gleason score of 3+3.
- Or, the biopsy missed cancer altogether (a “false negative”), even if they had Gleason 3+4 or higher disease.
This led to a series of confusing and conflicting statements from the U.S. Preventive Services Task Force about broad PSA screening, since for untold thousands of men it was doing more harm than good.
Need for a better blood test
The core problem was the test itself. All prostate cells, whether they are cancerous or not, have surface proteins called antigens. While PSA has a role to play in liquefying semen, some of it also makes its way into the bloodstream. Prostate cells “shed” PSA into the blood when the gland is stimulated or disturbed in some way. This can occur not only during sexual activity and ejaculation, but also by things like prostate inflammation, BPH (benign gland enlargement with aging), infection, even riding a bike or the digital rectal exam. And of course, cancer activity in the prostate also disturbs the gland, so more PSA is released. This is how PSA came to be understood as possible evidence of prostate cancer.
Thus, PSA is a biomarker because its presence in the blood is a measure of prostate activity. Does this automatically mean a man has prostate cancer? No, it does not, and that’s the problem.
The new IsoPSA test
In 2017, a group of researchers from the Cleveland Clinic announced that they had developed a new molecular blood test that could tell the difference between prostate cancer and noncancerous conditions. It could even identify which patients had likely high-risk disease. This was based on a preliminary study conducted at five academic and community urology centers. An accurate blood test would mean that men with negative results would not need a biopsy! However, the preliminary results needed more confirmation.
A validation study was completed in time for the 2018 American Urological Association annual meeting in May. The news was just as good the second time around. The Cleveland team’s lead researcher, Dr. Eric Klein, commented on the results:
…IsoPSA has a 94% sensitivity for detecting high-grade (Gleason score 7 or higher) cancer and a 93% negative predictive value for high-grade cancer, Dr Klein said. ‘If you have a low IsoPSA number, you’re about 93% certain that you don’t have high-grade cancer,’ he said. Results showed that 47% of prostate biopsies could have been avoided.[v]
The patients in the study also had multiparametric MRI which, in the hands of an expert, is able to detect high-grade cancer before a biopsy. During the clinical study, the combination of IsoPSA and mpMRI proved 86% accurate in pre-biopsy identification of high risk PCa. Dr. Klein commented, “That’s pretty good, certainly much better than standard PSA and free PSA.”[vi]
What’s the difference in blood tests?
The difference between conventional PSA and the new IsoPSA test has to do with the 3-dimensional molecular form of the PSA protein molecules. A traditional PSA test is a simple count, whereas the IsoPSA can define the distinctive 3-D structure of PSA from the cancer cells. Essentially, this “unmasks” prostate cancer, making it identifiable by a blood test.
But a word of caution is in order: the IsoPSA test is NOT the equivalent of a prostate biopsy, which diagnoses the physical tumor itself. Thus, IsoPSA is very highly accurate in showing whether or not a biopsy is needed, but a doctor cannot make a treatment decision based on a positive IsoPSA result alone.
The best way to obtain that information is by real-time MRI-guided targeted biopsy. Since mpMRI reveals the size, shape, location, and clues to aggression, Dr. Sperling can direct a minimum number of needles into the core of the tumor where the most dangerous cells are likely to be found. Unlike the standard TRUS biopsy, there is nothing random or blind about Dr. Sperling’s biopsy method – and the fewer the needles, the lower the risks.
Without a doubt, until something better comes along, the prostate cancer world will beat a path to the IsoPSA once it’s FDA-approved.
NOTE: This content is solely for purposes of information and does not substitute for diagnostic or medical advice. Talk to your doctor if you are experiencing pelvic pain, or have any other health concerns or questions of a personal medical nature.
[i] Stovsky M, Klein EA, Chait A, Manickam K et al. Clinical Validation of IsoPSA™, a Single Parameter, Structure Based Assay for Improved Detection of High Grade Prostate Cancer. J Urol. 2019 Jun;201(6):1115-1120.
[ii] Ask the Experts: Dr. Stacy Loeb. “Role of Prostate Cancer Biomarkers Assays in Prostate Cancer Detection and Management.” Renal & Urology News. No date. https://www.renalandurologynews.com/home/expert-perspectives/stacy-loeb-md/
[iii] Boggs, Will. Structure-based IsoPSA assay outperforms PSA concentration for prostate cancer diagnosis. Journal of Clinical Pathways. Apr. 24, 2017. https://www.journalofclinicalpathways.com/news/structure-based-isopsa-assay-outperforms-psa-concentration-prostate-cancer-diagnosis
[iv] Ask the Experts, ibid.
[v] Charnow, Jodie. “Novel Blood Test Improves Detection of High-Grade Prostate Cancer.” Renal & Urology News, May 18, 2018.