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IsoPSA cuts biopsy rate in half for newbies

‘Wonderful world’ ahead in AS? Better anyway.

(Update on on May 10, 2022: The National Comprehensive Cancer Network (NCCN) has recommended the IsoPSA test as means of helping patients and doctors decide whether they need a biopsy. This so far is for those with rising PSAs and not those on AS, but research could change that. a screening tool, IsoPSA can help about half of patients avoid biopsies.)


You probably haven’t heard of it until now.

But at least, you’ll be familiar with the PSA part as men who have undergone screening for prostate cancer.

We follow our PSAs to determine whether to have a biopsy. As Active Surveillors, we have been diagnosed with low-risk PCa and are following PSAs of above 4.0 ng/mL to determine if we need an mpMRI and a focused biopsy to determine next steps.

IsoPSA may hold the key to a new future for men who up to now were put on Active Surveillance. We’ll get to IsoPSA, which already is available commercially from, in a moment.

First, some biology.

You don’t have to be an A student as the late Sam Cooke crooned in 1960 in his hit “Wonderful World”: “Don’t know much biology/Don’t know much about a science book.”

You don’t have to know a lot. Just a little.

Prostate-specific antigens (PSA) are glycoproteins [sugar proteins] detected in blood tests. We’ve had PSAs to screen for prostate cancer and then, if the reading is above 4.0 ng/mL, we have PSAs to monitor our cancers and help determine if we need definitive treatment such as radical prostatectomy or radiation.

Depending on the source, as many at least one million American men undergo biopsies based on their PSA scores. Maybe half of those biopsies are unnecessary, wasting an estimated $4 billion in health funding per year.

Typically, these are transrectal biopsies that put men at risk of potentially deadly sepsis and other infections.

PSA is not cancer-specific since an enlarged prostate (benign prostatic hyperplasia) also can produce PSA. In fact, BPH is the leading cause of high PSAs.

Now back to IsoPSA and urologic oncologist Eric Klein, MD, emeritus chairman of the Glickman Urological and Kidney Institute at the Cleveland Clinic.


(Eric Klein, MD.)

(Note: Klein is currently on sabbatical and is an unpaid consultant faculty member at Cleveland Clinic and is a consultant to Cleveland Diagnostics. The Cleveland Clinic owns an equity stake in Cleveland Diagnostics. )

Don’t know chemistry?

Klein said: “PSA exists in multiple different forms, multiple different proteins in the blood that are called isoforms. An isoform is a slight variation in the structure of a protein.”

Fun fact:  BPH makes a slightly different form of PSA than cancer does. 

“If you have the right tools you can sort that out,” said Klein. “PSA exists in two general forms in the blood: free-floating PSA (called free PSA) and PSA that is bound to other blood proteins (called bound PSA).”

There’s basic total PSA, which most of us have tested with a regular PSA assay quarterly or annually.

But there also are the phi (Prostate Health Index from Beckman Coulter Inc.), which combines free and bound forms of PSA plus an isoform known as pre-pro precursor (PreProPSA)

to produce a phi score, and the 4kscore Test (OPKO), which looks at total, free and intact forms plus the isoform human kallikrein 2 [hK2].

4Kscore and phi are used after a man has an abnormal reading above 4 before the patient has undergone a biopsy to help determine the risk of cancer being present and to help decide if a biopsy is indicated because of that risk.

“When you put them in the algorithm they can improve the ability to say this elevation in a concentration of PSA is more likely due to BPH or due to cancer. And they do that well. They are better than PSA alone,” Klein said.

While IsoPSA, which has been studied since 2011, is now used as a reflex test to help decide on who should have a biopsy, studies evaluating the utility of isoPSA for active surveillance are in the planning stages, he said, emphasizing that currently there is no established role for isoPSA in men on surveillance.  

More than concentrations in the blood

Regular PSAs, phi and 4kscore tests measure the concentration of PSA in the blood. 

IsoForm is more dynamic. The test measures all the isoforms–dozens, maybe hundreds– in the blood, increasing its accuracy. Unlike standard PSA tests, which assess the blood concentration of this protein, the IsoPSA test detects cancer by identifying cancer-related structural changes in PSA.

Klein said the net effect of how the isoforms interact with the solvent in the isoPSA test kit is what matters: separating isoforms of PSA based on protein structure and other physicochemical properties prior to determining the concentration of PSA structural variants using traditional immunoassay techniques.

Change for the better?

OK, we’re coming up to the good part for patients.

In studies of tissue of men about to undergo biopsies, IsoPSA outperformed regular PSA.

IsoPSA reduced the biopsy rate by 55% and eliminated the need for mpMRIs by 9% in a study at the Glickman Urological and Kidney Institute that involved test ordering and recommendations by general urologists, fellowship-trained urologic oncologists, and advanced practice providers. 

Brian Helfand, MD, PhD, head of NorthShore University HealthSystem in suburban Chicago, who uses the phi test, said, the tests “have not gone head-to-head. They claim (IsoPSA) is different, but don’t have the comparisons. In addition, they have not published (to my knowledge) how it performs in men on AS.”

Klein responded: “Let me be very clear. We have not tested IsoPSA in men on Active Surveillance. We have not. This is used as a reflex test for men who are not diagnosed with cancer where we’re trying to figure out whether or not we should do a biopsy.”

What’s a reflex test? Klein explained that refers to the reflex of the urologist of what to do when a patient’s PSA is between four and 10. “And I have a question in my head about whether that represents BPH or prostate cancer, so my reflex currently is to do a biopsy. A few years ago, we changed to do these other blood tests to see if we can refine our prediction of the likelihood of having cancer. Now, isoPSA, 4Kscore and phi all do that.

The main advantage that IsoPSA may bring to the active surveillance space is to substantially decrease the number of biopsies that show only low-grade cancer – fewer men with this result would mean fewer men having to go on active surveillance, with its attendant worry and need for repeated MRI and biopsies.”

Another issue

This brings up another issue. Patients–and maybe some doctors– find the results from 4Kscore and phi difficult to read.

Klein said, “The challenge with them is that they are hard to interpret. Have you ever seen the lab reports for either of those?” My answer is yes and yes.

As one of Helfand’s patients, my eyes defocus when I read my phi results. I look for a bottom line reading such as “no change.”

Klein said IsoPSA reports are patient-friendly. Patients look at whether they are above or below a threshold. It looks like a pregnancy test.

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