This story has been updated to include responses from Bio-Techne regarding commentary on the paper from unaffiliated academic sources.
NEW YORK – Bio-Techne expects the recently published results of a prospective clinical utility study on the non-invasive ExoDx Prostate IntelliScore (EPI) test from subsidiary Exosome Diagnostics will convince private insurance groups to cover the costs of the prostate cancer risk indicator assay.
The Minneapolis-based firm believes the assay can successfully serve as a clinical indicator for patients at risk of developing high-grade prostate cancer (HGPC), thereby improving prostate cancer management.
In order to gauge prostate cancer risk, a urologist usually measures the concentration of prostate-specific antigen (PSA) in a patient's urine sample to determine whether a tissue biopsy might be needed. However, PSA testing can often be unspecific, in many cases either not finding a tumor or identifying an aggressive cancer that needs be treated right away.
Exosome Diagnostics, which was acquired by Bio-Techne in 2018, developed the EPI test to more accurately predict HGPC and help clinicians decide whether to proceed with a prostate biopsy or to defer the surgery.
The EPI test involves isolating exosomes from 10 to 15 ml of a patient's urine sample, extracting exosomal RNA, and performing RT-qPCR. The firm's software then assigns a numerical score between 0 and 100 based on the relative expression of three genes. If the score is above 15.6, the patient is deemed to be at an increased risk for high-grade prostate carcinoma, (HGPCa) necessitating a subsequent biopsy
Exosome Diagnostics CSO and study senior author Johan Skog explained that his team partnered with Baltimore-based Chesapeake Urology to launch the study in 2017 to drive health plan coverage for the assay. Results of the study were published last week in Prostate Cancer and Prostatic Diseases.
"Clinicians [we worked with] agreed that if the risk score was below 15.6, it's safe to defer a biopsy," Skog said. "If the EPI score is above that number, however, such as at 30, then you're at about 30 percent of finding prostate cancer."
While the RT-qPCR portion of the process only requires a few hours, Skog said the commercial workflow has a turnaround time of about two days including sample delivery to Exosome Diagnostics' CLIA-certified, CAP-accredited lab in Cambridge, Massachusetts, qPCR, and downstream analysis.
Ronald Tutrone, national medical director of research at United Urology Group and study lead investigator, highlighted that the EPI test could potentially help defer invasive tissue biopsies that can lead to infection, bleeding, and other surgical complications.
In the study, Skog and his group enrolled 1,094 patients with 72 urologists from 24 urology practices across Maryland. After undergoing an EPI test, patients were randomly placed into EPI (458) and control arms (484), where the EPI arm received results to inform their biopsy decision.
In the EPI arm, 93 patients received negative EPI scores (below 15.6). Urologists advised 63 percent of this cohort to defer prostate biopsy, with 74 percent following the recommendation.
For the 365 patients with EPI-positive (15.6 or above), the urologists advised the group to undergo tissue biopsy, leading to a 72 percent compliance rate.
Importantly, Skog's team observed that tissue biopsies performed in the EPI-positive cohort led to a 30 percent increase in prostate cancer detection compared to the control arm. The researchers also estimated that the urologists missed 49 percent fewer HGPC cases because of deferrals compared to standard of care.
"We thought that we'd only reduce biopsies, but we also learned that [by] using the standard of care in the blinded arm, there were a lot of HGPCs missed," Skog said. "When EPI was used, we saw that not only did we reduce the number of biopsies but found more HGPC when the EPI test was positive."
Overall, the researchers noted that 68 percent of urologists reported that the EPI tests influenced their biopsy decision.
"To our knowledge, this is the first report on a [prostate cancer] biomarker utility study with a blinded control arm," the study authors said. "The study demonstrates that the EPI test influences the overall decision to defer or proceed with a biopsy and improves patient stratification."
"We saw a lot of patients with slightly elevated PSA, where we might have considered indicating deferring of biopsy," Tutrone said. "But with an EPI score of above 40 or 50, that placed the patients at a much higher risk, [with] almost 50 percent having high-grade cancer."
However, Badar Mian, a professor of surgery and urology at Albany Medical College who was not involved with the study, pointed out that the decision-making process and accompanying counseling for prostate tissue biopsies is a complex process that is difficult to quantify. He argued that there are confounding factors that may supersede tests results, as indicated by the study.
"Despite having a positive test result, urologists [in the study] recommended not performing biopsies in 13 percent of the samples, while 28 percent of the patients didn't undergo biopsy despite the recommendation due to a positive test," Mian noted. "Why would a patient refuse the biopsy if the PSA level was elevated, the EPI test was positive, and the doctor recommended the test?"
Skog argued that the items that Mian noted are not confounding factors to the test results, as the study was intended to establish a "real-world perspective" on the decision process and without the EPI test.
Mian suspects that other problems might have been at play with a patient's decision to move forward, such as increased age, a history of infections stemming from biopsies, or that the data may have not been presented to them in a convincing enough manner.
Skog argued that the issues Mian brought up are not problems but instead standard-of-care factors that are always considered in the process.
"This is the point of the controlled utility study, [as we seek to] learn how much the test can change clinical practice," Skog emphasized. "By comparing [the EPI cohort] to the blinded control arm, which we have uniquely done, we measured the difference in the blinded control arm to learn how much the test influenced clinical practice."
While noting that a blinded control group is crucial to compare results, Mian said the control arm does not nullify other issues with the study. Mian found it especially strange that the urologists in the study used a traditional ultrasound-guided approach for the biopsy. He explained that a technique called pre-biopsy magnetic resonance imaging [MRI] is now becoming standard practice in the prostate cancer space,since the technique can help detect higher-grade cancer. He therefore wondered whether the EPI test would have had a similar performance if the team used the MRI-based approach.
However, Skog pointed out that MRI was not used for initial biopsies by the clinicians who participated in the Maryland-based study. "EPI integration with MRI is a completely different study… and the goal of a utility study is to look at the outcome in the test's intended use population," Skog argued. "MRI has a sensitivity of 88 percent and a specificity of 45 percent for [a Gleason score of seven or greater]."
Tutrone emphasized that more patients did indeed listen to urologists and heed their advice as to when to get a biopsy performed, minimizing potential costs of invasive procedures.
"When half received their results and half did not, the ones that did really adhered to our advice," Tutrone said. "If the score was high enough, say 40, 50, or 60, then there's a bit more pressure for them to comply."
Practical challenges
Because of the study's large patient population, Skog acknowledged that his team could not realistically perform in-depth conversations with every doctor to track the clinical decision-making process for each case. While the doctor filled out a clinical trial form for each patient, Skog believes that his team might have missed details that would help future trials demonstrate the assay's clinical utility.
Skog also noted that his team dealt with about a 6 percent assay failure rate, usually because a patient's urine was too diluted before collection at a physician's office.
"We typically requested patients not to urinate within an hour of testing [to allow] prostate exosomes enough time to migrate into the urethra," Skog said. "If the sample doesn't have enough prostate exosomes, we report it as a failure, since we have a set [minimum] as to how many gene copies we need to see to report our results."
However, Tutrone noted that the device used to collect the first 10 ml of a patient's urine was difficult to use properly, and that the collection process did not always fit in the standard workflow of a urology appointment.
"In most practices, patients usually provide a urine sample and wait to receive their PSA score before meeting the urologist," Tutrone explained. "If we then notify the patient that their PSA rose this year and consider they should have another urine-based test … well they've already urinated and will have to reschedule an appointment to perform the EPI test."
The researchers have since launched a follow-up pilot trial to monitor the patients over the next few years to understand the long-term outcomes of the biopsy decisions.
Commercial implications
Bio-Techne believes that the study's results will help show US private payors that they should cover the EPI test for patients at high risk of prostate cancer. Bio-Techne previously received coverage for the test from Medicare in October.
"The big national insurers initially wouldn't get behind a test like this until there's a peer-reviewed utility study," Bio-Techne CEO and President Charles Kummeth said. "This study gives us credibility, which helps private payors to come on board and pay more completely, and national insurers will start doing their analysis and potentially pick it up."
Due to the shelter in place orders issued to reduce the spread of COVID-19, Bio-Techne launched an at-home collection kit last month to increase access to the EPI test. Doctors can employ a telehealth solution by ordering the test online for their patients who are concerned about their prostate health. Because patients can then send in urine samples to prior visiting a urologist, they can be proactively pre-screened and have the EPI test results when they eventually visit the clinician's office.
"We think that over time, this will have a bigger impact on the overall business because a lot of people don't want to see urologists," Kummeth said. "The easier you get the sample collection kit to people, the more likely that the patients will get the test done."
While the EPI test is offered as a laboratory-developed test, Kummeth said that his team is still debating whether to follow a pre-market approval route with the US Food and Drug Administration. Despite the test having a list price of $795, Skog said that its cost widely varies among healthcare plans and reimbursement policies, and that there are no out-of-pocket costs for patients covered by Medicare.
"We've had orders from 15 percent of the about 17,000 urologists here in the US, and 80 percent have also reordered, so clearly they've liked the test," Kummeth said. "The plan is to now contact more urologists, convince them to use our test, and with the more [local coverage determination] expansion we get, the more traction we gain in ordering."
Tutrone highlighted that the EPI test has helped his team to avoid over-diagnosing low-risk prostate cancer and performing unneeded biopsies.
"Beforehand, we overtreated the disease when it wasn't necessary, as we didn't stratify patients into low, medium, and high-risk populations," Tutrone noted. "With the test, we can weed out patients who we could safely determine [that] their score is too low, instead of putting them through active surveillance."
However, Tutrone pointed out that other companies like MDxHealth and Beckman Coulter do offer similar tests for prostate cancer risk monitoring.
Like Bio-Techne's assay, MDxHealth's SelectMDx test is a urine-based molecular diagnostic that is intended to help stratify patients that have clinical signs of prostate cancer — such as elevated PSA levels — into lower and higher risk categories, potentially avoiding unneeded biopsies.
Beckman Coulter also offers an immunoassay-based prostate health index (PHI) test that detects PSA and two of its isomers from a patient's blood sample to determine the risk of prostate cancer. The test includes four groups based on a numerical range from 0-100 that determines the patient's risk: a score of below 27 suggests a very low risk, between 27 to 35 indicates a low risk, between 35 to 55 indicates an intermediate risk, and 55 and above indicates a high risk.
"On the extreme ranges, [PHI] is pretty useful, but in the middle, it's not that beneficial to patients," Tutrone explained. "In a perfect world, we would perform the PHI-score test, followed by EPI as an adjunct test for patients in the middle range, to determine if they're at risk for prostate cancer.
However, Skog argued that other liquid biopsy firms developing risk scores for prostate cancer have skewed data supporting their test's clinical utility. Without performing a blinded arm portion of a trial, he believes that the firms incorrectly assume that all patients in a study will receive a biopsy.
"We found that it's not always the case in the shared decision-making process between clinicians and their patients," Skog said. "So, even if your test has [perfect] sensitivity and specificity, you wouldn't reduce the number of biopsies performed, which is what other tests in the space claim."