NEW YORK (360Dx) – A blood test being prepared for launch around the end of this year could enable early diagnosis of aggressive prostate cancer and reduce the number of men undergoing painful biopsies and unnecessary surgeries, according to its developers.
Earlier this year, they formed a company called Nanostics to prepare their technology for a commercial launch.
The test, developed by researchers at the Alberta Prostate Cancer Research Initiative, uses a panel of biomarkers that work in tandem — one to identify extracellular vesicles from the prostate that are circulating in the blood, and the other three to calculate the risk associated with the vesicles metastasizing.
Of the four biomarkers, the test developers have so far named only two — prostate specific membrane antigen, or PSMA, and ghrelin, the hunger hormone, which the researchers, among others, identified as being over expressed in prostate cancer cells several years ago.
Importantly, in a prospective cohort study involving 377 Albertan men with suspected prostate cancer, the biomarker panel, while running on a flow cytometry instrument, demonstrated a sensitivity for aggressive prostate cancer of 95 percent and a specificity of 56 percent, said John Lewis, who developed the test with colleagues and leads a prostate cancer research team at the University of Alberta.
With that level of sensitivity, men with aggressive prostate cancer can be accurately identified, and up to 56 percent of them could avoid a biopsy altogether, Lewis noted, adding that in the same cohort, prostate specific antigen alone was only 17 percent specific at 95 percent sensitivity.
In testing for prostate cancer, the most commonly diagnosed cancer in men, clinicians generally use PSA as a biomarker. The test is frequently prescribed by a physician for men aged 40 and up.
However, in diagnosing prostate cancer, PSA lacks specificity, Lewis said, adding that men with elevated PSA levels "have about a 25 percent chance of having prostate cancer."
Still, when doctors or urologists see elevated PSAs, they normally recommend a biopsy, he said, because it has been the only way to diagnose prostate cancer. The biopsy is an ultrasound-guided procedure in which needles are placed throughout the prostate, and a pathologist examines removed tissue in providing input for a diagnosis.
"The procedure is potentially very painful and can come with a fairly significant chance of infection and even sepsis," Lewis said.
He noted that infection rates from prostate biopsies are about 5 to 6 percent of all biopsies, and the sepsis rate, which carries with it the risk of morbidity, is 1 to 2 percent.
About 1 in 7 men is diagnosed with prostate cancer during his life, and men age 65 or older account for about 60 percent of this type of cancer. About 1.3 million prostate biopsies are performed in North America each year. However, prostate cancer frequently turns out to be indolent and doesn't require treatment.
Most importantly, the University of Alberta extracellular vesicle fingerprint "can differentiate between men who harbor indolent prostate cancer and those who harbor aggressive prostate cancer," said Adrian Fairey, a urologic oncologist and cancer surgery physician at the University of Alberta, who was a co-principal investigator along with Lewis and the University of Calgary's Bryan Donnelly.
The information from their "diagnostic test can then be used to determine which men should be advised to undergo immediate biopsy and which men should be advised to defer biopsy and continue screening," he added.
Men with high levels of prostate specific antigen are increasingly put on active surveillance, involving additional PSA testing and a biopsy each year. The effects of prostate cancer surgery include "significant urinary and sexual dysfunction," Lewis said, but many men decide to have cancer removed with the prostate. "Typically, 30 to 40 percent of men drop out of active surveillance after the first year, because they don't want to go through the biopsy procedure again," he said.
Many men with non-aggressive cancers can not only avoid biopsies, they "can go on to live a long healthy life," Lewis said, adding that "for those men who will not need treatment, our position is that they would prefer to not even know that they have cancer."
For several years, the test developers searched for biomarkers associated with the spread of prostate cancer. "We began by looking at things that were circulating in the blood, such as circulating tumor cells," Lewis said, but they found that there are relatively few prostate cancer cells circulating in the blood, especially in the early stages of the disease. The team then began investigating prostate cell fragments floating in the blood. These extracellular vesicles, some of which are around 80 nanometers, are far smaller than micron-size cell-size particles frequently measured with flow cytometry, he said.
During the prospective cohort study, the team's microflow cytometer, an Apogee A50 from Apogee Flow Systems, needed no special preparation of vesicles. A laser measures particles in plasma – looking at their number and size, and the level of biomarker on each vesicle.
Measuring extracellular vesicles with a laser by flow cytometry is one important part of the test. The instrument provides measurements without using an ultracentrifuge or precipitation to isolate the vesicles — a requirement of many tests that use vesicle measurements that can, nonetheless, render them difficult to apply clinically because of the time and expense involved.
The application of machine learning is a second important part of the test. The researchers developed an algorithm to analyze the data being generated by the laser. "We're getting about 15 million pieces of data from one drop of blood, from each patient," Lewis said. "Our machine learning algorithm extracts the fingerprint of aggressive prostate cancer from all of that data," and produces a predictive score.
Based on the prospective study of Albertan men with suspected prostate cancer, which was completed about a month ago, they were able to develop and validate the algorithm, he said.
The diagnostic method, without the need for a centrifuge, is suitable for testing in the laboratory and at the point of care, Lewis said. "It does require a specialized instrument," but a point-of-care test could be developed, he added.
The system fits on a desktop and provides a test result in less than 10 minutes.
The development team spun out Nanostics early this year to commercialize the test. The company is preparing it for launch later this year in North America by licensing it as a laboratory-developed test. Eventually, they plan to make the test available internationally, and obtain US Food and Drug Administration clearance three to five years in the future, Lewis said.
The company is participating in a seed round of financing of an undisclosed value provided by angel investors.
The researchers are preparing a paper for an undisclosed peer-reviewed journal, which describes the initial clinical validation and accuracy of the test in the prospective pre-diagnosis patient cohort, including validation of its sensitivity and specificity. They expect to name the two biomarkers other than PSMA and ghrelin when they publish the paper and patents have been granted, Lewis said.
Clinicians who work with prostate cancer patients are particularly anxious for more dynamic tools, and progress is evident in recent literature related to predicting the response of prostate cancer patients to therapies.
For example, new data published last week provides a foundation for future tests to predict prostate cancer patients' response to PARP inhibitors, with added potential for monitoring emerging resistance so that treatment can be altered in a more dynamic and personalized manner.
The results, published in Cancer Discovery by a team from the UK's Institute for Cancer Research, reflect a burgeoning effort to lay the groundwork for the validation of liquid biopsy tests that not only detect the molecular features of a cancer, but also track its response to treatment and its evolution in response to specific drugs.
In May, researchers reported in a study published online in JAMA Oncology that a gene expression-based classification signature originally developed for distinguishing luminal and basal breast cancer cases is showing promise in classifying prostate cancer cases in ways that help predict response to post-operative androgen deprivation therapy.
In a meta-analysis of miRNA expression profiles for prostate cancer recurrence following radical prostatectomy published on Monday in the open-access journal PLOS One, a team of researchers found that the miRNAs "are candidate predictive markers for recurrent [prostate cancer] after radical prostatectomy."
In a step forward for tests that measure the aggressiveness of prostate cancer, Myriad Genetics recently received coverage from Medicare contractor Palmetto GBA for the company's Prolaris test for patients who are at intermediate risk for the disease.
In the local coverage determination, which becomes effective on July 10, Palmetto said it would cover the 46-gene expression test for men with favorable intermediate risk prostate cancer determined by needle biopsy that can be conservatively managed and doesn't require surgery or radiation treatment.
The Alberta researchers estimate that their alternate approach to use of needles could eliminate up to 600,000 unnecessary biopsies, 24,000 hospital stays, and up to 50 percent of the unnecessary treatments for prostate cancer. "Novel tests that improve the diagnostic accuracy of PSA and reduce the number of unnecessary prostate biopsies are urgently needed," Fairey said.