NEW YORK – A team of researchers from Hong Kong Baptist University and the Chinese University of Hong Kong have developed a new test for diagnosing patients with prostate cancer and have plans to make it available clinically in both Hong Kong and Mainland China.
The test relies on a spermine risk score coupled with a urine test to predict which patients are most likely to have prostate cancer. The researchers believe their approach can be used in lieu of conventional methods to decide which patients merit undergoing a prostate biopsy procedure.
The researchers recently discussed the development of their approach in the journal Prostate Cancer and Prostatic Diseases.
Peter Ka-fung Chiu, an associate professor of urology at CUHK, said the investigators began work on their approach in 2014, with the aim of overcoming the shortcomings of conventional methods to select patients for invasive biopsy, such as the prostate specific antigen (PSA) test, or digital rectal examinations.
"PSA is not sensitive or specific for prostate cancer diagnosis, and has led to a lot of unnecessary prostate biopsies in men with abnormally elevated PSA levels," said Chiu, "and there are a lot of equivocal findings in digital rectal examination and therefore it is not a reliable method for prostate cancer diagnosis."
This lack of sensitivity and specificity has led to a situation where individuals flagged for biopsy because of high PSA levels, or a suspect DRE finding, undergo unwarranted biopsies, which can result in other complications. According to Chiu, about three-quarters of these patients don't have cancer.
In their search for a more accurate marker, Chiu and colleagues learned that prostate cancer patients tend to have lower levels of spermine, a marker found in urine, which could be used to detect the presence of prostate cancer. To research the marker, the investigators looked at 905 patients between 2015 and 2019, all of whom had either high PSA results or an abnormal DRE, and had biopsies scheduled. Six hundred patients had elevated PSA and underwent biopsy, which revealed that just 185, or 31 percent, actually had prostate cancer.
The researchers also analyzed urine samples from this subcohort, determining that about half of the patients with the lowest spermine levels had cancer, whereas just 17 percent of those with the highest levels did. They used ultra-high performance liquid chromatography with an Agilent Technologies 6460 triple quadrupole mass spectrometer to assess spermine levels in the urine samples.
The investigators then folded the spermine level results into a risk score with PSA, DRE, as well as prostate volume, resulting in the spermine risk score. The higher the risk score, the more likely a patient will develop prostate cancer. And patients with scores of higher than 6.2 should progress to biopsy. In addition, they reported that the negative predictive value of the score for prostate cancer was 95 percent, meaning those with a low score are unlikely to have cancer.
"This is the first time a urine spermine test has been tested in a large group of men with elevated PSA, and the results showed that urine spermine level can predict risk of prostate cancer better than the commonly used PSA test," said Chiu of the findings.
He noted the utility of the negative predictive value in ruling out prostate cancer, as well as the ability to reduce unnecessary biopsies. Chiu also said that some existing urine tests for prostate cancer require prostatic massage prior to sample collection, whereas with the Hong Kong researchers' test, there is no need for such a massage. One such test is SelectMDx, sold by MDxHealth, which is used to stratify prostate cancer patients. Other groups are presently involved in developing urine-based prostate cancer tests, including a team at the University of East Anglia in the UK, and another at the University of Birmingham.
According to Chiu, plans are underway to apply the new spermine risk score test in the clinic, perhaps by the end of this year. It initially will be provided by a commercial firm in Hong Kong, and there are plans to set up labs in mainland China and other locations in the future. Chiu declined to name the partner. He also said the investigators are planning to validate the test in other ethnic groups. Plans are also in the pipeline to enable the testing of spermine levels at the point of care using a device, as opposed to sending samples to laboratories for analysis, he said.
'A very crowded space'
Andrew Vickers, a biostatistician at Memorial Sloan Kettering Cancer Center in New York in an email called the Hong Kong researchers' work a "generally well-done study of an interesting marker," but said noted that they so far had looked at just a few hundred patients, versus other studies on prostate cancer risk scores that involved thousands of subjects.
He noted a blood-based assay called the Prostate Health Index, as well as a separate blood-based test called the 4Kscore test, commercialized by Opko Diagnostics of Woburn, Massachusetts, as examples of tests that had been developed in studies involving far larger cohorts. Vickers noted that he helped to develop the 4Kscore test.
"They are trying to enter a very crowded space," Vickers acknowledged, citing other potential competitors, such as Bio-Techne's ExosomeDx test and MiR Scientific's miR Sentinal PCa test.
Vickers also pointed out that the Hong Kong team's marker has some disadvantages, such as requiring a DRE, an uncomfortable procedure. Moreover, the discrimination on the test, a measurement of how accurate it is, "isn't very good," Vickers maintained, about 0.72, whereas other diagnostic markers tend to have discrimination in the range of .75 to .82.
To achieve discrimination of .82, the researchers need the prostate volume component of the test, yet this is also invasive and costly, as it involves having an ultrasound probe inserted in one's rectum which is "not only time-consuming and expensive, but not something the average man would want to go through," Vickers said.
"The investigators are going to have to do many more studies and show that the marker has better discrimination than existing markers, without the use of prostate volume, before it could be of clinical value," Vickers said.
Anssi Auvinen, a professor of epidemiology at Tampere University in Finland, echoed views similar to Vickers'. "The new method seems to perform reasonably well," he said, while drawing attention to the need to further validate the findings. Auvinen is the director of the prostate cancer research center at Tampere, and is principal investigator on several prostate cancer randomized controlled trials. He is also the author on a recent study that developed a prognostic index for predicting prostate cancer survival, which appeared in the journal Cancers this month.
"The good news is that the new marker has a reasonable performance in distinguishing men with normal prostates from those with cancer, and brings additional information besides the well-established risk indicators," said Auvinen via email. "However, I was a bit disappointed at the validation, as only bootstrap was used in evaluating the risk score, while no independent development and validation materials were employed as would be ideal," he said. "This means that the performance can easily be overestimated, a problem called overfitting or overparametrization."
As such, Auvinen stressed the need to further develop the new spermine risk score. "The bottom line is that further conformation is needed in independent datasets," said Auvinen. "My estimate is that it might be a promising approach, but not a breakthrough," he said. "Time will tell."