When used in combination with the standard prostate-specific antigen test for prostate cancer (PCa), a new epigenetic assay can improve diagnostic accuracy and potentially reduce the frequency of unnecessary screening or biopsies. The pilot study, published in the journal Cancers, is the result of a collaboration between Imperial College London, the University of East Anglia and Oxford BioDynamics.
The epigenetics of the prostate
According to Prostate Cancer UK, more than 47,000 men are diagnosed with the disease each year in England alone. In their lifetimes, 1 in 6 men will face a PCa diagnosis and it is the second leading cause of cancer-related deaths in the Western world. Unfortunately, symptoms are notoriously difficult to pick up on, which often leads to late diagnoses.
The typical diagnosis method for PCa involves a prostate-specific antigen blood test followed by MRI screening and potentially a targeted needle biopsy. As it stands, 3.0 ng/mL is used as an indicator for further investigation when using this blood test. At this cut-off, the test has a sensitivity of 59% with specificity of 87% for detection of any PCa. This low level of accuracy can potentially lead to unnecessary prostate biopsies in men with no cancer – or worse, false reassurance.
“There is currently no single test for prostate cancer, but PSA blood tests are among the most used, alongside physical examinations, MRI scans and biopsies”, said Professor Dmitry Pshezhetskiy of UEA’s Norwich Medical School. “However, PSA blood tests are not routinely used to screen for prostate cancer, as results can be unreliable. Only about a quarter of people who have a prostate biopsy due to an elevated PSA level are found to have prostate cancer. There has therefore been a drive to create a new blood test with greater accuracy.”
In recent years, there has been increasing evidence that epigenetic modifications, such as histone modifications, are associated with PCa onset. One such epigenetic modulator is the 3D conformation of chromatin, and research has shown that long-range alterations in chromatin conformations (CCs) are present in primary prostate tumours and circulating DNA from PCa patients.
Professor Dmitry Pshezhetskiy and his team had already developed an epigenetic assay, EpiSwitch, that uses algorithmic-based analysis to determine the presence of CCs in the blood of patients with melanoma. In this current pilot study, they decided to investigate whether EpiSwitch could improve the diagnostic accuracy of traditional PCa tests in 147 patients.
Rapid results
First, they worked to identify a new five-set biomarker panel based on PSA and qPCR readouts (Figure 1). They showed that this new test for PCa requires only minimal volumes of blood and can give clinicians a readout within hours.
The next step was to analyse its performance. For comparison, they demonstrated that the traditional PSA test showed a low positive predicted value (PPV) of 0.14 and a high negative predicted value (NPV) of 0.93. In contrast, combining PSA and Episwitch tests significantly increased the PPV to 0.81, though the NPV reduced to 0.78. To combat this, the team looked at integrating PSA as a continuous variable (rather than a dichotomised 3 ng/mL cut-off). Using this new approach, the team demonstrated that their Prostate Screening EpiSwitch (PSE) test yielded a combined PPV of 0.92 and NPV of 0.94.
These results are promising, and there is a potential for the new approach to greatly reduce unnecessary referrals for invasive MRIs or biopsies. However, more work is needed to confirm the findings. The next step for the team is to conduct larger blinded cohort validation studies, and to test their approach on a low cancer prevalence cohort.
