Aim To determine the performance of prostate cancer screening using prostate-specific antigen (PSA) along with other markers, expressing the markers at age- and age-specific multiples of the median (MoM). Methods A prospective nested case-control study used stored serum from 571 men who died or had a history of prostate cancer (cases) and 2169 matched controls. Total, free, and intact PSA, human kallikrein-related peptidase 2 (hK2), and microseminoprotein were measured and converted to MoM values. The distribution parameters of screening markers were estimated in cases and controls. Monte Carlo simulation used these in a risk-based algorithm to estimate detection performance (detection rates [DR] and false positive rates [FPR]). Results Almost all cases (99%) occurred after the age of 55 years . Marker values were similar in cases that died and did not die from prostate cancer. Combining age, total PSA, and hK2 MoM values (other markers added little or no discrimination) yielded an FPR of 1.2% (95% CI: 0.2–4.8%) for a DR 90% (59–98%) in men who died of or with a diagnosis of prostate cancer within 5 years of having blood drawn (risk limit 1 in 20), two-thirds less than 4.5 % FPR using total PSA alone measured in ng/ml for the same 90% DR (cutoff 3.1 ng/ml). Detection performance over 10 years yielded an FPR of 33% (22–46%) for a DR of 90%. Conclusion Screening up to every 5 years starting at age 55 with the multimarker risk-based screening algorithm for future prostate cancer achieves a high DR and much lower FPR than using PSA alone , resulting in reductions in overdiagnosis and overtreatment. |
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Calculating a person’s risk of developing prostate cancer using the results of two blood markers would improve the accuracy of detecting the disease, reports a new study led by a UCL (University College London) researcher.
Calculating a person’s risk of developing prostate cancer using the results of two blood markers would improve the accuracy of detecting the disease, reports a new study led by a UCL researcher.
Prostate cancer is the most common form of cancer in men, with more than 10,000 men dying from the disease each year in the UK, but there is currently no national screening programme.
This is partly because the current best first-line test, a blood test that detects elevated levels of prostate-specific antigen (PSA), is not entirely reliable , missing some harmful cancers and giving false positives.
False positives include not only false alarms where there is no cancer, but also the discovery of harmless cancers that are treated unnecessarily.
In a new study, published in the Journal of Medical Screening , researchers developed an algorithm that calculates a person’s risk of developing prostate cancer based on age and levels of two prostate cancer markers, PSA and hK2 (calinecin human peptidase).
They tested how well the algorithm could predict prostate cancer by comparing blood samples from men who later died after a prostate cancer diagnosis with those who were never diagnosed with the disease.
They found that by setting a risk threshold above which men are counted as "test positive," the approach would reduce the number of false positives by three-quarters compared to a standard PSA test, while detecting the same proportion of cancers.
Lead author Professor Sir Nicholas Wald (UCL Institute of Health Informatics) said: "A key drawback of prostate cancer screening using a PSA test alone is the increased risk of a false positive, which which can lead to an unnecessary invasive biopsy and unnecessary treatment of a clinically insignificant cancer that would have caused no harm anyway.
“Our study shows that a different detection approach could reduce the number of false positives by three quarters. This would make prostate cancer screening safer and more accurate, reducing overdiagnosis and overtreatment.
“The next step is to test the feasibility of this approach in practice with a pilot project inviting healthy men to undergo screening. “If the project is successful, we believe this approach should be considered as part of a national screening program for all men.”
Co-author Jonathan Bestwick (Queen Mary University of London) said: “The approach is innovative for cancer as it assesses people based on their overall risk rather than the results of a single test. “This is the same approach used in screening during pregnancy for certain maternal and fetal health conditions.”
Professor Roger Kirby, president of the Royal Society of Medicine and vice-president of Prostate Cancer UK, who was not involved in the study, said: "This is a novel approach using levels of two prostate cancer markers, PSA and hK2 ( human kallikrein peptidase) to refine the detection of prostate cancer. The use of PSA alone has significant drawbacks in terms of detection, but the addition of the hK2 marker in this context holds genuine promise of significantly reducing the mortality rate of this most cancer. common in men."
For the study, researchers analyzed data and blood samples from more than 21,000 men recruited into the prospective BUPA study more than 40 years ago.
They analyzed a series of prostate cancer markers in blood samples from 571 men who later died from or with prostate cancer, comparing them with a control group of 2,169 men who were never diagnosed with the disease.
They noted that while hK2 was a relatively weak marker for prostate cancer on its own, it was relatively independent of PSA, so the two together produced a more accurate test.
They classified the total PSA and hK2 test results based on how far they were from the average based on the participant’s age. They also included age in their risk assessment.
All men who were estimated to have a risk of one in 20 or more of developing prostate cancer in the next five years were counted as "positive."
The researchers found that if men aged 55 and older were screened for at least five years using this risk cutoff, 90% of cancer cases would be detected, and only 1.2% of cases would be false positives.
If a PSA test had been used to detect the disease alone, in a scenario modeled by the researchers, a detection rate of 86% would have been accompanied by a false positive rate of 2%. By comparison, if the risk-based approach had been adjusted to have a detection rate of 86%, the false positive rate would have been 0.5%, a three-quarter reduction.
Professor Wald is one of several UCL researchers seeking to improve the way prostate cancer is detected and screened.
In 2019, findings from the PRECISION trial, led by Professor Caroline Moore (UCL Division of Surgery and Interventional Sciences), resulted in new guidance from the National Institute of Clinical Excellence (NICE) that all men with a positive test of PSA must undergo an MRI before the biopsy. This step has been shown to preserve the detection of aggressive cancers while reducing overdiagnosis and unnecessary treatment of insignificant cancers.
In the latest study, researchers also found that men’s PSA levels were significantly elevated up to 30 years before prostate cancer diagnosis, suggesting that a cause of prostate cancer plays a role long before it is diagnosed. . However, PSA levels are not high enough to be useful in screening so far in advance of the diagnosis of the disease.
Screening performance
Our results show that a multi-marker risk-based screening algorithm incorporating a man’s age, total PSA value, hK2 value, with the markers expressed in MoM, produces improved screening performance compared to the use of total PSA alone.
The predictive effect of PSA is similar for men whose cause of death is prostate cancer and those who have nonfatal prostate cancer. Our results show that the proposed detection algorithm used to identify men with a 1 in 20 (5%) 5-year risk achieves a detection rate of 90% for a false positive rate of 1.2%, which which gives a probability of being affected for 5 years. years given a positive result of around 1:1 (50%).
Conclusion
These results show that if screening is to be performed, it should be done using a multimarker risk-based screening algorithm rather than a fixed PSA cutoff level. With minimal additional cost, this would achieve a high detection rate and, more importantly, compared to conventional PSA-only screening, reduce the false positive rate by approximately three-quarters.
This, in turn, would reduce the number of unnecessary prostate operations and biopsies, and reduce overdiagnosis and overtreatment associated with prostate cancer screening.
The study involved researchers from UCL, Queen Mary University of London and St George’s, University of London.
