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Addition of a novel blood test to MRI-targeted biopsy in prostate cancer screening decreased overdetection while maintaining the ability to detect clinically significant cancer, Swedish researchers reported.

They found that use of the test -- called Stockholm3 -- in a screening setting where MRI and targeted biopsies were used, performed at least as well as a traditional strategy of using prostate-specific antigen (PSA) measurements and systematic biopsies. The number of MRI procedures was reduced by 36% and the number of men referred for biopsy was reduced by 8%, reported Tobias Nordström, MD, PhD, of Karolinska Institutet in Stockholm, and colleagues.

"The ultimate aim of any screening program is to decrease mortality and harm among participants. Although our study does not include prostate cancer mortality endpoints, we argue that, based on previous evidence of a mortality benefit from prostate cancer screening using PSA and systematic biopsies, it is plausible that maintained detection of significant cancer will translate to future mortality benefits," the researchers wrote in the study online in .

They also found that when compared with a screening approach of PSA combined with standard transrectal ultrasound-guided biopsies, Stockholm3 testing followed by MRI-targeted biopsy improved the detection of clinically significant prostate cancers and reduced the detection of low-grade cancers.

While the availability of MRI will be a limiting factor, "we now show that a novel blood test as adjunct to MRI can reduce the number of MRIs performed by a third," said co-author Martin Eklund, PhD, also of the Karolinska Institute, in a statement.

"Compared with the traditional PSA-based diagnostic strategy, we show that the novel strategy of combining the Stockholm3 test and an MRI-targeted biopsy approach is associated with a 69% reduction in the rate of overdetection, while maintaining the sensitivity to detect clinically significant prostate cancer," the researchers wrote. "This finding provides a viable option for prostate cancer screening, in which the mortality benefit of prostate cancer screening is maintained and the overdetection decreased compared with a traditional screening strategy (using PSA and systematic biopsies)."

In an , Caroline Moore, MD, of University College London, called the study "an important step towards smarter screening for prostate cancer."

The blood-based Stockholm3 test uses an algorithm to analyze clinical data (age and previous biopsy status), and a combination of genetic and protein markers (including PSA) to yield a percentage risk of clinically significant prostate cancer.

In a , the test was shown to reduce benign biopsies by 44% and the detection of clinically insignificant cancers by 17%. At the same time, Nordström and colleagues pointed out, studies (such as PRECISION) have shown that using MRI before biopsy can reduce overdetection and increase detection of clinically significant prostate cancers.

The new study was a prospective, population-based, randomized, open-label non-inferiority trial that included 12,750 men ages 50 to 74. Of these, 2,293 were considered to have an elevated risk of prostate cancer (i.e., a PSA level ≥3 ng/mL or a Stockholm3 score ≥11) were randomized 2:3 to either the standard group (systematic prostate biopsies) or the experimental group (biparametric MRI followed by MRI-targeted and systematic biopsy in MRI-positive men).

The primary outcome was detection of clinically significant cancer (Gleason score of 3+4 or higher). Secondary outcomes included the proportion of men with clinically insignificant prostate cancer (defined as a Gleason score of 3+3), and the number of any prostate MRI and biopsy procedures performed.

In the intention-to-treat analysis, Stockholm3 score ≥11 detected more clinically significant prostate cancers than did PSA (227 vs 192; relative proportion [RP] 1.18, 95% CI 1.09-1.28). However, compared with a PSA of 3 ng/mL or higher, Stockholm3 ≥11 was also associated with detection of a similar number of low-grade prostate cancers (50 vs 41; RP 1.22, 95% CI 0.96-1.55) and a greater number of MRIs and biopsy procedures.

Use of Stockholm3 ≥15 resulted in fewer MRI procedures performed compared with PSA (545 vs 846; RP 0.64, 95% CI 0.55-0.82), the researchers reported, adding that the number of biopsy procedures performed was also lower, although not significantly different (311 vs 338, respectively).

The investigators also compared the performance of two diagnostic workflows for the entire cohort of 12,750 men, and found that Stockholm3 combined with MRI-targeted and systematic biopsy (7,609 men) detected clinically significant cancers in 3% of that group compared with 2.1% of the men tested with PSA plus standard biopsy (RP 1.44, 95% CI 1.15-1.81).

Stockholm3 ≥11 plus MRI also detected fewer low-grade cancers (0.7% vs 1.4%, RP 0.46, 95% CI 0.32-0.66), and led to fewer biopsy procedures than did the PSA plus standard biopsy workflow.

Study limitations, the researchers said, included that as with all prostate cancer research, there is no universal definition of clinically significant prostate cancer; that there were no subsequent screening rounds; that not all invited men participated in the trial and some participants did not undergo the assigned intervention; and that despite the use of prostate biopsy procedures, the true disease status of participants was unknown.

Moore pointed out in her commentary that in screening programs in general, getting high enough uptake of the invitation to participate can be problematic. Nordström and colleagues reported a 26% uptake of the screening invitation, compared with 32% in the in The Netherlands (which eventually increased to 42%).

She suggested that a combination of interventions may help increase participation, particularly if the need for digital rectal examination is eliminated.

Another challenge is implementing high-quality MRI during screening: "This diagnostic strategy is markedly more challenging than standard transrectal ultrasound-guided biopsy," Moore wrote. "Implementation requires a coordinated approach across multiple departments, including imaging, urology, and histopathology, and might include a formal quality assurance and quality control program, with accreditation by professional bodies."

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