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Prostate cancer

Predicting Grade group 2 or higher cancer at prostate biopsy by 4Kscore in blood and uCaP microRNA model in urine

We evaluated the ability of the 4Kscore to detect Grade group 2 or higher prostate cancer in an independent Danish cohort of TRUS biopsy, where we observed high discrimination (AUC = 0.763; 95% CI: 0.696, 0.829). Additionally, when adjusted for age, DRE, and total PSA levels, the urine microRNA model, uCaP had similar accuracy to predict Grade group 2 or higher prostate cancer in TRUS biopsy as the 4Kscore in patients with available uCaP score (AUC = 0.759, 95% CI: 0.680, 0.839; AUC = 0.758 95% CI: 0.682, 0.834; respectively). However, while there was no additional gain in precision by combining the two models (AUC = 0.766, 95% CI: 0.688, 0.844), both models were more accurate than the base model alone (AUC = 0.733; 95% CI: 0.661, 0.805), though this improvement was not statistically significant (test of equality of AUC between base model, 4Kscore, and uCaP model = 0.5).

The ability of the 4Kscore to improve the prediction of Grade group 2 or higher prostate cancer in biopsy naïve men over total PSA alone is in line with previous studies in other cohorts6,16,17 in terms of direction. The AUC found here is comparable to a large meta-analysis, which included data from 12 studies and close to 17,000 patients (AUC = 0.81 for detecting GG ≥ 2)18. However, the magnitude of the improvement over the base model was smaller as compared with other studies.

The study has potential limitations. The cohort we used here had higher risk than is commonly reported for biopsy cohorts6,15, with 34% of patients having a positive DRE prior to biopsy and nearly one fifth having GG 4 or 5. Among the 205 patients, 38% (95% CI: 31%, 45%) had Grade group 2 or higher cancer on biopsy. For comparison, the ProtecT cohort, upon which the coefficient for the 4Kscore was built, reported only 12.9% with Grade group 2 or higher cancer, and < 2% with GG 4 or 56. A possible explanation for this discrepancy could be that in the ProtecT cohort, men were invited for a PSA test (i.e. PSA screening), while the cohort in this study encompassed patients referred by their general practitioner upon clinical suspicion of prostate cancer. This is also reflected in the median PSA levels for patients with positive TRUS biopsy in the two cohorts, with 7.5 ng/ml here and 5.4 ng/ml in the ProtecT cohort.

More recently, multiparametric MRI (mpMRI) with MRI-targeted biopsies has shown improvement for prostate cancer detection over TRUS biopsy19,20,21. This is also reflected in the recently updated European guidelines for prostate cancer22, which now recommend mpMRI before biopsy. Consequently, future studies might include patients referred to mpMRI scans, to ensure the 4Kscore and uCaP remains useful in this setting as well. A recent study where the 4Kscore was combined with PiRADS score have suggested that this is indeed the case for the 4Kscore23. Nonetheless, a potential criticism of our study may be that we used as an endpoint Grade group 2 or higher prostate cancer on systematic biopsy, whereas many contemporary biopsies are done with MRI-guidance. We have two responses. First, MRI-targeted biopsy is far from universal. Due to lack of equipment and trained personnel, mpMRI is a very limited resource, unavailable at many centers, and still misses some prostate cancers that may be detected by the random TRUS biopsy approach5,24. Consequently, TRUS biopsy may be the preferred or only available option at many centers. Second, concerns have been raised that the apparently superior results of MRI may be an artifact of grade inflation25. There is evidence that cancers found by MRI-targeted biopsies are not, grade-for-grade, equivalent to those found on systematic. Specifically, high-grade cancers found only on targeted biopsy appear to be far less aggressive26. Hence our findings remain robust for the identification of clinically significant cancer. Similar considerations apply to template biopsies.