Men with a previous negative biopsy and a persistent risk of clinically-significant cancer offer a unique clinical challenge. While multiple tools have been proposed for risk stratification, the vast majority of validation data are derived from the biopsy-naïve setting [10]. In the current analysis, we established and validated a straightforward clinical approach to MPS-based risk stratification in the repeat biopsy population. In an independent validation cohort, we found that MPS ≤ 15 was associated with 100% NPV and 100% sensitivity for GG ≥ 2 cancer. By contrast, men with MPS > 40 had an approximately one in five risk of GG ≥ 2 disease. The intermediate range of MPS 15–40 was associated with a 6.5% risk of GG ≥ 2 disease. In the setting of shared decision-making, these data suggest that men with MPS ≤ 15 can confidently forego biopsy (0% risk of GG ≥ 2 PCa), most men with MPS 15–40 are unlikely to benefit from repeat biopsy (6.5% risk of GG ≥ 2 PCa), and those with MPS > 40 harbor risk of GG ≥ 2 cancer (19%) that supports proceeding to repeat biopsy [14].
There are limited data describing the use of biomarkers in clearly-defined repeat biopsy populations [10]. McKiernan and colleagues assessed various thresholds of the ExoDx Prostate (Intelliscore), or EPI test, in one cohort of 229 men with PSA 2–10 ng/ml that underwent repeat biopsy. Consistent with our study population and the available literature, 12% of their cohort had GG ≥ 2 cancer on repeat biopsy. Using the EPI score of 15.6, they found that 27% of unnecessary repeat biopsies could have been avoided with 82% sensitivity and 92% NPV for GG ≥ 2 disease [15]. As validated herein, the lower MPS threshold of 15 would have prevented 23% of unnecessary biopsies with 100% sensitivity and 100% NPV for GG ≥ 2 disease. An upper EPI threshold of 29.6 would have avoided 65% of unnecessary biopsies with 68% sensitivity and 94% NPV. Similarly, we found that the upper MPS threshold of 40 would have avoided 70% of unnecessary biopsies, with 68% sensitivity and 95% NPV. Moreover, the upper MPS threshold of 40 provided 98% NPV for GG ≥ 3 disease. As such, available data suggest that biomarker assays are likely to provide clinically useful information to the majority of men considering repeat biopsy.
Multiparametric MRI (mpMRI) is similarly proposed to better inform patients considering repeat biopsy. Unlike biomarkers, a positive mpMRI can allow clinicians to target visible lesions, improving the yield of biopsy [16]. By contrast, mpMRI is subject to several practical limitations. For one, MRI is subjectively interpreted, and its accuracy varies across and within medical centers [17, 18]. Moreover, MRI is not an option for some patients (e.g. metallic implants, claustrophobia) and is not universally accessible, emphasizing the need for multiple diagnostic testing options. A 2020 meta-analysis found that there were insufficient data to assess the diagnostic accuracy of MRI in the non-academic setting [18] – where the majority of patients receive care. Among academic centers, the NPV for PI-RADS 1–2 mpMRI ranged from 67–100%, with a pooled NPV of 92.7%, and the proportion of patients that would have avoided biopsy based on negative MRI ranged by study from 3–67%. Acknowledging the limitations of cross-study comparisons, it is notable that the MPS threshold of 40 would have avoided 67% of biopsies – the highest proportion observed across MRI studies – with 95% NPV. Thus, MPS appears to offer potential as an objective, expandable, cost-effective tool that can be routinely obtained in the urology clinic [19].
There are notable limitations of the current analysis. For one, our data do not capture PSA kinetics or the specific indications for repeat biopsy. Second, patients in the current analysis underwent standard systematic prostate biopsy, which results in underdetection of GG ≥ 2 cancer relative to the pathologic gold standard (i.e. prostatectomy specimen). Notably, however, recent data support that MPS is strongly associated with surgical pathology findings in men with low-risk biopsy features [8], further corroborating its widely-reported association with biopsy pathology. Additionally, previous data have demonstrated the relationship of MPS with long-term oncologic outcomes [9]. As the current analysis was performed outside the context of mpMRI, these findings support use of MPS as a standalone test that can be used to avoid MRI or biopsy – as such, the absence of MRI is appropriate for the proposed clinical application of the test. While the validation cohort was limited in size and events, the number of participants exceeds similar published repeat biopsy cohorts, and the event rate is consistent with previously published repeat biopsy data [15]. Ultimately, this study population reflects one of the largest repeat biopsy cohorts to undergo biomarker testing under a prospective, standardized biospecimen protocol. Still, additional data will help corroborate these findings.