Using Prostate Health Index and MRI in Combination for Cost-effectively Detecting High-Grade Prostate Cancer

Northwestern University At Chicago, Evanston IL

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Abstract

Rationale: PSA screening detects too many low risk prostate cancers (PCas) and subjects too many men to prostate biopsy (PB). Hence, new diagnostic tests with improved specificity for aggressive PCa are needed. Prostate Health Index (PHI) measures 3 kallikrein isoforms and has been validated in multiple cohorts in Europe and the US for prediction of Gleason grade ≥3+4 clinically significant (cs) PCa at PB. The test could prevent 30-58% of unnecessary PBs at a cost of deferring or missing detection of very few high-grade PCas. Multi-parametric MRI of the prostate (mpMRI) is similarly promising for detecting Gleason ≥3+4 PCa. The PROMIS study from the UK resulted in a 27% reduction in unnecessary PBs with few missed cancers. However, both tests low specificity still subjects over half of men to unnecessary PB. Moreover, there is limited validation across men with high baseline risk of prostate cancer (men with 1st degree family history of prostate cancer, germline mutations in BRCA2, BRCA1, ATM, CHEK2, and HOXB13 (G84E variant), Lynch Syndrome, elevated polygenic risk score, agent orange exposure and African ancestry) and low risk (men with low polygenic risk score/no family history, Asian/Pacific Islander, Native American race or Hispanic ethnicity, and men <age 55y/o), thus precluding meaningful estimates of predictive accuracy in both low and high-risk populations. Our long-term goal is to cost-effectively reduce PCa over-detection and unnecessary prostate biopsies. Brief Description: Aim 1 is a single arm trial to identify effective thresholds of PHI and MRI used alone, in series (i.e. PHI +/- mpMRI and mpMRI+/-PHI) or in parallel (PHI & MRI) for detecting csPCa. Aim 2 is a study to determine the most cost-effective strategy stratified by high versus low prostate risk group. Aim 3 will assess the csPCas that were missed by MRI by careful pathologic and radiologic review and highlighting the missed csPCa for corroboration on mpMRI to see if they were truly not present on the MRI. All PIRADS 3-5 lesions will be marked in a blinded fashion on pre-prostatectomy MRI. The csPCas not seen on MRI will be characterized for Gleason grade, tumor size and extracapsular extension. We will also look for other aggressive features like comedonecrosis, cribriform histology, intraductal carcinoma, neuroendocrine differentiation, and lymphovascular and perineural invasion. We will address these objectives with the following Specific Aims: 1)Identify the biopsy strategies with highest specificity using PHI and MRI alone, in series, and in parallel to maximize the detection of clinically significant prostate cancer for biopsy- naïve low risk and high risk men; 2A) Compare the costs of the biopsy strategies for the detection of Gleason ≥3+4 PCa at initial biopsy; 2B) Estimate the cost-effectiveness of each strategy relative to biopsying all men as the cost per Gleason ≥3+4 PCa detected; 3) Characterize the MRI-blind lesions in low- and high-risk men undergoing radical prostatectomy.