The ReIMAGINE prostate cancer risk study protocol: A prospective cohort study in men with a suspicion of prostate cancer who are referred onto an MRI-based diagnostic pathway with donation of tissue, blood and urine for biomarker analyses

Abstract

Introduction: The ReIMAGINE Consortium was conceived to develop risk-stratification models that might incorporate the full range of novel prostate cancer (PCa) diagnostics (both commercial and academic).

Methods: ReIMAGINE Risk is an ethics approved (19/LO/1128) multicentre, prospective, observational cohort study which will recruit 1000 treatment-naive men undergoing a multi-parametric MRI (mpMRI) due to an elevated PSA (≤20ng/ml) or abnormal prostate examination who subsequently had a suspicious mpMRI (score≥3, stage ≤T3bN0M0). Primary outcomes include the detection of ≥Gleason 7 PCa at baseline and time to clinical progression, metastasis and death. Baseline blood, urine, and biopsy cores for fresh prostate tissue samples (2 targeted and 1 non-targeted) will be biobanked for future analysis. High-resolution scanning of pathology whole-slide imaging and MRI-DICOM images will be collected. Consortium partners will be granted access to data and biobanks to develop and validate biomarkers using correlation to mpMRI, biopsy-based disease status and long-term clinical outcomes.

Results: Recruitment began in September 2019(n = 533). A first site opened in September 2019 (n = 296), a second in November 2019 (n = 210) and a third in December 2020 (n = 27). Acceptance to the study has been 65% and a mean of 36.5ml(SD+/-10.0), 12.9ml(SD+/-3.7) and 2.8ml(SD+/-0.7) urine, plasma and serum donated for research, respectively. There are currently 4 academic and 15 commercial partners spanning imaging (~9 radiomics, artificial intelligence/machine learning), fluidic (~3 blood-based and ~2urine-based) and tissue-based (~1) biomarkers.

Conclusion: The consortium will develop, or adjust, risk models for PCa, and provide a platform for evaluating the role of novel diagnostics in the era of pre-biopsy MRI and targeted biopsy.

Fig 1

a. ReIMAGINE Prostate Cancer Risk Study Design. ReIMAGINE Prostate Cancer Risk is a multi-centre, prospective, observational, longitudinal cohort study of patients referred to secondary care with a suspicion of prostate cancer (elevated PSA and/or abnormal digital rectal exam) or those who are having further tests for re-stratification of pre-existing low risk disease. Consenting men will be asked to donate research samples (blood, urine and fresh prostate tissue) for biomarker analysis at the time of their NHS standard of care prostate biopsies (Visit 1). Consent will also be sought for research access to pre-biopsy prostate mpMRI data and national medical records until death (should further funding be secured). Biomarker analysis of donated samples will complete the cross-sectional component of the study (both academic and commercial). Participants exit the study following collection of tissue samples and revert to the NHS standard of care prostate cancer pathway. Standard of care pathology results are provided during a routine NHS clinic in accordance with local hospital protocol. Access to standard of care diagnostic biopsy tissue will be sought once the participating centre has completed all necessary diagnostic evaluation. Formalin-fixed paraffin-embedded (FFPE) tissue blocks and haematoxylin and eosin (H&E) stained slides will be requested by ReIMAGINE staff and anonymised H&E slides will be scanned using high resolution scanners and uploaded to the ReIMAGINE digital pathology database. Consent will be sought to obtain long-term patient outcomes from national health records, such as the Office for National Statistics, NHS Digital, Public Health England and other applicable NHS information systems or national databases. Initially, data will be collected for three years after the last patient visit with the intention to collect data up to participant death once adequate funding is secured. This will complete the longitudinal component of the study. b. ReIMAGINE Prostate Cancer Risk Study SPIRIT schedule of enrolment, interventions, and assessments.

Fig 2. Location of research prostate tissue cores in ReIMAGINE prostate cancer risk.

A) Cores 1 and 2 are collected from the centre of the highest scoring lesion (denoted as Likert / PIRADSv2.1 score 4 in this figure) if there are no other lesions of the same score. The area of Likert / PIRADSv2.1 score 3 tissue in the left peripheral zone is not sampled for research. Core 3 is collected from an area of Likert / PIRADSv2.1 score 1 or 2 tissue (denoted as Likert / PIRADSv2.1 score 2 tissue in this figure). B) Where there is more than one lesion of the highest score, Core 1 is collected from the centre of the highest scoring lesion with greatest volume and Core 2 from the centre of the next largest lesion with the same score (both denoted as Likert / PIRADSv2.1 score 4 PZ lesions in this figure). Core 3 is collected from an area of Likert / PIRADSv2.1 score 1 or 2 tissue. C) If there is diffuse Likert / PIRADSv2.1 score 3 change to one peripheral zone (PZ) the cores should be collected from the centre of the area of score 3 change denoted on the radiology report (Cores 1 and 2). The third research core will be collected from an area of non-suspicious (Likert / PIRADSv2.1 score 1 or 2) tissue. D) If there is diffuse Likert / PIRADSv2.1 score 3 to the PZs bilaterally, the side of greater suspicion should be sampled first (Core 1), and a second core collected from the contralateral score 3 PZ (Core 2). The third research core will be collected from an area of non-suspicious (Likert / PIRADSv2.1 score 1 or 2) tissue.

Fig 3. ReIMAGINE prostate cancer risk tissue collection form denoting the location of each donated prostate tissue research core.

Consenting patients will donate three research cores of prostate tissue at the time of their standard of care NHS prostate biopsy and the location of each will be recorded on a ReIMAGINE Prostate Cancer Risk tissue collection form. The first research core will be collected from the centre of the lesion with the highest Likert / PIRADSv2.1 score and greatest volume (lesion 1). The second sample will be collected from the centre of lesion 1 unless multiple lesions with the same Likert / PIRADSv2.1 score exist. If multiple lesions with the same Likert / PIRADSv2.1 score exist, the second core should be collected from the next largest lesion with the same MRI score. The third and final research core will be collected from an area of radiologically normal tissue (defined as Likert / PIRADSv2.1 1 or 2).