Norris, Joseph Michael; (2025) Revealing the Invisible: Systematic Investigation of Prostate Cancer Undetected by Multiparametric Magnetic Resonance Imaging. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Multiparametric magnetic resonance imaging (mpMRI) has improved risk stratification for patients with suspected prostate cancer. However, as with other diagnostic instruments, there remains a disease spectrum undetected by mpMRI. Through systematic analysis, the aim of this doctoral research was to enhance current understanding of mpMRI-undetected prostate cancer and thus potentially refine the modern diagnostic prostate cancer pathway. The PROMIS (Prostate Magnetic Resonance Imaging Study; n = 576) and PICTURE (Prostate Imaging Compared to Transrectal Ultrasound [TRUS]-Guided Biopsy for Significant Prostate Cancer Risk Evaluation Study; n = 249) trials assessed diagnostic performance of prostate mpMRI against a stringent reference standard (5mm transperineal template mapping biopsy) and, as such, enabled analysis of the histopathological characteristics of mpMRI-undetected prostate cancer in this doctoral research. In both studies, all patients underwent 5mm mapping biopsy, regardless of their mpMRI result, thus providing a unique opportunity to study prostate cancer that is not detected by pre-biopsy mpMRI (i.e. a biopsy was done for both visible and non-visible cancer, thus allowing comparative analysis). To delineate the molecular landscape of mpMRI-undetected prostate cancer, a combination of systematic literature synthesis and bioinformatic analysis of publicly-available MRI-correlated genetic data was undertaken. Finally, patient perspectives on prostate mpMRI, and mpMRI-undetected cancer, were elicited and analysed using mixed methodology in the PACT (Patient Acceptance of Magnetic Resonance Imaging) study. In both PROMIS (biopsy-naïve patients) and PICTURE (non-biopsy-naïve patients) cohorts, mpMRI-undetected cancer appeared to be significantly lower in pathological grade (p = 0.0007, and p = 0.02) and tumour size (p < 0.0001, and p < 0.02) compared to mpMRI-detected disease. Furthermore, none of the most aggressive cancers (Gleason Grade Groups 4–5) were overlooked by mpMRI, in either cohort. Next, through systematic literature review, mpMRI-undetected prostate cancer appeared to have significantly reduced enrichment of the genetic hallmarks of aggressivity, compared to mpMRI-detected disease. Bioinformatic analysis of large public genetic databases demonstrated 42 genes (including, alanyl aminopeptidase [ANPEP] and, cholinergic receptor nicotinic alpha 2 subunit [CHRNA2]) that appeared to be significantly associated with prostate cancer detection on mpMRI. These genes appear to be linked to biological processes (e.g. cell proliferation) and clinical events (e.g. biochemical recurrence post-radical prostatectomy) that may help provide a link between the mpMRI visible prostate cancer phenotype and prognostic implications. In the PACT study, views from 117 patients undergoing mpMRI for suspected cancer (predominantly, due to raised levels of serum prostate-specific antigen [PSA]) were surveyed. The majority (96%) appeared to express favourable opinion towards mpMRI, and lower levels of concern regarding mpMRI-undetected prostate cancer, provided follow-up 4 measures were instigated (e.g. PSA surveillance). During selected in-depth, semi-structured interviews (n = 20), thematic analysis suggested that avoidance of invasive procedures, and improved diagnostic accuracy, were key themes. Most patients seemed to favour the non-invasive nature of pre-biopsy mpMRI, and the possibility of avoiding biopsy. Fear of invasion may have been informed by prior individual experience or negative second-hand reports regarding unpleasant biopsy side-effects. When biopsy was required, most patients seemed to value increased accuracy of MRI-guidance, however, mixed views were expressed regarding biopsy strategy, with some preferring MRItargeted biopsy alone, and others favouring concomitant systematic biopsy (approximately 50:50 split between the two approaches). In conclusion, this doctoral research provides a degree of support to the primacy held by mpMRI in the current prostate cancer diagnostic paradigm, by suggesting, at several levels of analysis, the reassuring nature of prostate cancer undetected by mpMRI. Furthermore, mixed methods research in the PACT study appeared to demonstrate cohesive views held by patients that directly experience this novel technology. Upcoming future research will focus on correlating baseline mpMRI phenotypes to longitudinal clinical outcomes to further expound the long-term prognostication that may be afforded in this setting.

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