All risk stratification strategies in cancer overlook a spectrum of disease. The Prostate MR Imaging Study (PROMIS) provides a unique opportunity to explore cancers that are overlooked by multiparametric magnetic resonance imaging (mpMRI). To summarise attributes of cancers that are systematically overlooked by mpMRI. PROMIS tested performance of mpMRI and transrectal ultrasonography (TRUS)-guided biopsy, using 5 mm template mapping (TPM) biopsy as the reference standard. Outcomes were overall and maximum Gleason scores, maximum cancer core length (MCCL), and prostate-specific antigen density (PSAD). Cancer attributes were compared between cancers that were overlooked and those that were detected. Of men with cancer, 7% (17/230; 95% confidence interval [CI] 4.4-12%) had significant disease overlooked by mpMRI according to definition 1 (Gleason ≥ 4 + 3 of any length or MCCL ≥ 6 mm of any grade) and 13% (44/331; 95% CI 9.8-17%) according to definition 2 (Gleason ≥ 3 + 4 of any length or MCCL ≥ 4 mm). In comparison, TRUS-guided biopsy overlooked 52% (119/230; 95% CI 45-58%) of significant disease by definition 1 and 40% (132/331; 95% CI 35-45%) by definition 2. Prostate cancers undetected by mpMRI had significantly lower overall and maximum Gleason scores (p = 0.0007; p < 0.0001) and shorter MCCL (median difference: 3 mm [5 vs 8 mm], p < 0.0001; 95% CI 1-3) than cancers that were detected. No tumours with overall Gleason score > 3 + 4 (Gleason Grade Groups 3-5; 95% CI 0-6.4%) or maximum Gleason score > 4 + 3 (Gleason Grade Groups 4-5; 95% CI 0-8.0%) on TPM biopsy were undetected by mpMRI. Application of a PSAD threshold of 0.15 reduced the proportion of men with undetected cancer to 5% (12/230; 95% CI 2.7-8.9%) for definition 1 and 9% (30/331; 95% CI 6.2-13%) for definition 2. Application of a PSAD threshold of 0.10 reduced the proportion of men with undetected disease to 3% (6/230; 95% CI 1.0-5.6%) for definition 1 cancer and to 3% (11/331; 95% CI 1.7-5.9%) for definition 2 cancer. Limitations were post hoc analysis and uncertain significance of undetected lesions. Overall, a small proportion of cancers are overlooked by mpMRI, with estimates ranging from 4.4% (lower boundary of 95% CI for definition 1) to 17% (upper boundary of 95% CI for definition 2). Prostate cancers undetected by mpMRI are of lower grade and shorter length than cancers that are detected. Prostate cancers that are undetected by magnetic resonance imaging (MRI) are smaller and less aggressive than those that are detected, and none of the most aggressive cancers are overlooked by MRI.

Multiparametric magnetic resonance imaging (mpMRI) detects most, but not all, clinically significant prostate cancer. The genetic basis of prostate cancer visibility and invisibility on mpMRI remains uncertain. To systematically review the literature on differential gene expression between mpMRI-visible and mpMRI-invisible prostate cancer, and to use bioinformatic analysis to identify enriched processes or cellular components in genes validated in more than one study. We performed a systematic literature search of the Medline, EMBASE, PubMed, and Cochrane databases up to January 2020 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. The primary endpoint was differential genetic features between mpMRI-visible and mpMRI-invisible tumours. Secondary endpoints were explanatory links between gene function and mpMRI conspicuity, and the prognostic value of differential gene enrichment. We retrieved 445 articles, of which 32 met the criteria for inclusion. Thematic synthesis from the included studies showed that mpMRI-visible cancer tended towards enrichment of molecular features associated with increased disease aggressivity, including phosphatase and tensin homologue (PTEN) loss and higher genomic classifier scores, such as Oncotype and Decipher. Three of the included studies had accompanying publicly available data suitable for further bioinformatic analysis. An over-representation analysis of these datasets revealed increased expression of genes associated with extracellular matrix components in mpMRI-visible tumours. Prostate cancer that is visible on mpMRI is generally enriched with molecular features of tumour development and aggressivity, including activation of proliferative signalling, DNA damage, and inflammatory processes. Additionally, there appears to be concordant cellular components and biological processes associated with mpMRI conspicuity, as highlighted by bioinformatic analysis of large genetic datasets. Prostate cancer that is detected by magnetic resonance imaging (MRI) tends to have genetic features that are associated with more aggressive disease. This suggests that MRI can be used to assess the likelihood of aggressive prostate cancer, based on tumour visibility.

Multiparametric magnetic-resonance imaging (mpMRI) has proven utility in diagnosing primary prostate cancer. However, the diagnostic potential of prostate-specific membrane antigen positron-emission tomography (PSMA PET) has yet to be established. This study aims to systematically review the current literature comparing the diagnostic performance of mpMRI and PSMA PET imaging to diagnose primary prostate cancer. A systematic literature search was performed up to December 2021. Quality analyses were conducted using the QUADAS-2 tool. The reference standard was whole-mount prostatectomy or prostate biopsy. Statistical analysis involved the pooling of the reported diagnostic performances of each modality, and differences in per-patient and per-lesion analysis were compared using a Fisher’s exact test. Ten articles were included in the meta-analysis. At a per-patient level, the pooled values of sensitivity, specificity, and area under the curve (AUC) for mpMRI and PSMA PET/CT were 0.87 (95% CI: 0.83–0.91) vs. 0.93 (95% CI: 0.90–0.96, p < 0.01); 0.47 (95% CI: 0.23–0.71) vs. 0.54 (95% CI: 0.23–0.84, p > 0.05); and 0.84 vs. 0.91, respectively. At a per-lesion level, the pooled sensitivity, specificity, and AUC value for mpMRI and PSMA PET/CT were lower, at 0.63 (95% CI: 0.52–0.74) vs. 0.79 (95% CI: 0.62–0.92, p < 0.001); 0.88 (95% CI: 0.81–0.95) vs. 0.71 (95% CI: 0.47–0.90, p < 0.05); and 0.83 vs. 0.84, respectively. High heterogeneity was observed between studies. PSMA PET/CT may better confirm the presence of prostate cancer than mpMRI. However, both modalities appear comparable in determining the localisation of the lesions.

False positive multiparametric magnetic resonance imaging (mpMRI) phenotypes prompt unnecessary biopsies. The Prostate MRI Imaging Study (PROMIS) provides a unique opportunity to explore such phenotypes in biopsy-naïve men with raised prostate-specific antigen (PSA) and suspected cancer. To compare mpMRI lesions in men with/without significant cancer on transperineal mapping biopsy (TPM). PROMIS participants (n=235) underwent mpMRI followed by a combined biopsy procedure at University College London Hospital, including 5-mm TPM as the reference standard. Patients were divided into four mutually exclusive groups according to TPM findings: (1) no cancer, (2) insignificant cancer, (3) definition 2 significant cancer (Gleason ≥3+4 of any length and/or maximum cancer core length ≥4mm of any grade), and (4) definition 1 significant cancer (Gleason ≥4+3 of any length and/or maximum cancer core length ≥6mm of any grade). Index and/or additional lesions present in 178 participants were compared between TPM groups in terms of number, conspicuity, volume, location, and radiological characteristics. Most lesions were located in the peripheral zone. More men with significant cancer had two or more lesions than those without significant disease (67% vs 37%; p< 0.001). In the former group, index lesions were larger (mean volume 0.68 vs 0.50 ml; p< 0.001, Wilcoxon test), more conspicuous (Likert 4-5: 79% vs 22%; p< 0.001), and diffusion restricted (mean apparent diffusion coefficient [ADC]: 0.73 vs 0.86; p< 0.001, Wilcoxon test). In men with Likert 3 index lesions, log2PSA density and index lesion ADC were significant predictors of definition 1/2 disease in a logistic regression model (mean cross-validated area under the receiver-operator characteristic curve: 0.77 [95% confidence interval: 0.67-0.87]). Significant cancer-associated MRI lesions in biopsy-naïve men have clinical-radiological differences, with lesions seen in prostates without significant disease. MRI-calculated PSA density and ADC could predict significant cancer in those with indeterminate MRI phenotypes. Magnetic resonance imaging (MRI) lesions that mimic prostate cancer but are, in fact, benign prompt unnecessary biopsies in thousands of men with raised prostate-specific antigen. In this study we found that, on closer look, such false positive lesions have different features from cancerous ones. This means that doctors could potentially develop better tools to identify cancer on MRI and spare some patients from unnecessary biopsies.

Objectives: To assess the clinical outcomes of mpMRI before biopsy and evaluate the space remaining for novel biomarkers. Methods: The INNOVATE study was set up to evaluate the validity of novel fluidic biomarkers in men with suspected prostate cancer who undergo pre-biopsy mpMRI. We report the characteristics of this clinical cohort, the distribution of clinical serum biomarkers, PSA and PSA density (PSAD), and compare the mpMRI Likert scoring system to the Prostate Imaging–Reporting and Data System v2.1 (PI-RADS) in men undergoing biopsy. Results: 340 men underwent mpMRI to evaluate suspected prostate cancer. 193/340 (57%) men had subsequent MRI-targeted prostate biopsy. Clinically significant prostate cancer (csigPCa), i.e., overall Gleason ≥ 3 + 4 of any length OR maximum cancer core length (MCCL) ≥4 mm of any grade including any 3 + 3, was found in 96/195 (49%) of biopsied patients. Median PSA (and PSAD) was 4.7 (0.20), 8.0 (0.17), and 9.7 (0.31) ng/mL (ng/mL/mL) in mpMRI scored Likert 3,4,5 respectively for men with csigPCa on biopsy. The space for novel biomarkers was shown to be within the group of men with mpMRI scored Likert3 (178/340) and 4 (70/350), in whom an additional of 40% (70/178) men with mpMRI-scored Likert3, and 37% (26/70) Likert4 could have been spared biopsy. PSAD is already considered clinically in this cohort to risk stratify patients for biopsy, despite this 67% (55/82) of men with mpMRI-scored Likert3, and 55% (36/65) Likert4, who underwent prostate biopsy had a PSAD below a clinical threshold of 0.15 (or 0.12 for men aged <50 years). Different thresholds of PSA and PSAD were assessed in mpMRI-scored Likert4 to predict csigPCa on biopsy, to achieve false negative levels of ≤5% the proportion of patients whom who test as above the threshold were unsuitably high at 86 and 92% of patients for PSAD and PSA respectively. When PSA was re tested in a sub cohort of men repeated PSAD showed its poor reproducibility with 43% (41/95) of patients being reclassified. After PI-RADS rescoring of the biopsied lesions, 66% (54/82) of the Likert3 lesions received a different PI-RADS score. Conclusions: The addition of simple biochemical and radiological markers (Likert and PSAD) facilitate the streamlining of the mpMRI-diagnostic pathway for suspected prostate cancer but there remains scope for improvement, in the introduction of novel biomarkers for risk assessment in Likert3 and 4 patients, future application of novel biomarkers tested in a Likert cohort would also require re-optimization around Likert3/PI-RADS2, as well as reproducibility testing.