Risk-based MRI-directed diagnostic pathway outperforms non-risk-based pathways in suspected prostate cancer biopsy-naïve men: a large cohort validation study.

OBJECTIVES: To investigate and compare the performance of different proposed diagnostic pathways in a cohort of biopsy-naïve men at risk for prostate cancer (PCa), in terms of biopsy avoidance, accurate diagnosis of clinically significant prostate cancer (csPCa), and reduction in overdiagnosis of clinically insignificant cancer (cisPCa), with particular focus on a recently suggested "risk-based" MRI-directed diagnostic pathway. METHODS: Single-center, retrospective cohort study, including 499 biopsy-naïve men at risk for PCa. All men underwent PI-RADS-compliant prostate MRI, transrectal ultrasound fusion-guided targeted (TBx), and systematic biopsy (SBx). Five diagnostic pathways were retrospectively evaluated and compared for. Outcome measures were biopsy avoidance, combined with missed csPCa and detected cisPCa. csPCa and cisPCa were defined as ISUP grade group ≥ 2 and grade = 1, respectively. Chi-square test was used for statistical analysis. Decision curve analyses were used to compare the benefits of the pathways across a range of biopsy thresholds. RESULTS: The prevalence (detection-focused [reference] pathway) of csPCa and cisPCa was 52.9% (264/499) and 23.0% (115/499). MRI-focused pathway (no biopsy in PI-RADS 1-2 men) did not significantly reduce ISUP ≥ 2 cancer detection (52.1% (260/499); p = 0.13), but significantly reduced ISUP 1 cancers diagnosed (20.6% (103/499); p < 0.01), and biopsy avoidance was 11.8% (59/499). The risk-based MRI-directed pathway (no biopsy in low-risk PI-RADS 1-3 men) resulted in a small reduction of ISUP ≥ 2 diagnosed (51.7% (258/499); p = 0.04), however non-significant when compared to MRI-focused pathway (p = 0.625). Moreover, the risk-based pathway further reduced detection of ISUP 1 (18.6% (93/499); p < 0.01), and biopsy avoidance was 19.2% (96/499). Decision curve analysis showed maximized net benefit of the risk-based pathway, for the range of threshold probabilities between 6.25 and 65%. CONCLUSION: The risk-based MRI-directed pathway for prostate cancer diagnosis was optimal in balancing accurate diagnosis, reducing overdiagnosis, and maximizing biopsy avoidance. This substantial evidence should inform guideline recommendations towards using "risk-based" MRI-directed biopsy decisions in biopsy-naïve men at risk of significant prostate cancer. KEY POINTS: • Our study recognizes the added value of prostate MRI and MR-targeted biopsies in order to propose clinical diagnostic pathways for prostate cancer, towards maximizing the potential avoidance of unnecessary biopsies, while maintaining optimal detection rate of clinically significant prostate cancer. • The risk-based MRI-directed pathway incorporates risk factors such as PSA density, digital rectal examination, and family history to further refine the initial stratification of patients based on PI-RADS scores. • In this study, the risk-based pathway had the most optimal performance in terms of combination of outcomes, with the highest rate of biopsy avoidance (19.2%), while keeping a high detection rate of clinically significant prostate cancer (51.7%), when compared to the reference standard (52.9%).

Next-Generation Sequencing Reveals Potential Predictive Biomarkers and Targets of Therapy for Urothelial Carcinoma in Situ of the Urinary Bladder.

Bacillus Calmette-Guérin instillation after removal of the tumor is the first line of treatment for urothelial carcinoma in situ (CIS), the precursor lesion of most muscle-invasive bladder cancers. Bacillus Calmette-Guérin therapy fails in >50% of cases, and second-line radical cystectomy is associated with overtreatment and drastic lifestyle consequences. Given the need for alternative bladder-preserving therapies, we identified genomic alterations (GAs) in urothelial CIS having the potential to predict response to targeted therapies. Laser-capture microdissection was applied to isolate 30 samples (25 CIS and 5 muscle controls) from 26 fresh-frozen cystectomy specimens. Targeted next-generation sequencing of 31 genes was performed. The panel comprised genes frequently affected in muscle-invasive bladder cancer of nonpapillary origin, focusing on potentially actionable GAs described to predict response to approved targeted therapies or drugs that are in registered clinical trials. Of CIS patients, 92% harbored at least one potentially actionable GA, which was identified in TP53/cell cycle pathway-related genes (eg, TP53 and MDM2) in 72%, genes encoding chromatin-modifying proteins (eg, ARID1A and KDM6A) in 68%, DNA damage repair genes (eg, BRCA2 and ATM) in 60%, and phosphatidylinositol 3-kinase/mitogen-activated protein kinase pathway genes (eg, ERBB2 and FGFR1) in 36% of the cases. These data might help guide the selection of targeted therapies to be investigated in future clinical CIS trials, and they may provide a basis for future mechanistic studies of urothelial CIS pathogenesis.

Pure high-grade papillary urothelial bladder cancer: a luminal-like subgroup with potential for targeted therapy.

PURPOSE: Non-invasive high-grade (HG) bladder cancer is a heterogeneous disease that is characterized insufficiently. First-line Bacillus Calmette-Guérin instillation fails in a substantial amount of cases and alternative bladder-preserving treatments are limited, underlining the need to promote a further molecular understanding of non-invasive HG lesions. Here, we characterized pure HG papillary urothelial bladder cancer (pure pTa HG), a potential subgroup of non-invasive HG bladder carcinomas, with regard to molecular subtype affiliation and potential for targeted therapy. METHODS: An immunohistochemistry panel comprising luminal (KRT20, ERBB2, ESR2, GATA3) and basal (KRT5/6, KRT14) markers as well as p53 and FGFR3 was used to analyze molecular subtype affiliations of 78 pure pTa HG/papillary pT1(a) HG samples. In 66 of these, ERBB2 fluorescence in situ hybridization was performed. Additionally, targeted sequencing (31 genes) of 19 pTa HG cases was conducted, focusing on known therapeutic targets or those described to predict response to targeted therapies noted in registered clinical trials or that are already approved. RESULTS: We found that pure pTa HG/papillary pT1(a) HG lesions were characterized by a luminal-like phenotype associated with frequent (58% of samples) moderate to high ERBB2 protein expression, rare FGFR3 alterations on genomic and protein levels, and a high frequency (89% of samples) of chromatin-modifying gene alterations. Of note, 95% of pTa HG/papillary pT1 HG cases harbored at least one potential druggable genomic alteration. CONCLUSIONS: Our data should help guiding the selection of targeted therapies for investigation in future clinical trials and, additionally, may provide a basis for prospective mechanistic studies of pTa HG pathogenesis.

Comparative genomic profiling of glandular bladder tumours.

Primary glandular bladder tumours (bladder adenocarcinoma [BAC], urachal adenocarcinoma [UAC], urothelial carcinoma with glandular differentiation [UCg]) are rare malignancies with histological resemblance to colorectal adenocarcinoma (CORAD) in the majority of this subgroup. Definite case numbers are very low, molecular data are limited and the pathogenesis remains poorly understood. Therefore, this study was designed to complement current knowledge by in depth analysis of BAC (n = 12), UAC (n = 13), UCg (n = 11) and non-invasive glandular lesions (n = 19). In BAC, in addition to known alterations in TP53, Wnt, MAP kinase and MTOR pathway, mutations in SMAD4, ARID1A and BRAF were identified. Compared to published data on muscle invasive bladder cancer (BLCA) and CORAD, UCg exhibited frequent "urothelial" like alterations while BAC and UAC were characterised by a more "colorectal" like mutational pattern. Immunohistochemically, there was no evidence of DNA mismatch repair deficiency or PD-L1 tumour cell positivity in any sample. Depending on the used antibody 0-45% of BAC, 0-30% of UCg and 0% UAC cases exhibited PD-L1 expressing tumour associated immune cells. A single BAC (9%, 1/11) showed evidence of ARID1A protein loss, and two cases of UCg (20%, 2/10) showed loss of SMARCA1 and PBRM1, respectively. Taken together, our data suggest at least in part involvement of similar pathways driving tumourigenesis of adenocarcinomas like BAC, UAC and CORAD independent of their tissue origin. Alterations of TERT and FBXW7 in single cases of intestinal metaplasia further point towards a possible precancerous character in line with previous reports.