European urology oncology最新文献

Background: Pathogenic variants (PVs) in monogenic genes and polygenic risk scores (PRS) have been associated with kidney cancer risk. However, their joint contributions in the general population remain unclear.

Design, setting, and participants: Associations of kidney cancer with PVs in 15 core renal cell carcinoma (RCC) hereditary genes and 22 other cancer-susceptibility genes, and a published PRS (PGS004908) were evaluated in two large cohorts: the United Kingdom Biobank (UKB; N = 452 208) and the Genomic Health Initiative (GHI; N = 20 452).

Outcome measurements and statistical analysis: Cox proportional hazards models were fitted using a time-to-event framework with age as the underlying time scale.

Results and limitations: In UKB, aggregated PVs in the 15 core-RCC genes, but not in the 22 cancer-susceptibility genes, were significantly associated with kidney cancer risk (p < 0.001 and p = 0.4, respectively). PRS, modeled as a continuous variable, was also significantly associated with kidney cancer (p < 0.001). These associations corresponded to a higher age-specific hazard and earlier accumulation of diagnoses across age. Substantial differences in kidney cancer incidence rates were observed across combined genetic risk strata; notably, non-carriers with high PRS had higher absolute incidence rates than PV carriers with low PRS. In a restricted cohort of participants free of kidney cancer at recruitment, addition of genetic risk factors to clinical risk factors significantly improved discrimination (C-statistic 0.67 vs 0.65, p < 0.001). The association of PRS with kidney cancer was replicated in the GHI across participants with both European and non-European ancestries.

Conclusion: PRS meaningfully complements monogenic PVs in genetic risk assessment for kidney cancer and may improve risk stratification beyond established clinical factors.

Patient summary: Many patients with kidney cancer do not carry rare inherited mutations. Our study shows that common genetic factors, captured in a PRS, can also identify high-risk individuals. Combining both rare mutations and common polygenic risks provides a more complete assessment of kidney cancer risk and may aid in earlier screening and prevention.

Background and objective: Transurethral resection of bladder tumors (TURBT) remains the standard treatment for non-muscle-invasive bladder cancer (NMIBC) but is associated with procedural risks and health care burden. Chemoresection using intravesical mitomycin C (MMC) has emerged as a minimally invasive alternative. This randomized controlled trial presents 5-yr follow-up data evaluating long-term outcomes of MMC chemoresection versus standard surgical management in patients with intermediate-risk NMIBC.

Methods: From 2018 to 2024, 120 patients with recurrent Ta low-grade or high-grade NMIBC and >1 papillary tumor <2 cm were randomized 1:1 to receive either short-term, intensive chemoresection (6 MMC instillations over 2 wk) or standard care with TURBT/biopsy followed by adjuvant instillations with a 5-yr follow-up. Primary end points were the number of procedures (TURBT or biopsy/fulguration) and recurrence-free survival (RFS).

Key findings and limitations: Fewer patients in the intervention group underwent TURBT (64% vs 89%, p = 0.003), and more patients avoided procedures entirely (17% vs 0%, p = 0.002). Nonresponders shifted from TURBT to office procedures (p = 0.029). At 5 yr, RFS was 14% vs 28% (p = 0.3), with no statistically significant between-group difference (hazard ratio = 1.32, 95% confidence interval 0.86-2.01). Patients with fewer baseline tumors had better RFS (p = 0.012). Findings are limited by a few high-grade tumors at baseline.

Conclusions and clinical implications: Chemoresection reduces the need for surgical procedures in patients with recurrent NMIBC without compromising long-term oncological outcomes. These findings support its integration as a less-invasive treatment option in selected patients.

Background and objective: Urothelial bladder cancer (UBC) carries significant mortality and treatment morbidity. Conventional diagnostic and monitoring methods, including cystoscopy and biopsy, are invasive and limited in sensitivity. Circulating tumor DNA (ctDNA), a minimally-invasive "liquid biopsy," has emerged as a promising tool for real-time disease assessment. This study aimed to systematically evaluate the diagnostic, prognostic, and predictive value of plasma and urine ctDNA in localized, locally advanced, and metastatic UBC.

Methods: A systematic review was conducted according to PRISMA guidelines using PubMed, MEDLINE, and Web of Science databases (January 2016-October 2025). Eligible studies evaluated plasma and urine ctDNA. Main outcomes included diagnostic performance, correlation with tissue mutations, disease monitoring, and prognostic or predictive value. Data synthesis focused on ctDNA detection methods, timing relative to treatment, and survival outcomes. KEY FINDINGS AND LIMITATIONS: ctDNA showed strong concordance with tumor tissue mutations and high potential for real-time monitoring of tumor burden. Data are more robust in muscle-invasive bladder cancer (MIBC) than non-muscle-invasive bladder cancer (NMIBC). Postcystectomy ctDNA positivity was an independent predictor of recurrence-free, progression-free, and overall survival. ctDNA clearance correlated with response to neoadjuvant chemotherapy and immune checkpoint inhibitors. In metastatic disease, high ctDNA mutation burden was associated with shorter overall survival and resistance mechanisms, such as PIK3CA-mediated fibroblast growth factor receptor inhibitor resistance. Limitations included heterogeneous methodologies, variable assay sensitivity, and small patient cohorts.

Conclusions and clinical implications: ctDNA represents a powerful non-invasive biomarker for diagnosis, surveillance, and treatment guidance in UBC. Ongoing phase III trials (IMvigor011, TOMBOLA, MODERN) may establish its clinical utility as a standard tool for personalized disease management.

Background and objective: The aim of our study is to determine whether the addition of metformin to enzalutamide can improve the outcomes of men with metastatic castration-resistant prostate cancer (mCRPC).

Methods: From 2016 to 2021, patients with mCRPC were randomized to receive enzalutamide plus metformin or enzalutamide alone, with body mass index (BMI) as a stratification factor. Primary end point was disease-control rate (DCR) at 15 mo. Secondary end points included event-free survival (EFS), time to prostate-specific antigen progression (TTPSAP) or radiologic progression (TTRP), and overall survival (OS). Post hoc analyses include tumor phosphatase and tensin homolog (PTEN)-protein expression.

Key findings and limitations: Enzalutamide plus metformin (n = 84) did not increase DCR or secondary end points compared with enzalutamide alone (n = 82; DCR 52% vs 56%, p = 0.64). Post hoc analysis suggests that addition of metformin to enzalutamide may improve TTPSAP (p = 0.0074) in patients with PTEN-expressing tumor (n = 64), but not in patients with PTEN-negative tumor (n = 65, p > 0.6). Patients who were overweight/obese at baseline (BMI ≥25 kg/m²) had better DCR, OS, EFS, TTPSAP, and TTRP than patients with BMI <25 kg/m², independent of treatment arm (p < 0.009).

Conclusions and clinical implications: The addition of metformin to enzalutamide did not improve the study end points in the whole study cohort. PTEN status as a potential predictive biomarker and the obesity paradox warrant further investigation.

Patient summary: This study found that adding the diabetes drug metformin to standard treatment with enzalutamide did not improve outcomes in men with advanced prostate cancer. However, men whose tumors express PTEN protein seemed to benefit from metformin. Interestingly, overweight/obese men lived longer than those of normal weight.

Traditional accuracy metrics no longer suffice for comparing diagnostic pathways for prostate cancer; new comparative performance metrics are needed that prioritize the overall benefit-to-harm ratio. Key performance metrics, such as biopsy efficiency, biopsy (grade) selectivity, and biopsy avoidance safety, enable meaningful patient-level comparisons across studies. Standardized benefit-to-harm metrics reporting enhances quality assurance, informs personalized diagnostics, and supports integration into clinical guidelines to improve the safety of prostate cancer diagnosis.

Background and objective: Retinoic acid receptor-related orphan receptor gamma (RORγ) is frequently overexpressed in metastatic castration-resistant prostate cancer (mCRPC) and, together with retinoic acid-related orphan receptor gamma t (RORγt), can increase androgen receptor (AR) signalling and promote a proinflammatory tumour microenvironment.

Methods: In this phase 1 dose-finding study (NCT05124795), men with mCRPC received the oral RORγ/RORγt inverse agonist IMU-935 across three dose levels (150 mg, 300 mg, or 450 mg twice daily). The primary objective was to determine the recommended phase 2 dose according to a Bayesian optimal interval design. Key secondary endpoints included evaluation of pharmacokinetics and pharmacodynamics, as well as antitumour activity in terms of prostate-specific antigen (PSA), circulating tumour cells (CTCs), and responses according to Response Evaluation Criteria in Solid Tumours.

Key findings and limitations: Eighteen men received IMU-935. No dose-limiting toxicities (DLTs) or any grade (G) ≥3 adverse events (AEs) were reported. The most common treatment-related AEs (TRAEs) were G1 nausea (n = 4; 22%) and G1 vomiting (n = 3; 17%). The only G2 TRAEs observed were anaemia (n = 2; 11%) and gastroesophageal reflux disease (n = 1; 6%). Overall, six men (33%) had a decrease in CTC level from ≥5 to <5 cells/7.5 ml, while one participant whose tumour had mismatch repair deficiency (MMRd) experienced a ≥50% decline in PSA and radiologically stable disease for >6 mo. The median time to PSA progression was 8 wk (range 2-36 wk), and median radiological progression-free survival was 11 wk (range 3.4-36 wk).

Conclusions and clinical implications: IMU-935 was well tolerated with no DLTs. One participant with MMRd mCRPC experienced a PSA response. Overall, however, robust antitumour activity was not observed in this molecularly unselected cohort.

Background and objective: Multiparametric magnetic resonance imaging (mpMRI) with targeted biopsies improves detection of clinically significant prostate cancer (csPC), commonly defined as Gleason grade group (GG) ≥2. Current practice combines targeted and systematic biopsies, which increases csPC detection but also increases detection of insignificant PC (GG 1), which contributes to overdiagnosis. Perilesional sampling around MRI-visible lesions has been proposed as a strategy to mitigate targeting imprecision while limiting sampling outside the MRI lesion area and GG 1 detection. The primary objective is to determine the diagnostic performance of the experimental targeted + perilesional biopsy scheme for detection of csPC in comparison to the standard targeted + systematic biopsy scheme.

Clinical trial design and timeframe: TARGET is a prospective, multicentre, open-label, comparative clinical trial. Each patient acts as their own control, as each patient will undergo all three types of biopsy (targeted, perilesional, and systematic). The inclusion period will last for 21 mo, and the participation duration for each patient is 3 mo.

Endpoints: The primary endpoint is the sensitivity and specificity of the targeted + perilesional scheme for csPC detection in comparison to the targeted + systematic scheme. Secondary endpoints include differences in the detection rate for insignificant PC (GG 1) and aggressive PC (GG ≥3) between the experimental and standard biopsy schemes.

Data sources and statistical analysis plan: The data collected will include patient demographics and laboratory, radiology, and pathology reports. Analyses will be performed with SAS version 9.4 using a locked database.

Strengths and limitations: Strengths include the prospective and multicentre design. The main limitation is the open-label design.

Funding: TARGET is funded by Ramsay Générale de Santé (Paris, France), and supported by the Prostate Cancer Committee of Association Française d'Uologie.

Ethics and trial registration: The trial was assessed by the CPP Ouest VI ethics committee and is registered on ClinicalTrials.gov as NCT07296042.

Patient summary: Our multicentre trial is comparing two different approaches for prostate biopsy to determine if sampling the area around lesions seen on an MRI (magnetic resonance imaging) scan can maintain the detection rate for clinically significant prostate cancer while reducing detection of low-risk disease.

Background and objective: Up to 25% of bladder cancer cases harbour histological subtypes (HSs) distinct from conventional urothelial carcinoma (UC), often with more aggressive behaviour and variable treatment response. Accurate staging is essential, but the optimal approach for HSs remains unclear. Fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography ([¹⁸F]FDG-PET/CT) may improve staging in invasive bladder cancer (IBC), though its value in HSs is unestablished. This study evaluates the diagnostic performance and utility of [¹⁸F]FDG-PET/CT in staging HSs.

Methods: We included 112 patients with histologically confirmed IBC containing ≥75% HS content, treated at a national comprehensive cancer centre (2012-2024). An expert pathological review was performed. All patients underwent standard staging with contrast-enhanced CT (CECT) and [¹⁸F]FDG-PET/CT. The primary endpoint was visualisation of the primary tumour. The secondary endpoints included incremental diagnostic value (change in nodal or metastatic stage compared with CECT), exploratory comparison with a matched UC cohort, and pathological correlation assessment.

Key findings and limitations: The predominant HSs were neuroendocrine carcinoma (40%), squamous cell carcinoma (34%), adenocarcinoma (11%), and sarcomatoid carcinoma (11%). The primary tumour was FDG-avid in 87%, and FDG-negative in 5%. In 20%, [¹⁸F]FDG-PET/CT modified staging, mainly through upstaging. Differences in FDG avidity and staging impact across HSs and between pure (≥95%) and mixed (75-94%) content were small. A matched UC cohort showed similar rates of [¹⁸F]FDG-PET/CT-induced stage modification. Pathological confirmation was limited to a small selected subgroup, restricting the assessment of diagnostic accuracy.

Conclusions and clinical implications: The use of [¹⁸F]FDG-PET/CT demonstrated high visualisation rates for primary tumour detection and altered staging in one of five patients, supporting its consideration as a complementary modality in HS staging.