Exploring membranous NECTIN-4 expression patterns and enfortumab vedotin response in prostate cancer.

Antibody-drug conjugates (ADCs) represent a novel type of targeted cancer therapy combining the specificity of monoclonal antibodies with the cytotoxicity of conventional chemotherapy. Recently, ADCs have demonstrated practice-changing efficacy across diverse solid cancers. The anti-NECTIN-4 ADC enfortumab vedotin (EV) has just been approved for patients with urothelial cancer and is currently under investigation for patients with castration-resistant prostate cancer (CRPC e.g. Phase II ENCORE trial). Our objective was to evaluate the efficacy of EV in established prostate cancer (PCa) cell lines and to examine the membranous NECTIN-4 expression in primary tumours (PRIM) and distant metastases (MET). NECTIN-4 was heterogeneously expressed in the panel of PCa cell lines. EV led to growth inhibition in NECTIN-4 expressing PCa cells (22Rv1 and LNCaP), whereas the NECTIN-4-negative PC-3 cells were significantly less responsive to EV, emphasizing the dependence of EV response on its target expression. Immunohistochemical staining revealed moderate membranous NECTIN-4 expression only in a small subgroup of CRPC patients with lung and peritoneal MET [n = 3/22 with H-score ≥100, median H-score 140 (IQR 130-150)], while 100% of PRIM (n = 48/48) and 86.4% of common MET sites (n = 19/22), including lymph node, bone and liver MET, were NECTIN-4 negative. In summary, EV may be effective in NECTIN-4-positive PCa. However, our findings demonstrate that the tumoural NECTIN-4 expression is predominantly low in metastatic PCa, which suggests that EV may only be effective in a biomarker-stratified subgroup.

Preclinical evidence for the use of anti-Trop-2 antibody-drug conjugate Sacituzumab govitecan in cerebral metastasized castration-resistant prostate cancer.

PURPOSE: Improved survival rates have been observed in castration-resistant prostate cancer (CRPC) due to advancements in treatment options. However, individuals with brain metastases still have limited therapeutic options and an unfavorable prognosis. Therefore, there is an urgent need to explore new therapeutic avenues, such as antibody-drug conjugates (ADCs), which have demonstrated significant clinical activity against active brain metastases in solid tumors. Our objective was to determine the expression levels of the ADC targets Trop-2 and NECTIN-4 in cerebral metastasized CRPC (mCRPC). METHODS: Immunohistochemical staining of Trop-2 and NECTIN-4 with evaluation of H-score was performed in CRPC brain metastases (n = 31). Additionally, we examined Trop-2 protein expression in prostate cancer cell lines and studied their responsiveness to the anti-Trop-2 ADC Sacituzumab govitecan (SG) in vitro. RESULTS: Our analysis revealed that most patients exhibited moderate to strong Trop-2 expression [n = 27/31 with H-score ≥100, median H-score 220 (IQR 180-280)], while NECTIN-4 was absent in all cerebral metastases. Mechanistically, we demonstrated that the efficacy of SG depends on Trop-2 expression levels in vitro. Overexpression of Trop-2 in Trop-2-negative PC-3 cells led to sensitization to SG, whereas CRISPR-Cas9-mediated knockdown of Trop-2 in Trop-2-expressing DU-145 cells conferred resistance to SG. CONCLUSION: The substantial expression of Trop-2 in cerebral metastases, along with our preclinical in vitro results, supports the efficacy of SG in treating cerebral mCRPC. Thus, our results extend the understanding of the potential of ADCs in prostate cancer treatment and provide an additional treatment strategy for the challenging subset of patients with cerebral metastases.

Trophoblast cell surface antigen-2: a promising new biomarker and potential therapeutic target in penile squamous cell carcinoma.

OBJECTIVE: To evaluate the potential utility of antibody-drug conjugates targeting trophoblast cell surface antigen-2 (TROP-2) in patients with primary penile squamous cell carcinoma (PSCC), patients with recurrence (REC cohort), and patient-matched distant metastases (MET cohort), and to assess the potential use of TROP-2 as a predictive non-invasive biomarker in PSCC. METHODS: A cohort comprising a PRIM (n = 37), REC (n = 5) and MET subcohort (n = 7), with MET including lymph node and lung metastases, was analysed using quantitative real-time PCR, ELISA and immunohistochemical staining with evaluation of H-score. RESULTS: TROP-2 mRNA and serum protein levels were significantly increased in primary and recurrent PSCC compared to cancer-free controls (both P < 0.001). Immunohistochemical analysis revealed that most of the PRIM cohort (n = 34/37, median H-score 260, interquartile range [IQR] 210-300), as well as all patients in the REC (median [IQR] H-score 200 [165-290]) and MET cohorts (median [IQR] H-score 280 [260-300]) exhibited moderate to strong membranous TROP-2 expression. Additionally, The H-score (membranous TROP-2 expression) was positively correlated with TROP-2 mRNA (ρ = 0.69, P < 0.0001, R2 = 0.70) and protein levels (ρ = 0.86, P < 0.0001, R2 = 0.59), indicating its potential as a non-invasive biomarker in PSCC. CONCLUSION: In summary, our results support further studies on TROP-2 as a diagnostic and therapeutic target in primary, recurrent and metastatic PSCC.

Bellmunt risk score as a survival predictor in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: The prognosis of metastatic castration-resistant prostate cancer (mCRPC) is influenced by numerous individual factors. Despite various proposed prognostic models, the clinical application of these remains limited, probably due to complexity. Our study aimed to evaluate the predictive value of the Bellmunt risk score, which is well-known for urothelial carcinoma and easily assessed, in mCRPC patients. METHODS: The Bellmunt risk score was calculated from three risk factors (Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥1, serum hemoglobin <10 g/dL, presence of liver metastases) in 125 patients who received first-line mCRPC treatment between 2005 and 2023. In addition, a modified score was established (one point each for hemoglobin <10 g/dL and the presence of liver metastases added to the ECOG PS). Associations with overall survival (OS) under first- and second-line therapy were tested using Cox regression analyzes, log-rank tests, concordance index (C-index) and time-dependent receiver operating characteristic. RESULTS: There is a significant correlation between the level of the Bellmunt risk score and shorter OS (hazard ratio: 3.23, 95% confidence interval: 2.06-5.05; log-rank p < 0.001; C-index: 0.724). The semi-quantitative modified risk score showed even better prognostic discrimination (log-rank p < 0.001, C-index: 0.764). The score and its dynamics were also predictive in the second-line setting (log-rank p < 0.001 and = 0.01; C-index: 0.742 and 0.595). CONCLUSIONS: The Bellmunt risk score is easy to assess and provides useful prognostic information in mCRPC, and can support physicians in their treatment decisions.

Elucidating the need for prostate cancer risk calculators in conjunction with mpMRI in initial risk assessment before prostate biopsy at a tertiary prostate cancer center.

OBJECTIVE: Utilizing personalized risk assessment for clinically significant prostate cancer (csPCa) incorporating multiparametric magnetic resonance imaging (mpMRI) reduces biopsies and overdiagnosis. We validated both multi- and univariate risk models in biopsy-naïve men, with and without the inclusion of mpMRI data for csPCa detection. METHODS: N = 565 men underwent mpMRI-targeted prostate biopsy, and the diagnostic performance of risk calculators (RCs), mpMRI alone, and clinical measures were compared using receiver operating characteristic curve (ROC) analysis and decision curve analysis (DCA). Subgroups were stratified based on mpMRI findings and quality. RESULTS: csPCa was detected in 56.3%. PI-RADS score achieved the highest area under the curve (AUC) when comparing univariate risk models (AUC 0.82, p < 0.001). Multivariate RCs showed only marginal improvement in csPCa detection compared to PI-RADS score alone, with just one of four RCs showing significant superiority. In mpMRI-negative cases, the non-MRI-based RC performed best (AUC 0.80, p = 0.016), with the potential to spare biopsies for 23%. PSA-density and multivariate RCs demonstrated comparable performance for PI-RADS 3 constellation (AUC 0.65 vs. 0.60-0.65, p > 0.5; saved biopsies 16%). In men with suspicious mpMRI, both mpMRI-based RCs and the PI-RADS score predicted csPCa excellently (AUC 0.82-0.79 vs. 0.80, p > 0.05), highlighting superior performance compared to non-MRI-based models (all p < 0.002). Quality-assured imaging consistently improved csPCa risk stratification across all subgroups. CONCLUSION: In tertiary centers serving a high-risk population, high-quality mpMRI provides a simple yet effective way to assess the risk of csPCa. Using multivariate RCs reduces multiple biopsies, especially in mpMRI-negative and PI-RADS 3 constellation.

Key learnings from concordant systematic biopsies in prostate-specific membrane antigen positron emission tomography/computed tomography-guided prostate biopsies: Enhancing targeting accuracy.

BACKGROUND: Prostate cancer (PCa) diagnosis and staging have evolved with the advent of 68Ga-Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA-PET/CT). This study investigates the role of complementary systematic biopsies (SB) during PSMA-PET/CT-guided targeted prostate biopsies (PET-TB) for PCa detection, grading, and distribution. We address the uncertainty surrounding the necessity of SB in conjunction with PET-TB. METHODS: We analyzed PCa grading and distribution in 30 men who underwent PET-TB and SB because of contraindication to magnetic resonance imaging or high clinical suspicion of PCa. Tumor distribution was assessed in relation to the PET-highlighted lesions. Standardized reporting schemes, encompassing SUVmax, PRIMARY score, and miTNM classification, were evaluated. RESULTS: 80% of patients were diagnosed with PCa, with 70% classified as clinically significant (csPCa). SB detected more csPCa cases than PET-TB, but the differences were not statistically significant. Discordant results were observed in 25% of cases, where SB outperformed PET-TB. Spatial analysis revealed that tumor-bearing cores from SB were often located in close proximity to the PET-highlighted region. Reporting schemes showed potential for csPCa detection with significantly increased SUVmax in csPCA patients. Subsequent follow-up data underscored the importance of SB in precise PCa grading and staging. CONCLUSIONS: While PET-TB can simplify prostate biopsy and reduce invasiveness by core number, SB cannot be omitted yet due to potential PET-TB targeting errors. Factors such as limited spatial resolution and fusion inaccuracies contribute to the need for SB. Standardization in reporting schemes currently cannot compensate for targeting errors highlighting the need for refinement.

Ring Finger Protein 34 (RNF34) as a Prognostic Biomarker for Clear Cell Renal Cell Carcinoma.

INTRODUCTION: Ring finger proteins play pivotal roles in diverse cellular processes and are implicated in contribution to cancer. Ring finger protein 34 (RNF34) has antiapoptotic and oncogenic properties. RNF34 is upregulated during carcinogenesis and tumor progression in the colorectal adenoma-carcinoma sequence and was already described to mediate chemoresistance. In clear cell renal cell carcinoma (ccRCC), however, the role and expression patterns of RNF34 are unknown. METHODS: First, we investigated the association of RNF34 mRNA expression with clinicopathological parameters and survival using data obtained from The Cancer Genome Atlas (TCGA) ccRCC cohort (N = 533). To assess RNA34 protein expression, we performed immunohistochemical (IHC) staining of an established ccRCC cohort (University of Bonn) in a tissue microarray (TMA) format. This validation cohort contains 109 primary ccRCC samples. IHC data were associated with clinicopathological parameters and overall survival (Kaplan-Meier analysis). Adjustment for covariables was done using the Cox regression model. RESULTS: RNF34 expression is correlated with adverse clinicopathological parameters. Survival analysis revealed an association between RNF34 expression and shortened survival. Cox regression analysis confirmed RNF34 expression as an independent prognostic parameter. CONCLUSION: Our study provides evidence for RNF34 as a prognostic biomarker in ccRCC and points toward a major role of this protein in renal cell carcinoma carcinogenesis.

Delayed symptomatic renal arteriovenous fistula in a 24 years old male following renal biopsy.

We report a case of a 24-year-old male with a history of kidney biopsy at young age due to chronic renal dysfunction and challenging hypertension, who presented with flank pain and hematuria. Initial imaging suggested renal pelvis enlargement, but MRI revealed a massive renal arteriovenous malformation (AVM). Angiographic embolization was abandoned due to extensive effluent flow, followed by successful surgical resection preserving healthy kidney tissue. This case underscores the importance of considering renal AVMs in the differential diagnosis of young patients with gross hematuria or refractory hypertension to prevent complications and improve patient outcomes.