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Background: Metastatic urothelial carcinoma (mUC) has a poor prognosis, despite recent therapeutic advancements. Prostaglandin Reductase 1 (PTGR1) is essential for activating acylfulvens, a promising class of drugs for treating a subset of urothelial carcinoma (UC) patients. The efficacy of acylfulvens depends on PTGR1 activity and defects in the nucleotide excision repair (NER) pathway, notably ERCC2 mutations present in 10-15% of bladder tumors. This study identifies patients eligible to be included in acylfulven clinical trials based on the presence of PTGR-1 by immunohistochemistry (IHC) staining, RNA expression level and mutations in the NER pathway. Additionally, it evaluates PTGR-1 expression as a prognostic biomarker., Methods: Three PTGR-1 antibodies were tested in a kidney cancer cell line A498 and in tissues with known PTGR1 expression (liver, tonsils, pancreas, small intestine, etc.). Patients with untreated mUC receiving 1st line platinum from Dec. 2019 to Dec. 2021 in the Capital Region, Denmark, were included retrospectively. FFPE tumor samples were collected, and tissue microarrays (TMAs) were constructed. TMAs were stained with the best-performing PTGR1 antibody, RNA expression was analyzed using Nanostring nCounter PanCancer panel and gene mutations were assessed using a targeted genomic panel (TSO-500). Kaplan-Meier and multivariate Cox regression assessed overall survival and covariate impacts., Results: The AB181131 PTGR1 antibody was the most reliable in validation tissues. Tumors from 71 mUC patients were used to construct the TMA, and 40% of tumors scored positive for PTGR1 by IHC staining. A normalized PTGR1 RNA cutoff at 2,550 normalized counts achieved an AUC of 0.9, defining 35 samples as positive with a sensitivity of 96% and specificity of 85% in relation to IHC-positivity. Differential expression showed a significant upregulation of PTGR1 RNA in PTGR1 IHC-positive cases. NER-deficiency and PTGR1 positivity (mutations in ERCC1, ERCC2, ERCC3, ERCC4) was seen in 9 patients (13%). Median overall survival was 16 months in the cohort. Overall survival (OS) analysis indicates that overexpression of PTGR1 RNA was associated with a reduced median OS (12 months vs. 25 months, p = 0.039, log-rank)., Conclusion: PTGR1 IHC staining pattern using the Abcam AB181131 antibody is highly correlated with PTGR1 RNA expression. 13% in our cohort were identified as NER deficient and PTGR1 positive. Lower levels of PTGR1 indicates better outcome in this cohort., Competing Interests: Declarations Competing interests The authors declare no competing interests. Conflict of interest D.R.S. received educational and research funding from Pfizer and Merck Serono and served on advisory boards for Merck Sharp and Dome (MSD), Bristol Meyers Squibb (BMS), and Johnson and Johnson, unrelated to this study. S.L. No COI to report. B.G.T. Speaker fee from BMS unrelated to this study. L.H.D: No COI to report. L.C.M.: No COI to report. Z.S: Research funding from Lantern Pharma Inc; M.R: received personal fees from AstraZeneca and MSD and served on advisory board of MSD outside the submitted work.; H.P: Research funding from Pfizer and Merck unrelated to this study. K.W.M: Advisory/consulting work for EMD Serono, Pfizer, UroGen, and Riva Therapeutics; has received research support from Pfizer and Novo Ventures; has equity in Riva Therapeutics; has received writing/editor fees from UpToDate; has received speaking fees from OncLive; and is a co-inventor listed on an institutional patent application for analysis of mutational signatures of DNA repair deficiency., (© 2024. The Author(s).)

Introduction: Urothelial tract cancer (UTC) ranks as the tenth most prevalent cancer and holds the seventh position in terms of mortality worldwide. Despite its prevalence and mortality ranking, there are still gaps in the knowledge of the mutational landscape in patients with advanced disease who have limited therapeutic options after multiple lines of prior treatment. This study compares the genomic and transcriptomic landscape, and targeted treatment options between metastatic UTC (mUTC) patients treated with multiple lines of therapy compared to newly diagnosed, untreated Muscle Invasive Bladder Cancer (MIBC)., Methods: We compared genomic and clinical data from two cohorts: mUTC patients who received multiple lines of therapy and were referred to the Copenhagen Prospective Personalized Oncology (CoPPO) project at Rigshospitalet, University of Copenhagen. Data for MIBC UTC patients were acquired from the Cancer Genome Atlas Bladder Cancer (TCGA BLCA) cohort. Biopsies in CoPPO were performed at the time of enrollment. 523 highly important cancer-related genes (TrueSight Oncology-500 targeted sequencing panel) were used from both cohorts for comparative analysis. Analyses included RNA count data to compare predicted molecular subtypes in each cohort separately., Results: Patients from the CoPPO cohort had a lower median age at first-line treatment than the TCGA BLCA cohort, with no significant gender disparity. The predominant histology was urothelial cell carcinoma in both cohorts. Genomic analysis revealed no significant difference between the top mutated genes in the two cohorts, specifically looking into DNA damage repair genes. Molecular subtyping indicated a higher frequency of neuroendocrine differentiation in the CoPPO cohort. 13% of patients in the CoPPO cohort received targeted therapy based on genomic findings, and 16% received non-targeted treatment, totaling 29% receiving CoPPO treatment (9 patients). The remaining 71% received best supportive care. Kaplan-Meier analysis showed a non-significant survival benefit for the intervention group in the CoPPO cohort., Conclusion: When focusing on 523 highly relevant cancer genes, the mutational profile of mUTC patients who have undergone numerous treatment lines resembles that of newly diagnosed MIBC. These alterations can be targeted, indicating the potential advantage of early genomic testing for personalized treatment within clinical trials., (© 2024. The Author(s).)

Background: We assessed the accuracy of four estimated glomerular filtration rate (eGFR) methods: MDRD, Cockcroft-Gault, CKD-EPI, and Wright., Method: The four methods were compared to measure GFR (mGFR) in patients with urothelial urinary tract cancer (T2-T4bNxMx) receiving platinum-based chemotherapy at Rigshospitalet, Copenhagen, from January 2019 to December 2021. Using standardized assays, creatinine values were measured, and mGFR was determined using Technetium-99 m diethylenetriaminepentaacetic acid (Tc-99 m-DTPA) or Cr-51-ethylenediaminetetraacetic acid (Cr-51-EDTA) plasma clearance. Patients (n = 146) with both mGFR and corresponding creatinine values available were included (n = 345 measurements)., Results: The CKD-EPI method consistently demonstrated superior accuracy, with the lowest Total Deviation Index of 21.8% at baseline and 22.9% for all measurements compared to Wright (23.4% /24.1%), MDRD (26.2%/25.5%), and Cockcroft-Gault (25.x%/25.1%). Bland Altman Limits of agreement (LOA) ranged from - 32 ml/min (Cockcroft-Gault) to + 33 ml/min (MDRD), with CKD-EPI showing the narrowest LOA (- 27 ml/min to + 24 ml/min and lowest bias (0.3 ml/min). Establishing an eGFR threshold at 85 ml/min-considering both the lower limit of agreement (LOA) and the minimum cisplatin limit at 60 ml/min-allows for the safe omission of mGFR in 30% of patients in this cohort., Conclusion: CKD-EPI equation emerged as the most suitable for estimating kidney function in this patient group although not meeting benchmark criteria. We recommend its use for initial assessment and ongoing monitoring, and suggest mGFR for patients with a CKD-EPI estimated GFR below 85 ml/min. This approach could reduce costs and decrease laboratory time for 30% of our UC patients., (© 2024. The Author(s).)

Introduction: Many studies using Patient-reported outcomes (PRO) data have been conducted to monitor symptoms and health-related quality of life during follow-up after cancer treatment. However new ways of using (e)PROs have emerged. We aimed to explore the Danish landscape of the use of PRO in a research setting, where PRO is used actively in cancer patients undergoing treatment, and give an overview of how it is embraced by patients and clinicians., Methods and Materials: A literature search was performed in June 2023, using the keywords Denmark, cancer, and patient-reported outcomes. An expert on literature searches identified the search terms, and double screening was performed at both abstract and screening levels and full-text stage. The software tool Covidence was used., Results: 467 articles were retrieved and 19 studies were included. They described the type of ePRO instrument used and the application of active ePRO i.e. a dialogue tool in the clinical encounter, release of alerts to clinicians, and enhancement of self-management. Finally, a development in the use of active ePROs over time is elucidated and we show how it is embraced by patients and clinicians., Conclusion: This mini-review gives an overview of how ePRO solutions are tested in oncological research in Denmark and embraced by patients and clinicians. ePRO solutions in a Danish setting seem well-suited for self-management. However, if more impact is warranted, clinicians need to engage in reviewing and using ePROs. Moreover, for successful implementation, the integration of ePROs in electronic health records must be supported by IT specialists and management., (© 2023 The Authors.)

Ataxia-telangiectasia mutated (ATM) plays a central role in the cellular response to DNA damage and ATM alterations are common in several tumor types including bladder cancer. However, the specific impact of ATM alterations on therapy response in bladder cancer is uncertain. Here, we combine preclinical modeling and clinical analyses to comprehensively define the impact of ATM alterations on bladder cancer. We show that ATM loss is sufficient to increase sensitivity to DNA-damaging agents including cisplatin and radiation. Furthermore, ATM loss drives sensitivity to DNA repair-targeted agents including poly(ADP-ribose) polymerase (PARP) and Ataxia telangiectasia and Rad3 related (ATR) inhibitors. ATM loss alters the immune microenvironment and improves anti-PD1 response in preclinical bladder models but is not associated with improved anti-PD1/PD-L1 response in clinical cohorts. Last, we show that ATM expression by immunohistochemistry is strongly correlated with response to chemoradiotherapy. Together, these data define a potential role for ATM as a predictive biomarker in bladder cancer.

Due to a demonstrated lack of DNA repair deficiencies, clear cell renal cell carcinoma (ccRCC) has not benefitted from targeted synthetic lethality-based therapies. We investigated whether nucleotide excision repair (NER) deficiency is present in an identifiable subset of ccRCC cases that would render those tumors sensitive to therapy targeting this specific DNA repair pathway aberration. We used functional assays that detect UV-induced 6-4 pyrimidine-pyrimidone photoproducts to quantify NER deficiency in ccRCC cell lines. We also measured sensitivity to irofulven, an experimental cancer therapeutic agent that specifically targets cells with inactivated transcription-coupled nucleotide excision repair (TC-NER). In order to detect NER deficiency in clinical biopsies, we assessed whole exome sequencing data for the presence of an NER deficiency associated mutational signature previously identified in ERCC2 mutant bladder cancer. Functional assays showed NER deficiency in ccRCC cells. Some cell lines showed irofulven sensitivity at a concentration that is well tolerated by patients. Prostaglandin reductase 1 (PTGR1), which activates irofulven, was also associated with this sensitivity. Next generation sequencing data of the cell lines showed NER deficiency-associated mutational signatures. A significant subset of ccRCC patients had the same signature and high PTGR1 expression. ccRCC cell line-based analysis showed that NER deficiency is likely present in this cancer type. Approximately 10% of ccRCC patients in the TCGA cohort showed mutational signatures consistent with ERCC2 inactivation associated NER deficiency and also substantial levels of PTGR1 expression. These patients may be responsive to irofulven, a previously abandoned anticancer agent that has minimal activity in NER-proficient cells., (© 2023. The Author(s).)

Purpose: Head and neck cancer (HNC) patients are typically treated with radiotherapy (RT), which might lead to side effects and deterioration of quality of life (QoL). Studies in other cancers indicate that systematic use of patient-reported outcome (PRO) can be a tool to increase awareness of patients' symptoms and improve QoL. Multiple PRO questionnaires have been developed and validated for HNC, complicating the interpretation of results from scientific studies. In this exploratory study, symptom scores from four essential symptoms present in four different HNC-specific PRO questionnaires were evaluated., Methods: Four HNC-specific PRO questionnaires (EORTC QLQ-H&N35, FACT-H&N, MDASI-HN, and PRO-CTCAE) for patients undergoing radiotherapy were completed by eligible HNC patients up to ten times during and after RT. Four essential symptoms (pain, dysphagia, hoarseness, and dry mouth) were present in all questionnaires. The symptom scores for these symptoms were aligned and evaluated., Results: Twelve patients were included and completed a total of 328 PRO questionnaires out of 420. Similarity between symptom score for the four symptoms was found, when the symptom scores were aligned. The symptom scores increased during RT and decreased afterwards for all four symptoms and in all four questionnaires., Conclusion: Four HNC-specific PRO questionnaires are found similar in reflecting symptom scores over time concerning four important HNC symptoms (pain, dysphagia, hoarseness, and dry mouth). PRO can contribute with targetable information about symptoms, and PRO questionnaires might be a valuable add on to clinical practice enabling a varied picture of patients' symptoms during radiotherapy., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Checkpoint inhibitors have changed the treatment landscape of advanced urothelial carcinoma (mUC), and recently, a fibroblast-growth-factor-receptor (FGFR) inhibitor has been introduced. This study aimed at estimating programmed death-ligand 1 (PD-L1) expression in primary tumors (PTs) and the PD-L1 expression concordance between PTs and paired metastases in 100 patients with UC managed in the real-world setting. Further, the aim was to investigate FGFR1-3 aberrations and the correlation between FGFR1-3 aberrations and PD-L1 expression. PD-L1 immunohistochemistry was performed on 100 formalin-fixed paraffin-embedded archival primary UC samples and 55 matched metastases using the 22C3 PD-L1 assay. PD-L1 expression was determined by the combined positive score, considered positive at ≥10. Targeted next-generation sequencing on the S5+/Prime System with the Oncomine Comprehensive Assay version 3 was used to detect FGFR1-3 aberrations in PTs. We found that 29 of 100 PTs had positive PD-L1 expression. The PD-L1 concordance rate was 71%. FGFR1-3 aberrations were observed in 18% of PTs, most frequently FGFR3 amplifications or mutations. We found no association between FGFR1-3 aberrations and PT PD-L1 expression (p = 0.379). Our data emphasize the need for further studies in predictive biomarkers., (© 2022 The Authors. APMIS published by John Wiley & Sons Ltd on behalf of Scandinavian Societies for Medical Microbiology and Pathology.)

Background: Investigating the effect of newly approved oncological drugs in the real-world is warranted. With emerging novel treatments rapidly being approved for urothelial tract cancers, we aimed to assess real-world data, regarding effect and safety, during the first year after approval of pembrolizumab in Denmark for patients with locally advanced and unresectable or metastatic urothelial tract cancer (mUTC) in the first- and second-line setting., Materials and Method: At the six oncological departments treating mUTC in Denmark, we identified all mUTC patients receiving pembrolizumab during the first year after approval, between March 1, 2018 and February 28, 2019. A retrospective data collection was conducted from January to June 2020. Patient characteristics matching that of the relevant clinical trials for pembrolizumab in first- and second-line treatment-setting, overall survival (OS), progression-free survival (PFS), toxicity and tumor response were assessed., Results: 139 patients were identified, 53 in first-line treatment, 77 in second-line, and 9 receiving third or later lines of treatment. The population was characterized by a majority of males (70%), most patients had ECOG PS 0-1 (60.4%) and primary tumor in the bladder was predominant (90.6%). The overall response rate (ORR) in first-line was 30.2%, PFS was 3,5 months (95%CI 2,3-7,9 months) and OS 9,2 months (95%CI 7,0-20.9 months). For second-line treatment the ORR was 27,3%, PFS 2,9 months (95%CI 2,5-5,3) and OS 9.1 months (95%CI 5,4-12,8 months). Toxicity was comparable to clinical trials without any new toxicities registered., Conclusion: Real-world data on response rates, OS, PFS and toxicity for patients with mUTC receiving pembrolizumab in first- and second-line, shows comparable results to clinical trials. This study further establishes immunotherapy as an effective and tolerable treatment for mUTC., Competing Interests: H.P. has received research grants from Roche, MSD, Pfizer, and Pierre-Fabre. D.R.S has no conflict of interest to report. L.H.O has no conflict of interest to report. A.C. has no conflict of interest to report. G.A.T. has no conflict of interest to report. A.T. has no conflict of interest to report. L.H.D. has no conflict of interest to report. N.V.J. has no conflict of interest to report. A.B.A has no conflict of interest to report., (© 2021 – The authors. Published by IOS Press.)

Purpose: Poly (ADP ribose)-polymerase (PARP) inhibitors are approved for use in breast, ovarian, prostate, and pancreatic cancers, which are the solid tumor types that most frequently have alterations in key homologous recombination (HR) genes, such as BRCA1/2 . However, the frequency of HR deficiency (HRD) in other solid tumor types, including bladder cancer, is less well characterized., Experimental Design: Specific DNA aberration profiles (mutational signatures) are induced by HRD, and the presence of these "genomic scars" can be used to assess the presence or absence of HRD in a given tumor biopsy even in the absence of an observed alteration of an HR gene. Using whole-exome and whole-genome data, we measured various HRD-associated mutational signatures in bladder cancer., Results: We found that a subset of bladder tumors have evidence of HRD. In addition to a small number of tumors with biallelic BRCA1/2 events, approximately 10% of bladder tumors had significant evidence of HRD-associated mutational signatures. Increased levels of HRD signatures were associated with promoter methylation of RBBP8 , which encodes CtIP, a key protein involved in HR., Conclusions: A subset of bladder tumors have genomic features suggestive of HRD and therefore may be more likely to benefit from therapies such as platinum agents and PARP inhibitors that target tumor HRD., (©2021 American Association for Cancer Research.)

Background: Patient-reported outcome (PRO) can give information to caregivers and doctors about adverse effects and give real-world data on symptom burden for patients during treatment. We here report PROs from patients with metastatic castration resistant prostate cancer (mCRPC) receiving oncological treatment. Our findings are compared with adverse events from published findings in relevant registration studies and we discuss possible applications by looking at the level of interference with usual or daily activities., Material and Methods: An electronic PRO-Common Terminology Criteria for Adverse Events (ePRO-CTCAE) questionnaire, with 41 items corresponding to 22 symptoms/adverse events associated with the treatment regimens commonly used for mCRPC, were collected from 54 patients with mCRPC receiving medical oncological treatment. Eleven symptoms attributing interference with usual or daily living were selected and stratified by antineoplastic treatment administered. The responses were pooled and compared with data from relevant registration studies for docetaxel, cabazitaxel, radium-223 and abiraterone., Results: 168 questionnaires were completed, and among responses from patients receiving docetaxel, 89% of responses shows that fatigue interfered with their usual or daily activities to some degree and 22% to a high or very high degree. In the registration study for docetaxel fatigue is reported with 53% for all grades and 5% for grade 3 or above. For cabazitaxel, radium-223 and abiraterone the percentage of responses with interference of daily activities from fatigue range from 58% to 82%. Between four and six of the eleven chosen PRO-CTCAE symptoms are not reported in the registration studies as common side effects., Conclusion: PRO may help inform caregivers about symptoms not previously reported, interfering with usual or daily activities but also point to the use of this information to inform new patients. This may help clinicians and patients decide a treatment plan with an acceptable benefit-to-harm ratio.

Objective: This study aims to provide an overview of current treatment guidelines within the context of metastatic bladder cancer illustrated by a case report., Data Sources: International guidelines from The American Society of Clinical Oncology (ASCO), The European Society of Medical Oncology (ESMO), and scientific references supporting these clinical guidelines. To illustrate the implementation of current evidence-based guidelines a patient case report was presented., Conclusion: Historically, there have been limited treatment options available for metastatic bladder cancer for three decades. However, with the introduction of immunotherapy and emergent targeted therapies for metastatic bladder cancer increasing survival rates are expected., Implications for Nursing Practice: To achieve improved treatment outcome in people affected by metastatic bladder cancer it is important that both doctors and nurses are aware of contemporary evidence-based treatment options in keeping with ESMO and ASCO international clinical guidelines. Nurses play an important role in educating patients about the potential side effects of therapy and in offering timely, tailored, and supported self-management., (Copyright © 2020 Elsevier Inc. All rights reserved.)