What is a Bladder Cancer Molecular Subtype?


BACKGROUND: Several molecular classification systems for bladder cancer have been proposed, but due to differences on how to define molecular subtypes, controversies and misunderstandings have arisen.

OBJECTIVE: To discuss different aspects of the molecular classification of bladder cancer and to point to the consequences of using different conceptual approaches. To question some underlying assumptions when defining molecular subtypes.

METHODS: To critically reflect on some of the principles and methods used when defining molecular subtypes.

RESULTS: Depending on underlying assumptions and aims for the definitions of subtypes, different types of molecular subtypes will be arrived at.

CONCLUSION: The underlying assumptions and their consequences must be better clarified when defining molecular subtypes.

What is a Bladder Cancer Molecular Subtype? – Counterpoint


In an accompanying paper, Mattias Höglund discusses on what is a bladder cancer molecular subtype. He emphasizes the need to consider the aim of tumor classification, which is obviously critical to the approach. He also focuses on considering primarily the identity features of the neoplastic cells. Here, we provide a counterpoint. While largely agreeing with his views, we underline that other parameters that may vary in a spatial or temporal scale, and the tumor microenvironment, can also provide relevant information to render tumor classifications clinically useful. Furthermore, tumor heterogeneity and evolution during the disease course – natural or under therapeutic pressure – should be considered.

The “Commentary” article by Mattias Höglund [1], an expert and pioneer in the field of bladder cancer molecular classification [2–4], is certainly instructive and useful. His historical perspective points to the fact that humans have long aimed at classifying “the world around them” in order to better understand it.

Many of the points he raises are important, including the clear distinction between classifications primarily oriented to clinical applications and those oriented to dissect the biology of the tumor. The former are largely based on immunohistochemistry to characterize tumor cells and the latter use so far mainly bulk whole transcriptome data to assign tumors to molecular subtypes without discriminating which cell populations express the subtype-associated gene sets. As he points out, these two types of classifications do not always match. He asserts that molecular classification should be based on the phenotype of the tumor cells themselves, and not include the microenvironment, to define “intrinsic” subtypes (based on features of the cancer cells). He also argues that the molecular classification should also not depend on “state-related” tumor cell features such as proliferation signatures because proliferation is a continuous parameter that can change across time. Similarly, he proposes to avoid the use of tumor microenvironmental features to classify tumors because the extent of intratumoral stromal/inflammatory cell infiltration can be heterogeneous and therefore subject to sampling bias, and it can also change across time and in response to therapeutic pressure. Finally, he defends the idea that classification should encompass both non-muscle-invasive (NMIBC) and muscle-invasive (MIBC) tumors.

All these points merit further thought and many of them are relevant beyond bladder cancer. However, a few of them acquire particular importance in the context of this tumor. More specifically, bladder tumors display wide inter-tumor molecular heterogeneity [5], muscle invasion has a much greater impact on patient management than in other carcinomas, and sampling bias may also be a greater problem. In addition, the impact of intra-tumor heterogeneity is starting to be unraveled [6, 7], and bladder cancer has one of the highest rates of mutations in genes coding for chromatin regulators [8] – pointing to the relevance of epigenetic analyses and “lineage plasticity” – The ongoing revolution in bladder cancer therapy demands urgently better tools for precision medicine.

We would like to discuss some of the ideas that Mattias Hoglund raises as they have important consequences for future bladder cancer research.

Commentary on Novitas LCD


The role of biomarkers (aka, markers) in detecting and managing cancer is an evolving field. It is crucial to develop biomarkers robustly that mirror drug development in the pharmaceutical industry. The goal for markers should be to provide a clear benefit in managing patients that is additive to both clinical and laboratory information. Markers should be developed in phases, with initial assay development and validation followed by clinical studies to evaluate the marker’s performance characteristics in assessing specific clinical conditions (e.g., sensitivity, specificity, predictive value) and ability to improve a clinically meaningful outcome. Ultimately, economic validation is also warranted, especially as we move forward with value-based healthcare. Trials should focus on answering specific clinical questions and thereby demonstrate the incremental value of the marker in predicting the benefit of a treatment or detection of a defined disease state. Additionally, the benefits of the marker need to be balanced by any harmful interpretation that can occur from false positive and false negative results, which could lead to patient anxiety, unnecessary costs, and as well as potentially incorrect clinical decision making predicated on test result.

Molecular Basis of Tumorigenesis of Bladder Cancer and Emerging Concepts in Developing Therapeutic Targets


BACKGROUND: Advanced urothelial carcinoma (UC) is an aggressive disease whose mutagenic processes are yet to be elucidated. Targeted therapies are urgently needed, but the road from bench to bedside is slowly progressing. In this review, we discuss urothelial carcinoma etiology, along with the most recent advances in UC candidate targeted therapies.

METHODOLOGY: A comprehensive database search was performed. We aimed to review the most recent updates on UC genomics and targeted therapies. Pre-clinical as well as clinical studies were included.

RESULTS: Our review highlights the advances in understanding the molecular basis of urothelial tumorigenesis, including smoking, chemical parasitic carcinogens, inheritance, and APOBEC3 editing enzymes. We discussed how these factors contributed to the current mutational landscape of UC. Therapeutic options for UC are still very limited. However, several promising therapeutic approaches are in development to leverage our knowledge of molecular targets, such as targeting fibroblast growth factor receptors (FGFR), DNA damage repair pathways, and HER2.

CONCLUSIONS: Blindly testing targeted therapies based on other cancer data is not sufficient. UC-specific biomarkers are needed to precisely use the appropriate drug for the appropriate population. More efforts to understand UC biology and evolution are urgently needed.

Wake-Up Call to Address Sleep Health in Non-Muscle Invasive Bladder Cancer: Underappreciated Contributor to Poor Quality of Life


BACKGROUND: Few studies have specifically examined sleep health in patients with non-muscle invasive bladder cancer (NMIBC). Further study is warranted to inform future strategies in patients with NMIBC.

OBJECTIVE: We aim to describe sleep health in a cohort of patients with NMIBC, and its relationship with quality of life (QOL).

METHODS: We conducted an observational cross-sectional study in patients undergoing surveillance for NMIBC. The validated Pittsburgh Sleep Quality Index (PSQI) was used to assess sleep health (scores from 0-21) in the overall study population as well as stratified. We assessed QOL among participants with and without poor sleep quality using the SF-12 and QLQ-NMIBC-24.

RESULTS: In a cohort of 94 NMIBC patients, median age was 67 years (IQR: 58, 72) and median time since initial diagnosis was 27 months (IQR: 9, 41). The mean PSQI score was 6.3 (SD: 3.8) and 64% percent of participants met or exceeded the PSQI cut-off score of 5, with a score of 5 or more indicating overall poor sleep quality. In those with poor sleep quality, there were statistically significant detriments in multiple QOL domains.

CONCLUSIONS: In patients undergoing surveillance for NMIBC, there is a substantial burden of sleep disturbances and resulting decrements in QOL. These data support the need for future interventions to support sleep quality and highlight the importance of addressing sleep health as part of NMIBC survivorship care to improve QOL in patients with NMIBC.

Comparative Analysis of Very Reduced vs Full Dose BCG Treatment for High-Risk Non-Muscle Invasive Bladder Cancer: A Contemporary Experience from Chile


BACKGROUND: Adjuvant bacillus Calmette-Guérin (BCG) is recommended for high-risk (HR) non-muscle invasive bladder cancer (NMIBC), but BCG shortages have led to exploration of reduced-dose regimens and shortened maintenance durations out of necessity, with limited data on treatment efficacy in Latin America.

OBJECTIVE: Oncological outcomes of HR-NMIBC patients treated with reduced (RD,1/4th dose) vs full dose (FD) BCG instillations of Danish Strain 1331 BCG.

METHODS: We performed a retrospective study of HR-NMIBC patients treated with BCG between 2003 and 2022 at our center in Santiago Chile. We stratified patients according to either RD (1/4th dose) or FD BCG. Univariate and multivariable Cox regression models were used to predict recurrence. Kaplan-Meier method was used to calculate survival estimates.

RESULTS: Of a total of 200 patients, 116 (58%) had RD and 84 (42%) FD BCG. Median follow-up was 57 months (IQR: 29–100). Patients who received FD BCG had a lower risk of recurrence (HR: 0.41, 95% CI 0.22–0.74) and high-grade (HG)-recurrence (HR: 0.30, 95% CI 0.15–0.61; p = 0.001). More patients in the RD vs FD group progressed to MIBC (10/84 vs 2/116; p = 0.18). Additionally, patients were less likely to stop BCG treatment in the RD group compared to the FD group due to toxicity (5% vs 11%, p = 0.14).

CONCLUSIONS: A 1/4th dose of Danish Strain 1331 BCG treatment was associated with worse recurrence free rate and HG-recurrence rate in our cohort. Patients with RD had lower discontinuation treatment rates due to a reduced toxicity profile. These findings would suggest that RD BCG would compromise oncological outcomes in HR-NMIBC patients.

A Procedural Checklist for Transurethral Resection of Bladder Tumors (TURBT) Enhances Operative Dictation and Assesses Surgeon Accuracy of Tumor Characteristic Predictions


BACKGROUND: A lack of standardization is pervasive in procedural application and reporting templates for TURBT with the use of a surgical checklist proposed as a means for quality improvement.

OBJECTIVE: To introduce a TURBT checklist to assess surgeon prediction accuracy and the impact of standardized documentation on quality of resection and oncologic outcomes

METHODS: Nine critical elements of a high-quality TURBT identified by literature review were incorporated into a prospectively implemented checklist for operative reports. The checklist included both visualized and predicted tumor characteristics. A retrospective single-institution analysis compared quality of dictation pre- and post-checklist implementation. Surgeon predictions were compared to final pathology reports to determine rates of concordance. Kaplan-Meier curves examined the association of checklist use with recurrence free survival (RFS).

RESULTS: 333 operative reports were included in this analysis, of which 107 (32.1%) were completed pre-checklist implementation. The average number of critical elements reported was 8.69 with checklist use compared to 4.99 without (p < 0.001). There was no significant difference in RFS between the pre- and post-checklist cohorts (log-rank test p = 0.53). Surgeons were least and most accurate in predicting low grade tumor (43.5%) and absence of muscle invasion (96.6%), respectively.

CONCLUSIONS: Incorporation of a TURBT surgical checklist improves operative dictation and quality of reporting but did not directly impact RFS. With quality of initial resection a proven correlate to recurrence rates, checklist implementation to improve surgical performance and long-term oncologic outcomes reveals an interesting area of exploration highlighting the need for more standardized methodology when performing these procedures.

Longitudinal Analysis of Bladder Cancer-Specific Mortality Trends in the United States


BACKGROUND: Bladder cancer is the tenth leading cause of cancer death in the United States (US). Advances in diagnosis, imaging, and treatments have led to improvements in bladder cancer management.

OBJECTIVE: To evaluate longitudinal bladder cancer mortality trends from 1999–2020 in the US by gender, race, ethnicity, age, geographic region, and urbanization category.

METHODS: Age-adjusted bladder cancer death and incidence rates of individuals in the US of all ages between 1999–2020 were obtained using the CDC WONDER and NAACCR databases. Trends and average annual percent changes (AAPC) in age-adjusted Bladder Cancer-Specific Mortality (BCSM) and incidence rates were estimated. Data were analyzed from May 2023 to October 2023.

RESULTS: From 1999–2020, overall BCSM decreased by 0.4% annually, with a dramatic decrease in deaths between 2015–2020 (AAPC: –2.0% [95% CI: –2.6,–1.3]). However, BCSM rates and metastatic malignant bladder cancer incidence rates from 1999–2020 increased for individuals≥85 years old (AAPC for BCSM: 0.8% [95% CI:0.5,1.1]; AAPC for metastatic malignant incidence: 2.5% [95% CI: 2.0,2.9]). Increases in BCSM were found for certain years in the South, in rural areas, and for Non-Hispanic White and Asian or Pacific Islander individuals.

CONCLUSIONS: Overall mortality from bladder cancer has been decreasing in the US over two decades. Upon disaggregation, increasing trends were found for BCSM and for metastatic malignant bladder cancer incidence for individuals≥85 years old from 1999–2020. Further evaluation of these trends is essential to understand how to target specific populations to improve patient outcomes.

No Association Between BCG Instillations and COVID-19 Incidence in a Dutch Non-Muscle Invasive Bladder Cancer Cohort


Bacillus Calmette-Guérin (BCG) is well-known for its use as vaccine against tuberculosis. BCG vaccination also induces a non-specific (heterologous) response to a wide range of (unrelated) pathogens and a reduced incidence of respiratory infections and sepsis [1]. These non-specific effects are at least in part due to the induction of trained immunity, a de-facto immunological memory of innate immune cells. Trained immunity involves the long-term epigenetic and transcriptomic reprogramming of innate immune cells which leads to a more effective response towards a second, unrelated, challenge [2]. We recently showed that repeated bladder instillations with BCG in the treatment of non-muscle invasive bladder cancer (NMIBC) induces trained immunity as well. We also observed a reduced incidence of respiratory tract infections, in particular pneumonia, in BCG-exposed versus BCG-unexposed NMIBC patients [3].

PARP Inhibitors for Metastatic Urothelial Carcinoma: A Systematic Review of Efficacy and Safety


BACKGROUND: Poly (ADP-ribose) polymerase (PARP) inhibitors have activity in various cancers. Metastatic urothelial carcinoma (MUC) is platinum sensitive and a subset harbour DNA repair gene alterations.

OBJECTIVE: To assess evidence for efficacy and safety of PARP inhibition for MUC.

METHODS: This systematic review included randomised clinical trials (RCTs) evaluating PARP inhibitors as monotherapy, or in therapeutic combinations, compared to relevant comparators or best supportive care. The primary endpoint was progression free survival (PFS). We searched MEDLINE (Ovid), EMBASE, ClinicalTrials.gov and Cochrane Central Register of Controlled Trials from March 2013 to March 2023. Each study was appraised using the Cochrane Risk of Bias 2 Tool. Study results were synthesised descriptively. Registration: PROSPERO CRD42023403145.

RESULTS: From 247 identified reports, we included three phase 2 RCTs including 252 patients. Two RCTs assessed PARP inhibition in unselected patient groups (one first line platinum ineligible, one post chemotherapy maintenance) and found no evidence of efficacy. All three RCTs assessed subgroups defined by biomarker selection for somatic DNA repair defects. Two of these identified PFS benefit with PARP inhibition compared to a relevant comparator (one first line in combination with immunotherapy, one maintenance monotherapy). Safety outcomes were consistent with prior experience of PARP inhibitors. The risk of bias across the outcomes was generally low.

CONCLUSIONS: PARP inhibitors lack efficacy for unselected MUC patients. Phase 2 RCTs support further investigation of PARP inhibition within biomarker-selected patient subsets. The optimal biomarker is not yet determined. Limitations in the current evidence relate to small sample sizes and low statistical power.