Bladder Cancer Journal Vol. 7, Issue 1

Tumor Subtyping: Making Sense of Heterogeneity with a Goal Toward Treatment

ABSTRACT:

BACKGROUND: Bladder cancers have high total mutation burdens resulting in genomic diversity and intra- and inter-tumor heterogeneity that may impact the diversity of gene expression, biologic aggressiveness, and potentially response to therapy. To compare bladder cancers among patients, an organizational structure is necessary that describes the tumor at the histologic and molecular level. These “molecular subtypes”, or “expression subtypes” of bladder cancer were originally described in 2010 and continue to evolve secondary to next generation sequencing (NGS) and an increasing public repository of well-annotated cohorts.

OBJECTIVE: To review the history and methodology of expression-based subtyping of non-muscle invasive (NMIBC) and muscle invasive bladder cancer (MIBC).

METHODS: A literature review was performed of primary papers from PubMed that described subtyping methods and their descriptive feature including search terms of “subtype”, and “bladder cancer”.

RESULTS: 21 papers were identified for review. Tumor subtyping developed from N = 2 to N = 6 subtyping schemes with most subtypes comprised of at least luminal and basal tumors. Most NMIBCs are luminal cancers and luminal MIBCs may be associated with less aggressive features, while one study of basal tumors identified a better clinical outcome with systemic chemotherapy. Tumors with a P53-like may have intrinsic resistance to chemotherapy. The heterogeneity of tumors, which is likely derived from stromal components and immune cell infiltration, affect subtype calls.

CONCLUSION: Subtyping, while still evolving, is ready for testing in clinical trials. Improved patient selection with tumor subtyping may help with tumor classification and potentially match patient or tumor to therapy.

ABSTRACT:

BACKGROUND: The controlling nutritional status (CONUT) score is an objective indicator of general condition from the aspect of nutritional status, calculated from serum albumin, total cholesterol, and total lymphocyte count. The CONUT score is also considered to reflect the degree of tumor-derived chronic inflammation and the host immune status in patients with advanced cancer.

OBJECTIVE: To examine the prognostic role of the CONUT score in patients with advanced urothelial carcinoma (aUC) treated with first-line platinum-based chemotherapy.

METHODS: Associations of the CONUT score with clinical parameters and overall survival (OS) were investigated retrospectively in 147 patients with aUC receiving first-line platinum-based chemotherapy at a single cancer center from February 2003 to April 2019.

RESULTS: The median (range) CONUT score was 1 (0–7). A higher CONUT score was associated with lower hemoglobin (P < 0.001) and higher C-reactive protein levels (P = 0.023) but not with chemotherapy response (P = 0.432). The median OS for patients with CONUT scores 0–1, 2–3, and ≥4 were 23.3, 14.9, and 9.4 months, respectively (P < 0.001). In the multivariable analysis, a higher CONUT score was independently associated with shorter OS (scores 2–3 vs 0–1, HR 1.58, P = 0.048; scores ≥4 vs 0–1, HR 2.63, P = 0.008) along with poorer performance status (HR 4.79, P < 0.001), primary tumor site of the upper urinary tract (HR 1.70, P = 0.016), higher LDH (HR 3.85, P = 0.036), higher alkaline phosphatase (HR 3.06, P = 0.028), and non-responders to chemotherapy (HR 2.07, P < 0.001).

CONCLUSIONS: The CONUT score is a prognostic biomarker in patients with aUC receiving first-line platinum-based chemotherapy.

Survival by T-Stage for Patients with Localized Bladder Cancer: Implications for Future Screening Trials

ABSTRACT: 

BACKGROUND: There is insufficient data to recommend screening for bladder cancer (BC). For future BC screening trials, it is important to understand how and if tumor (T) stage can act as a surrogate outcome marker for overall (OS) and cancer-specific (CSS) survival.

OBJECTIVE: To characterize OS and CSS between primary tumor (T) stages in non-metastatic bladder cancer (BC) patients.

METHODS: Non-metastatic BC patients were identified in the National Cancer Database (NCDB; 2004-2015) (n = 343,163) and National Cancer Institute Surveillance, Epidemiology, and End Results database (SEER) (n = 130,751). Cox multivariable regression compared relationships between T stage (LGTa, HGTa, Tis, LGT1, HGT1, T2-T4) and OS or CSS for all patients and sub-cohorts.

RESULTS: Compared to stage LGTa as a reference, overall (SEER; NCDB) and cancer-specific (SEER) survival significantly declined with increasing T stage. Using SEER, OS ranged from HGTa (HR 1.16, CI 1.13–1.21, p < 0.001) to T4 (HR 5.70, CI 5.41–6.00, p < 0.001) with a steep inflection between HGT1 (HR 1.68, CI 1.63–1.73, p < 0.001) and T2 (HR 3.39, CI 3.30–3.49, p < 0.001), which was verified with NCDB. The association of stage and CSS was even more pronounced: HGTa (84% 10 year-CSS, HR 1.94, CI 1.81–2.08, p < 0.001), Tis (82% 10 year-CSS, HR 2.28, CI 2.09–2.47, p < 0.001), LGT1 (84% 10 year-CSS, HR 2.30, CI 2.11–2.51, p < 0.001), HGT1 (72% 10 year-CSS, HR 4.24, CI 4.01–4.47, p < 0.001), T2 (48% 10 year-CSS, HR 12.18, CI 11.57–12.82, p < 0.001), T3 (45% 10 year-CSS, HR 14.60, CI 13.63–15.64, p < 0.001), and T4 (29% 10 year-CSS, HR 22.76, CI 21.19–24.44, p < 0.001).

CONCLUSIONS: Earlier T stage at diagnosis was associated with better OS largely due to differences in CSS. A clinically significant difference between Stage I and Stage II was verified herein in multiple cohorts. Therefore, earlier stage at diagnosis, specifically preventing muscle invasive BC, could potentially improve survival.

Early Bone Metastases are Associated with Worse Outcomes in Metastatic Urothelial Carcinoma

ABSTRACT

BACKGROUND: Outcomes of patients with metastatic urothelial carcinoma (mUC) with early bone metastases (eBM) vs no early bone metastases (nBM) have not thoroughly been described in the age of immuno-oncology.

OBJECTIVE: To compare survival and other clinical outcomes in patients with eBM and nBM.

METHODS: We used a multi-institutional database of patients with mUC treated with systemic therapy. Demographic, metastatic site, treatment patterns, and clinical outcomes were recorded. Wilcoxon rank-sum, chi-square tests were performed. Survival was estimated by Kaplan-Meier method; multivariable Cox analysis was performed.

RESULTS: We identified 270 pts, 67% men, mean age 69±11 years. At metastatic diagnosis, 27% had≥1 eBM and were more likely to have de novo vs. recurrent metastases (42% vs 19%, p < 0.001). Patients with eBM had shorter overall survival (OS) vs. those with nBM, (6.1 vs 13.7 months, p < 0.0001). On multivariable analysis, eBM independently associated with higher risk of death, HR = 2.52 (95% CI: 1.75–3.63, p < 0.0001). OS was shorter for patients with eBM who received initial immune checkpoint inhibitor vs platinum-based chemotherapy, (1.6 vs 9.1 months, p = 0.02). Patients with eBM received higher opioid analgesic doses compared to patients with nBM and received quantitatively more palliative radiation.

CONCLUSIONS: Patients with mUC and eBM have poorer outcomes, may benefit less from anti-PD-1/PD-L1 therapy and represent an unmet need for novel therapeutic interventions. Dedicated clinical trials, biomarker validation to assist in patient selection, as well as consensus on reporting of non-measurable disease are required.

Well-being and Perceptions of Supportive Resources among Caregivers of Patients with Bladder Cancer

ABSTRACT: 

BACKGROUND: The unique burden of treatment and survivorship of patients with bladder cancer can negatively impact caregiver experience and their use of supportive care resources.

OBJECTIVE: To assess caregivers’ well-being and their perception of potential supportive resources.

METHODS: In this cross-sectional survey, caregivers of patients with bladder cancer (N = 630) were recruited through the nationwide Bladder Cancer Advocacy Network Patient Survey Network. We used stakeholder-developed questionnaires to examine caregiver well-being (i.e., physical well-being, tiredness, fear, worry, sadness), the perceived helpfulness of potential resources (i.e., web-based and print-based information, specialized support, personal stories of other caregivers, phone-call and online chat with other caregivers), and influencing factors.

RESULTS: Caregivers more frequently reported emotional well-being as a moderate to serious problem (67% for fear, 78% for worry, 66% for sadness) compared with physical well-being (30%) and tiredness (47%). Decreased well-being was associated with female gender of the caregiver, higher than high school education, or caring for a patient with advanced (versus non-invasive) bladder cancer. Of six potential resources, “web-based information” was perceived as “very helpful” among 79% of respondents, followed by “personal stories from other caregivers” (62%). Caregiver preferences for “web-based information” was not associated with any specific demographic or clinical factors.

CONCLUSIONS: Caregivers reported moderate to serious problems with emotional and physical well-being. Web-based platforms were perceived as beneficial supportive resources for bladder cancer caregivers. Future intervention research should target the influencing factors identified in this study to optimize the health outcomes of caregivers and enhance the supportive care resources for improving their well-being.

Evaluating Patient-Defined Priorities for Female Patients with Bladder Cancer

ABSTRACT:

BACKGROUND: Although bladder cancer is much more common in men than in women, female patients with bladder cancer present with more locally advanced tumors and have worse disease-specific outcomes than male patients, even after controlling for biological differences. There is a paucity of research regarding the optimal approach to caring for female patients with bladder cancer in ways that maximize patient satisfaction, preferences, and values.

OBJECTIVE: We sought to explore patient-defined priorities and areas in need of improvement for female patients with bladder cancer from the patient perspective.

METHODS: We conducted focus group sessions and semi-structured interviews of women treated for bladder cancer to identify patient priorities and concerns until reaching topic saturation. Transcripts were analyzed thematically.

RESULTS: Eight patients with muscle-invasive bladder cancer and six patients with non-muscle-invasive bladder cancer participated in two focus groups and seven interviews total. Three themes emerged as significantly affecting the care experience: physical impacts, mental health and emotional wellbeing, and the patient-provider interaction. Each theme included patient-defined specific recommendations on approaches to optimizing the care experience for women with bladder cancer.

CONCLUSIONS: Although most participants were satisfied with the quality of care they received, they identified several opportunities for improvement. These concerns centered around enhancing support for patients’ physical and mental needs and strengthening the patient-provider interaction. Efforts to address these needs and reduce gender disparate outcomes via quality improvement initiatives are ongoing.

Comparison of Heath-Related Quality of Life Between Japanese and American Patients with Bladder Cancer as Measured by a Newly Developed Japanese Version of the Bladder Cancer Index

ABSTRACT: 

INTRODUCTION: The aim of this study is to characterize health related quality of life (HRQOL) in Japanese patients after bladder cancer surgery and to perform cross-cultural comparison between Japanese and American patients.

METHODS:

Firstly, we cross-sectionally assessed HRQOL of 371 patients in Japan using the Bladder Cancer Index (BCI-Japanese). HRQOL of the four groups of patients (native bladder without intravesical therapy, native bladder with intravesical therapy, cystectomy with ileal conduit, and cystectomy with neobladder) were assessed. Secondly, we compared the Japanese with the American cohort (n = 315) from the original BCI paper. After adjusting for age and gender, the differences in each BCI subdomain score was analyzed.

RESULTS: Among Japanese patients, the urinary domain function score was significantly lower among the cystectomy with neobladder group, compared to the cystectomy with ileal conduit group (p < 0. 01). Despite this, the urinary bother was comparable between the two groups. Although there were apparent differences between Japanese and American patients, there were few differences in Urinary and Bowel HRQOL. In three of the four treatment groups (other than native bladder with intravesical therapy), Japanese patients were more likely than Americans to report poor sexual function (p < 0.05). However, Japanese patients were less likely than Americans to be bothered by their lower sexual function, regardless of treatment (p < 0.05).

CONCLUSIONS: HRQOL outcomes following treatment of bladder cancer in Japan are comparable to those in the USA, except for sexual functioning and sexual bother. The BCI can be used for cross-cultural assessments of HRQOL in bladder cancer patients.

Prognostic Role of mRNA-Expression of Aquaporins (AQP) 3, 4, 7 and 9 in Stage pT1 Non-Muscle-Invasive Bladder Cancer

ABSTRACT: 

BACKGROUND: AQP proteins show a variety of functions in human cell metabolism. The role of different AQP subtypes in tumor metabolism and prognosis are subject of ongoing research.

OBJECTIVE: To investigate the mRNA expression of Aquaporin (AQP) 3, 4, 7 and 9 in pT1 non-muscle-invasive bladder cancer (NMIBC) and its prognostic value in therapeutic decision making.

METHODS: Formalin-fixed-paraffin-embedded (FFPE) tissues from transurethral resection of the bladder (TURB) from 112 patients with initial diagnosis of stage pT1 NMIBC were analyzed retrospectively together with clinical data and therapeutic approaches. mRNA expression of AQP3, 4, 7 and 9 was measured and quantified using RT-qPCR.

RESULTS: Of the 112 patients (83.9%male, median age 72 years), 40 had a recurrence (35.7%), 16 a progression (14.3%) and 14 patients (12.5%) died tumor-related. mRNA expression for AQP3 was detected in 99.1%, AQP4 in 46.4%, AQP7 in 86.6%and AQP9 in 97.3%. Spearman analysis revealed statistically significant correlations between AQP3, AQP7 and AQP9 mRNA expression with adverse clinical and histopathological parameters (WHO1973 grade 3, concomitant Cis or multifocality). High AQP9 mRNA expression was associated with worse PFS in the total cohort (p = 0.034) and in Grade 3 tumors (p = 0.003) in Kaplan-Meier analysis. In patients with bladder sparing approach, high AQP3 mRNA expression was significantly associated with worse CSS in patients receiving BCG therapy (p = 0.029).

CONCLUSIONS: mRNA expression of AQP3, 7 and 9 correlates with adverse clinical and pathological parameters. AQP3 and 9 may help to identify a subgroup of highest risk patients who may be considered for early cystectomy.

Surface Labeling with Adhesion Protein FimH Improves Binding of Immunotherapeutic Agent Salmonella Ty21a to the Bladder Epithelium

ABSTRACT:

BACKGROUND: Bladder cancer is the ninth most common cancer in men. 70% of these tumors are classified as non-muscle invasive bladder cancer and those patients receive 6 intravesical instillations with Mycobacterium bovis BCG after transurethral resection. However, 30% of patients show recurrences after treatment and experience severe side effects that often lead to therapy discontinuation. Recently, another vaccine strain, Salmonella enterica typhi Ty21a, demonstrated promising antitumor activity in vivo. Here we focus on increasing bacterial retention in the bladder in order to reduce the number of instillations required and improve antitumor activity.

OBJECTIVE: To increase the binding of Ty21a to the bladder wall by surface labeling of the bacteria with adhesion protein FimH and to study its effect in a bladder cancer mouse model.

METHODS: Binding of Ty21a with surface-labeled FimH to the bladder wall was analyzed in vitro and in vivo. The antitumor effect of a single instillation of Ty21a+FimH in treatment was determined in a survival experiment.

RESULTS: FimH-labeled Ty21a showed significant (p < 0.0001) improved binding to mouse and human cell lines in vitro. Furthermore, FimH labeled bacteria showed ∼5x more binding to the bladder than controls in vivo. Enhanced binding to the bladder via FimH labeling induced a modest improvement in median but not in overall mice survival.

CONCLUSIONS: FimH labeling of Ty21a significantly improved binding to bladder tumor cells in vitro and the bladder wall in vivo. The improved binding leads to a modest increase in median survival in a single bladder cancer mouse study.

Bladder Cancer Health Literacy: Assessing Readability of Online Patient Education Materials

ABSTRACT

BACKGROUND: Understanding of health-related materials, termed health literacy, affects decision makings and outcomes in the treatment of bladder cancer. The National Institutes of Health recommend writing education materials at a sixth-seventh grade reading level. The goal of this study is to assess readability of bladder cancer materials available online.

OBJECTIVE: The goal of this study is to characterize available information about bladder cancer online and evaluate readability.

METHODS: Materials on bladder cancer were collected from the American Urological Association’s Urology Care Foundation (AUA-UCF) and compared to top 50 websites by search engine results. Resources were analyzed using four different validated readability assessment scales. The mean and standard deviation of the materials was calculated, and a two-tailed t test for used to assess for significance between the two sets of patient education materials.

RESULTS: The average readability of AUA materials was 8.5 (8th–9th grade reading level). For the top 50 websites, average readability was 11.7 (11–12th grade reading level). A two-tailed t test between the AUA and top 50 websites demonstrated statistical significance between the readability of the two sets of resources (P = 0.0001), with the top search engine results being several grade levels higher than the recommended 6–7th grade reading level.

CONCLUSIONS: Most health information provided by the AUA on bladder cancer is written at a reading ability that aligns with most US adults, with top websites for search engine results exceeding the average reading level by several grade levels. By focusing on health literacy, urologists may contribute lowering barriers to health literacy, improving health care expenditure and perioperative complications.

Challenging Cases in Urothelial Cancer: Case 19

Clinical Trials Corner Issue 7(1)

ABSTRACT: 

In this issue, we highlight several clinical trials for various stages of localized bladder cancer. These trials are currently actively recruiting and we hope to draw your attention to these trials in an effort to encourage accrual as they answer interesting clinical questions and hopefully can advanced our understanding of bladder cancer and improve upon current treatments for patients.