Purpose of Review
Epigenetics refers to processes that alter gene expression without altering primary DNA. Over that past decade, there is a growing focus on epigenetic mechanisms in cancer research ...and its importance in cancer biology. This review summarizes epigenetic dysregulation in bladder cancer.
Recent Findings
Epigenetic alterations are overall shared across various grades and stages of bladder cancer. High grade invasive tumors demonstrate a greater degree and intensity of methylation and may have a unique methylation pattern. Environmental exposures may influence epigenetic alterations directly independent of genomic change. Non-coding RNAs play an important role in cancer phenotype, especially in the context of integrative genomic analyses. DNA hypermethylation and non-coding RNAs have potential as robust bladder cancer biomarkers; however, they require further study and validation. Changes in chromatin and histone modification are attractive targets for therapy and are currently in clinical trials.
Summary
Epigenetic dysregulation may be an important key in improving the understanding of bladder cancer pathogenesis, especially through integrative genomic analyses. Deeper understanding of these pathways can help identify clinically relevant biomarkers and therapeutic targets to validate for diagnosis, monitoring, prognosis, and treatment for bladder cancer.
Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) targeting NECTIN4 (encoded by the
gene) approved for treatment-refractory metastatic urothelial cancer. Factors that mediate sensitivity or ...resistance to EV are unknown. In this study, we sought to (i) examine heterogeneity of
gene expression across molecular subtypes of bladder cancer and (ii) determine whether NECTIN4 expression mediates EV sensitivity or resistance.
Molecular subtyping and
expression data from seven muscle-invasive bladder cancer clinical cohorts (
= 1,915 total specimens) were used to assess
expression across molecular subtypes. The outcome of the transcriptomic analysis was relative
expression in the consensus molecular subtypes of bladder cancer. Expression of
was validated in bladder cancer cell lines. NECTIN4 was stably overexpressed or knocked down in basal and luminal bladder cancer cell lines and EV drug sensitivity assays were performed, as measured by cell proliferation and clonogenic assays.
expression is heterogenous across molecular subtypes of bladder cancer and significantly enriched in luminal subtypes.
expression is positively correlated with luminal markers
, and
across all cohorts.
expression is both necessary and sufficient for EV sensitivity in luminal and basal subtypes of urothelial bladder cancer cells. Downregulation of
leads to EV resistance.
Sensitivity to EV is mediated by expression of
, which is enriched in luminal subtypes of bladder cancer. These findings may have implications for biomarker development, patient selection, and the inclusion of molecular subtyping in ongoing and future EV clinical trials.
.
Active surveillance (AS) is an option for the initial management of early-stage prostate cancer. Current risk stratification schema identify patients with low-risk disease who are presumed to be most ...suitable for AS. However, some men with higher risk disease also elect AS; outcomes for such men have not been widely reported.
Men managed with AS at University of California, San Francisco, were classified as low- or intermediate-risk based on serum prostate-specific antigen (PSA), Gleason grade, extent of biopsy involvement, and T stage. Clinical and demographic characteristics, and progression in terms of Gleason score, PSA kinetics, and active treatment were compared between men with low- and intermediate-risk tumors.
Compared to men with low-risk tumors, those with intermediate-risk tumors were older (mean, 64.9 v 62.3 years) with higher mean PSA values (10.9 v 5.1 ng/mL), and more tumor involvement (mean, 20.4% v 15.3% positive biopsy cores; all P < .01). Within 4 years of the first positive biopsy, the clinical risk group did not differ in terms of the proportions experiencing progression-free survival, (low 54% v intermediate 61%; log-rank P = .22) or the proportions who underwent active treatment (low 30% v intermediate 35%; log-rank P = .88). Among men undergoing surgery, none were node positive and none had biochemical recurrence within 3 years.
Selected men with intermediate-risk features be appropriate candidates for AS, and are not necessarily more likely to progress. AS for these men may provide an opportunity to further reduce overtreatment of disease that is unlikely to progress to advanced cancer.
To characterize immune cell expression among patients with non-muscle invasive bladder cancer (NMIBC) treated with Bacillus Calmette-Guerin (BCG).
Patients with NMIBC treated with intravesical BCG ...(2008-2015) were identified, and a tissue microarray was constructed using paired pre- and post-BCG bladder samples. Among patients undergoing BCG, cystoscopic evaluation began 3 months after initiating BCG treatment to determine therapeutic response. IHC was performed for CD8, CD4, FoxP3, PD-L1 (SP-142 and 22C3), and PD-1. A full slide review of PD-L1
staining tumors was performed to characterize PD-L1 and CD8 colocalization. RNA-seq was performed on cored tumors from available specimens. We compared immune cell populations between BCG responders and nonresponders, and between pretreatment and postreatment tumor samples. Baseline PD-L1 staining in the BCG naïve population was then validated in a separate cohort.
The final cohort contained 63 pretreatment NMIBC cases, including 31 BCG responders and 32 BCG nonresponders. No differences in CD4, CD8, or FoxP3 expression were identified between responders and nonresponders. Baseline PD-L1 expression (22C3 and SP-142) was observed in 25% to 28% of nonresponders and 0% to 4% of responders (
< 0.01). PD-L1
cells in BCG nonresponders colocalized with CD8
T cells. In addition, BCG therapy did not increase PD-L1 gene expression (RNA-seq) or protein levels (IHC). The number of pretreatment CD4
T cells was very low among PD-L1
nonresponders (12%) and high among PD-L1
nonresponders (50%,
< 0.01). In a separate cohort of 57 patients with NMIBC undergoing BCG, baseline PD-L1 (22C3) staining was similar (26%).
One mechanism of BCG failure may be adaptive immune resistance. Baseline tumor PD-L1 expression predicts an unfavorable response to BCG and if validated, could be used to guide therapeutic decisions.
Active surveillance is now considered a viable treatment option for men with low-risk prostate cancer. However, little is known regarding changes in Gleason grade on serial biopsies over an extended ...period of time.
Men diagnosed with prostate cancer between 1998 and 2009 who elected active surveillance as initial treatment, with 6 or more months of follow-up and a minimum of six cores at biopsy, were included in analysis. Upgrading and downgrading were defined as an increase or decrease in primary or secondary Gleason score. Means and frequency tables were used to describe patient characteristics, and treatment-free survival rates were determined by life-table product limit estimates.
Three hundred seventy-seven men met inclusion criteria. Mean age at diagnosis was 61.9 years. Fifty-three percent of men had prostate-specific antigen of 6 ng/mL or less, and 94% had Gleason score of 6 or less. A majority of men were cT1 (62%), had less than 33% of biopsy cores involved (80%), and were low risk (77%) at diagnosis. Median number of cores taken at diagnostic biopsy was 13, mean time to follow-up was 18.5 months, and 29% of men had three or more repeat biopsies. Overall, 34% (129 men) were found to have an increase in Gleason grade. The majority of men who experienced an upgrade (81%) did so by their second repeat biopsy.
A proportion of men experience an upgrade in Gleason score while undergoing active surveillance. Men who experience early upgrading likely represent initial sampling error, whereas later upgrading may reflect tumor dedifferentiation.
Promotion Disparities in Academic Urology Breyer, Benjamin N.; Butler, Christi; Fang, Raymond ...
Urology (Ridgewood, N.J.),
April 2020, 2020-04-00, 20200401, Volume:
138
Journal Article
Peer reviewed
Open access
To better understand promotion timelines across gender and race/ethnicity and how academic output impacts promotion in urology.
We examined the 2017 census. An academic subset was asked questions ...regarding their promotion timeline. We obtained demographic, academic output, and family responsibility data.
Of 2926 academic urologists who identified a position of Assistant, Associate, or Full professor, 11.2% were women, 75% were White, and 94% were non-Hispanic. Men authored more papers and achieved principal investigator status more often than women. Non-Hispanics authored more papers than Hispanics. On average, women took 1.2 years longer than men to advance from Assistant to Associate Professor (7.3 years 95% CI: 6.8-7.8 vs 6.1 years, 95% CI: 5.8-6.6, P <.001). Advancement from Associate to Full Professor was similar between women and men (6.0 years 95% CI: 5.1-6.9 vs 6.6 95% CI: 6.1-7.1, P = .25). Compared to women, men were more likely to experience rapid promotion (≤4 years) to Associate Professor (odds ratio 3 95% CI: 1.8-5.1). There was no statistical difference across race/ethnicity for promotion from Assistant to Associate, Associate to Full Professor, or rapid promotion.
We identified disparities in promotion times based on gender but not race and ethnicity. The number of under-represented minority faculty in urology is low. Understanding the causes of disparities should be a priority in order to support fair promotion practices and retention of diverse faculty.
Racial disparities in guideline-based, appropriate treatment (ApT) may be a significant driving force for differences in survival for people with nonmetastatic muscle-invasive bladder cancer (MIBC). ...We hypothesize that receipt of ApT is influenced by factors such as race and socioeconomic status, irrespective of neighborhood-level differences in healthcare, variations in practice patterns, and clinical characteristics of patients with nonmetastatic MIBC.
Within the National Cancer Database, we identified individuals diagnosed with MIBC between 2004 and 2013. Multivariable logistic regression and mixed effects modelling was used to examine predictors of ApT, clustered within institutions.
A total of 51,350 individuals had clinically staged nonmetastatic, lymph node-negative MIBC. Black individuals comprised 6.4% of the cohort. Mean age was 72.6 years (SD 11.6) with a male predominance (71.4%). Less than half received ApT (42.6%). Fewer black individuals received ApT compared with white individuals (37% vs. 43%,
< 0.001). When clustered by institution, the odds of ApT were 21% lower for black individuals odds ratio (OR), 0.79; 95% confidence interval (CI), 0.73-0.87 compared with white individuals with nonmetastatic MIBC. When restricted to higher volume centers with more diverse populations, black individuals had 25% lower odds of ApT (OR, 0.75; 95% CI, 0.61-0.91;
< 0.01), compared with white counterparts.
Racial disparities in treatment persisted after accounting for various clinical factors and social determinants of health. Future efforts should focus on addressing racial bias to improve disparities in bladder cancer treatment.
If we are not delivering evidence-based care due to these biases (after accounting for access and biology), then it is expected that patients will experience inferior outcomes.
Optimizing cystectomy outcomes Porten, Sima P.; Master, Viraj A.
Cancer,
October 15, 2019, Volume:
125, Issue:
20
Journal Article
Peer reviewed
Both data analytics and patient‐centered approaches will be required to optimize outcomes after cystectomy and make meaningful changes. Advances in technology with mobile health may provide a ...platform for learning for patients and clinical utility for data‐driven feedback.
Prior studies have shown genetic similarities between upper tract and bladder urothelial carcinoma. However, upper tract urothelial carcinoma tends to be higher grade than bladder urothelial ...carcinoma and tends to form in patients with certain familial conditions (e.g. Lynch Syndrome), indicating there may be unique biologic processes in these tumors. The purpose of this study was to evaluate the differences in gene expression between upper tract and bladder urothelial carcinoma using microarray data.
A search of publicly available microarray datasets identified a clinically annotated dataset of 12 upper tract and 20 bladder urothelial carcinoma specimens. Gene expression analysis of data derived from the Affymetrix HGU133Plus2 chip was performed. Bioconductor packages were used to evaluate clustering, differential gene expression, pathways relevant to oncology, and a basal/luminal signature in upper tract versus bladder urothelial carcinoma.
When separated by pathologic T stage, there was evidence of differential clustering among pT3 tumors and significant gene expression differences in 81 genes. Pathway analysis revealed differences in HGF and TNF signaling pathways. Upper tract tumors tended to have high expression of genes associated with a luminal subtype. One of the genes most highly expressed in upper tract tumors, SLITRK6, is the target of an antibody drug conjugate (AGS15E) currently in phase I clinical trials.
This study provides evidence for molecular differences between upper tract and bladder urothelial carcinoma, some of which contribute to oncologic-relevant pathways. Upper tract tumors tended to express genes consistent with a luminal subtype. We also identify a marker, SLITRK6, as a potential target for patients with advanced upper tract urothelial carcinoma.
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