(UroToday.com) Cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy is recommended for patients with muscle-invasive bladder cancer (MIBC). A pathologic response (ypT0/Tis/Ta/T1N0) after NAC has been associated with improved long-term survival. However, clinicians are unable to predict which patients will have a pathologic response. Somatic deleterious mutations in ERCC2, gain-of-function mutations in ERBB2, and alterations in ATM, RB1, and/or FANCC have been shown previously to correlate with pathologic response after NAC in MIBC. However, none of these biomarkers have been validated in larger independent cohorts and are consequently not used in clinical practice. The objective of this study was to validate these genomic biomarkers in an independent retrospective cohort of 165 MIBC patients who had undergone NAC and radical cystectomy.
(UroToday.com) Fibroblast activation protein-α (FAP) is a transmembrane peptidase and a surrogate marker for cancer-associated fibroblasts (CAFs). FAP has been linked to worse prognosis and therapy resistance in several cancers. They hypothesised that FAP might have a prognostic biomarker potential to stratify patients with high-grade (HG) T1 non-muscle invasive bladder cancer (NMIBC).
(UroToday.com) In one of the Industry Meets IBCN sessions, Janssen presented the history and scientific rationale behind the trials designed for TAR200 and TAR210. TAR-200 is an innovative drug delivery system enabling sustained local drug delivery within the bladder. The TAR-200 platform is a bi-oval shaped, dual lumen silicone tube that allows for sustained rug delivery into the bladder over an extended period without any appreciable systemic exposure or associated AEs. This delivery mechanism has been tested previously through a rapid, in-office procedure using an urinary catheter-like inserter. Once released into the bladder, it curls into the a pretzel shape and dwells within the bladder without causing untoward side-effects or sensations. A proof-of-principle phase 1 trial - TAR-200-101 (NCT02722538) – demonstrated safety and tolerability in patients with cT2a-3b N0-1 M0 urothelial carcinoma, who refused or were ineligible to receive cisplatin-based combination chemotherapy. In 4/20 experienced a complete pathologic response at the time of radical cystectomy, while 10/20 experienced downstaging. 1 In another study using TAR-200 in MIBC patients refusing radical cystectomy (TAR-200-103), PFS following TAR-200 delivery at 12mo was 67.7% and median OS was 20.1 months.
(UroToday.com) The mortality among men due to bladder cancer is approximately twice as high in Poland as in other European countries. Bladder cancer is a result of multistep accumulation of genetic and epigenetic alterations and exposure to environmental factors. Aberrant methylation of CpG islands has been recognized as a potential early biomarker of carcinogenesis. Additionally, these changes affect tumor stage and grade, which may have an impact on the choice of the right treatment method.
(UroToday.com) Muscle-invasive urothelial carcinoma (MIBC) is treated with cisplatin-based chemotherapy even though it is only moderately efficient in many patients due to tumor heterogeneity and development of cisplatin resistance. To provide urothelial carcinoma (UC) patients with more personalized and efficient therapeutic options molecular biomarkers for predicting chemotherapy response are needed. They report a mass spectrometry proteomics analysis of cisplatin resistant UC cell lines (UCC) compared to naïve controls and tissue microarray analysis of identified biomarker candidates.
(UroToday.com) BTA stat®, Alere NMP22® BladderChek®, and UBC® rapid test are urine based rapid tests for the presence of urinary bladder cancer (BC). uromonitor® is a urine based test measuring FGFR3, KRAS, and TERT mutation. This multicentre study is the first to compare the performance of all available rapid tests with urine cytology.
(UroToday.com) Non-muscle-invasive bladder cancer (NMIBC) constitutes the majority of newly diagnosed bladder tumours. Scheduled frequent surveillance is indicated for NMIBC patients because of high recurrence rate and to avoid progression to muscle invasive disease. The gold standard for surveillance is flexible cystoscopy (FC). However, FC is invasive, expensive, and not always sensitive enough. The Xpert® Bladder Cancer Monitor (XBCM) is a urinary biomarker that has shown promising results as a safe replacement for FC. A previous study has shown a sensitivity of 83.3%, specificity of 75.8%, negative predictive value of 97.6%, and positive predictive value of 27.8% for high-grade NMIBC specifically. However, high-level evidence from randomised clinical trials is lacking before implementation of urinary biomarkers can be considered.
(UroToday.com) Prior randomized controlled trials comparing bladder preservation to radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC) closed due to lack of accrual. None are foreseen in the near future. Thus, we aimed to compare trimodality therapy (TMT, maximal transurethral resection of bladder tumor followed by concurrent chemoradiation) to radical cystectomy (RC) in matched cohorts of patients with MIBC.
(UroToday.com) Patients (pts) with locoregional advanced urothelial cancer (n=54) were preoperatively treated with ipilimumab (ipi) plus nivolumab (nivo) using different dosing regimens. Pts in cohort 1 and 2A were treated with ipi 3 mg/kg (ipi-high) and pts in cohort 2B were treated with ipi 1 mg/kg (ipi-low). A response, defined as ypT0/Tis/Ta/T1N0 for biomarker purposes, was achieved in 22/38 (58%) pts in the ipi-high cohorts and in 4/14 (29%) pts in the ipi-low cohort. They presented updated follow-up data and an exploratory biomarker analysis to better understand the difference between ipi-low and ipi-high. Using a multiplex PCR-based NGS assay (RaDaR), they aimed to confirm pre-operative plasma ctDNA detection to predict response in cohort 2.
(UroToday.com) Neoadjuvant/induction chemotherapy (NAIC) improves survival in patients with muscle-invasive bladder carcinoma (MIBC). On-treatment response assessment aims to detect chemo-(in)sensitive tumors to continue or cease NAIC. They investigated whether FDG-PET/CT could predict response to NAIC and compared to contrast-enhanced CT.
(UroToday.com) The most common sites for urothelial cancer (UC) dissemination are local recurrence (after curative treatment), lymph-nodes, lung, liver, and bone. Molecular subtypes in UC show profound differences in tumor biology, reflected by distinct genomic alterations and gene expression signatures, and are associated with different T-stage distributions and chemotherapy responses. To our knowledge, no studies have systematically investigated the association between molecular subtypes and metastatic sites in UC.
(UroToday.com) Single cell technology now makes it possible to study tumor ecosystems at single cell resolution and may improve our biological understanding of disease aggressiveness and tumor heterogeneity. Single nucleus RNA-sequencing (snRNA-seq) allows profiling of single nuclei isolated from frozen tumor tissue from patients with long term follow-up.
(UroToday.com) Urothelial carcinoma occurs throughout the urinary tract. The predominance of urothelial carcinoma of the bladder (UCB) has limited study of upper tract urothelial carcinoma (UTUC). UTUC is a rare disease with worse outcomes than UCB despite their high commonality in risk factors, mutational profiles and molecular subtypes. Whilst histologically-normal urothelium from bladder and upper tract tissues appears highly convergent, they investigated the underlying genomic architecture and transcriptomic networks to identify features that explain divergent UTUC/UCB progression.
(UroToday.com) Although targeted approaches have become available in second and third line settings, platinum-based chemotherapy remains the standard first-line treatment for advanced muscle-invasive bladder cancer (MIBC). Therefore, the prediction of platinum resistance is of utmost clinical importance. In this study, they established a routine compatible method for the molecular classification of MIBC samples according to the most relevant classifiers and applied this method to evaluate the impact of subtypes on survival after adjuvant chemotherapy.
(UroToday.com) The estimated hereditary component of urinary bladder cancer (UBC) is estimated to be up to 30%. Still, familial clustering is limited and high penetrant germline gene variants are predominantly found in cancer syndromes that present with a broader cancer spectrum.
(UroToday.com) The session started with an overview of Photocure from an organization's mission, vision, and values to optimize bladder cancer care. The Bladder Cancer Company has become evolved from many years of multiorgan and disease state enhanced detection and treatment of cancers using photodynamic therapy. Specific to bladder cancer, blue light cystoscopy (BLC) in the US has garnished increased use with prior evidence including level one to support decreased recurrence rates of non-muscle-invasive bladder cancer (NMIBC) when compared with conventional white light cystoscopy (WLC).
(UroToday.com) Bladder Cancer is the 6th most common type of cancer in the United States and is estimated that there will be 81,180 new cases with approximately 17,100 dying of this disease in 2022.1 Of newly diagnosed bladder cancer cases, approximately 75% are non-muscle-invasive bladder cancer (NMIBC).1 Racial disparity have been previously described with Blacks noted to have worse bladder cancer-specific survival and are associated with up to a 2-fold increase of bladder cancer-specific death when compared to Whites.2-6 Against this backdrop, and as new technologies emerge to diagnose and treat bladder cancer, it is critical to understand implementation taking into account disparities in treatments and outcomes.
Session Title: Cell-free DNA, Circulating Tumor Cells, Exosomes, and Bladder Cancer
(UroToday.com) Day 2 of the 8th Annual Leo & Anne Albert Institute for Bladder Cancer Care and Research (AIBCCR) Symposium was chaired by Dr Bishoy Faltas (Weill Cornell Medicine) who started the session with his talk on serial cell tumor DNA (ctDNA) analysis for evolution-directed therapy in patients with urothelial carcinoma. ctDNA represents a subset of cell-free DNA (sfDNA), where tumor DNA from cancer cells are shed in the blood stream. Given that urothelial cancer has a high tumor mutational burden (TMB), this allows for identification of ctDNA in the blood which provides a ‘window’ to mutations present in the primary tumor. The advantage of ctDNA allows for serial liquid biopsies to map evolutionally trajectories in patients with advanced bladder cancer.
Dr Faltas presented published data from his group based on 183 serial ctNDA samples from 53 patients with advanced urothelial carcinoma analyzed with the GUARDANT360 targeted sequencing panel. 1 He reported that p53 and PIK3CA mutations were identified in 50% and 19% of patients respectively with FGFR3 mutations found in 10 patients. ctDNA improved clinical prognostic models (c-statistic from 0.65 to 0.84) with serial sampling further improving these models compared to baseline ctDNA alone. The key benefit of cfDNA is the ability to dynamically track clonal cell evolution. Analysis of this patient cohort suggested that cfDNA has prognostic value and can predict oncological outcomes. Patients who were ctDNA positive prior to treatment and subsequently became ctDNA negative post treatment had a significantly lower risk of death independent to confounding factors suggesting that molecular remission predicts durable response to treatment. ctDNA was also showed to be highly correlated with radiological progression of disease. He concluded this talk with his vision of evolution-directed therapy, where tumor biopsy and liquid biopsies will undergo molecular profiling to allow for treatment selection and serial analysis of liquid biopsies would allow the prediction of tumor genomic evolution with the opportunity to intervene with therapeutics. 2
Vision of evolution-directed therapy 2
The second talk was delivered by Dr Petros Grivas (Fred Hutchinson Cancer Center) which was on the potential opportunities for screening, surveillance, monitoring and therapeutic guidance utilizing ctDNA in urothelial carcinoma. He started his talk by highlighting the relationship between cancer proliferation burden and ctDNA which can eb highly variable. Highly sensitive assays are crucial for the detection of somatic alterations in cfDNA because ctDNA only represents 0.1% of sfDNA which can limit of detection ability of assays. He highlighted important considerations in the application of ctNDA: 1) the different roles of liquid biopsies such as cancer detection (diagnostic, screening) versus genomic characterization (prognostic, predictive, therapeutic response, resistance monitoring), 2) assay characteristics (depth and breadth of sequencing, bioinformatics, large versus small panel assay and tissue specific versus agnostic assays) and 3) the different endpoints used in studies.
Dr Grivas highlighted a report which used a patient specific tumor 16-plex PCR amplicon test (Singnatera) to interrogate longitudinal ctDNA samples in patients with advanced bladder cancer. 3 Patients who were ctDNA positive prior to neoadjuvant chemotherapy and radical cystectomy as well as following radical cystectomy had a much higher risk of disease recurrence compared with patients with ctDNA negative. Similar findings were reported in patients treated with neoadjuvant immunotherapy in the single arm ABACUS trial. 4 ctDNA also had an average positive lead time of 3 months ahead of radiological identification of clinical recurrence. 3 However, it remains uncertain if earlier identification of disease recurrence would change cancer specific survival.
Translational endpoints from clinical trials may provide important data. In the INVIGOR 010, a randomized phase III trial of adjuvant atezolizumab versus observation in operable urothelial cancer, patients who were ctDNA positive had worse survival outcome (HR: 6.3, 95% CI: 4.45-8.92), but this same patient cohort had an improved disease-free survival (HR: 0.58, 95% CI: 0.43-0.79) and overall survival (HR: 0.59, 95% CI: 0.41-0.86) in the atezolizumab versus observational arm. 5 Dr Grivas concluded that ctDNA requires further validation work and well design trails with proven clinical utility is crucial before clinical adoption.
Negative ctDNA patients have better DFS and OS. In patients with positive ctDNA, treatment with atezolizumab resulted in better DFS and OS compared to observation 5
The next talk was on the utilization of extracellular vesicles (EV) as a diagnostic and therapeutic nanotool in bladder cancer delivered by Dr Yi-Fin Lee (University of Rochester Medical Center). She introduced the role of EV as an important regulator of intracellular communication. These lipid bilayer nanoparticles (30-250nm) are naturally released from all animal cells and transport protein, nucleic acid, lipids and metabolites. Cancer cells release more EV which is implicated in all cancer stages. EV may function in immune response modulation, biomarkers and vehicle for drug delivery. In bladder cancer, Dr Lee’s group has shown that EV can drive tumorigenesis by inducing unfolding of protein response in the endoplastic reticulum of non-cancer cells. 6 . Utilizing protein disulfide isomerase (PDI) as an example, she described how unfolded protein accumulates within the cancer cell resulting in endoplastic reticulum stress and unfolding of protein response. This results in the oxidized PDI which is packed into EV and released from the cancer cell. These EV are then endocytosed in normal cells and hydrogen peroxide is then released leading to DNA damage and malignant transformation. As a biomarker, her group has also reported that EV can modulate response to BCG therapy in bladder cancer, allowing for early identification of metastatic disease and disease recurrence. 7 She concludes that EV is an area of active research due to its physiological and pathological role in cancer and prognostic biomarkers to therapy although challenges exist in purification and characterization of EV as well as further validation studies.The final talk was delivered by Dr Steve Soper (University of Kansas) on the opportunities and challenges on liquid biopsies for cancer. He started his talk by highlighting difference in substrate concentration in circulating tumor cells (CTC) (6-600 pg of gDNA/ml), cfDNA (2.8 molecules/ ml) and exosomes (30 molecules/ml). CTC are dynamic due to upregulation and downregulation in EMT genes. Key limitations are the ability to detect the ‘needle in the haystack’. His team developed the BioFluidica, LiquidScan, a fully automated platform with allows interrogation of CTC, cfDNA and EVs which represents an growing area of research. 8
Presented by: Dr Bishoy Faltas, MD, Director, Bladder Cancer Research, Englander Institute of Precision Medicine, Weill Cornell Medicine; Dr Petros Grivas, MD, PhD, Professor of Medical Oncology, Fred Hutchinson Cancer Center; Dr Yi-Fin Lee, PhD, Professor of Urology, Pathology and Laboratory Medicine, University of Rochester Medical Center; Dr Steve Soper, PhD, Professor Chemistry and Mechanical Engineering, University of Kansas.
Written by: Wei Shen Tan MBBCh, PhD, FRCS (Urol), Urologic Oncology Fellow, Department of Urology, MD Anderson Cancer Center, Twitter: @drtanws during the 2022 8th Annual Leo & Anne Albert Institute for Bladder Cancer Care and Research (AIBCCR) Friday Sept 16 – Saturday Sept 17, 2022
- Shohdy KS, Villamar DM, Cao Y, et al. Serial ctDNA analysis predicts clinical progression in patients with advanced urothelial carcinoma. Br J Cancer 2022;126(3):430-39.
- Vlachostergios PJ, Faltas BM. Treatment resistance in urothelial carcinoma: an evolutionary perspective. Nature Reviews Clinical Oncology 2018;15(8):495-509.
- Christensen E, Birkenkamp-Demtröder K, Sethi H, et al. Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma. J Clin Oncol 2019;37(18):1547-57.
- Szabados B, Kockx M, Assaf ZJ, et al. Final Results of Neoadjuvant Atezolizumab in Cisplatin-ineligible Patients with Muscle-invasive Urothelial Cancer of the Bladder. Eur Urol 2022;82(2):212-22.
- Powles T, Assaf ZJ, Davarpanah N, et al. ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature 2021;595(7867):432-37.
- Wu CH, Silvers CR, Messing EM, Lee YF. Bladder cancer extracellular vesicles drive tumorigenesis by inducing the unfolded protein response in endoplasmic reticulum of nonmalignant cells. J Biol Chem 2019;294(9):3207-18.
- Liu YR, Ortiz-Bonilla CJ, Lee YF. Extracellular Vesicles in Bladder Cancer: Biomarkers and Beyond. Int J Mol Sci 2018;19(9).
- Muller R, Purushotham S, Diaz P, et al. Detection of CTCs from whole blood of lung cancer patients using the automated Liquid Scan. Cancer Research 2019;79(13_Supplement):3984-84.
Session: Sex as a Biological Variable in Bladder CancerThe afternoon session started with Dr. Ingersoll (Institut Pasteur) discussing sex in bladder cancer. She started by explaining the difference between sex and gender. Sex is dependent on chromosome organization, sex steroids levels, reproductive organs, and sexually dimorphic characteristics. Gender is a social construct and related to behaviors. Sex differences are responsible for the difference in bladder cancer incidence while gender related differences are observed because of differences in smoking and bladder cancer occupational risk factors. Drivers of sex bias in bladder cancer are likely related to sex chromosomes in terms of genetic and epigenetic differences and sex hormones and their downstream receptors such as ERα, ERβ, GPER1, and androgen receptor (AR). In her research, she reported no difference in immune cells infiltration between sexes except for tumor specific T cells. She concluded by citing a study of 1000 healthy individuals where they evaluated the effects of sex on transcriptional responses of most immune-related genes using microbial challenges.1 They noted sex differences in gene expression of CD4+T cells and monocytes.
During the second talk, Dr. Miyamoto (University of Rochester) provided an overview of the molecular biology of sex hormone receptors in bladder cancer. Specifically, he discussed the role of AR in tumorgenicity, progression and response to conventional chemotherapy and immunotherapy. In a mice model study, 92% of the male wild-type AR mice developed bladder cancer while 50% of castrated male wild-type mice developed cancer. In comparison, 42% of the wild-type female mice developed cancer and none of the female AR knock out mice developed cancer. Overall, there was a trend of AR activity down regulating tumor suppressors such as UGT1A1 and upregulating oncogenic molecules such as NFKB in non-neoplastic urothelial cells. AR pathway targets within bladder cancer cells include EGFR, AKT, WNT, ELK, NFKB, ATF2, and FOXO1. Finally, in terms of therapeutic resistance, he noted decreased BCG therapy efficacy via modulation of Rab27b induced exocytosis in AR+ cancers. Furthermore, AR positive cells were more resistant to cisplatin chemotherapy and radiation therapy.2 In the estrogen domain, he discussed the potential outcome of having ER+ tumors depending on subunit of the estrogen receptor present; with ERα likely protective and ERβ likely oncogenic.3
The role of sex chromosomes and sex hormones were presented by Dr. Sean Li (Boston Children’s Hospital and Harvard Medical School). Utilizing four different sex genotypes in his lab including XYM, XYF, XXM and XXF, he observed that having two copies of the X chromosome was protective in bladder carcinogenesis via kdm6a gene modulation. When comparing XY versus XX, there was a 2.5-fold increase in cancer risk and when comparing testes versus ovaries, there was a 4.7-fold increase in cancer risk. Tumor infiltrating CD8+ T cells also demonstrated superior effector function in female mice. He concluded the talk by discussing decreased CD8+T cell exhaustion and suppressed tumor growth after castration in invivo studies.
In the last talk of the afternoon, Dr. Koti (Queen’s University) closed the session by addressing sex differences in responses to BCG induced B cell treatment of bladder cancer. She presented findings from her lab showing that female patients with high grade NMIBC have higher density of tumor infiltrating B cells and this was associated with shorter progression free survival and earlier recurrence. 4 Tertiary lymphoid structures (TLSs) are concentrations of immune cells that are found in the setting of chronic inflammation including cancer. In newer studies, she observed no difference in TLS from BCG responders and non-responders. However, she found that BCG induces TLS formation in the bladder microenvironment of female aging mice. Finally, she reported that decreased expansion of B-cells in male mice post BCG treatment.
- Molly Ingersoll PhD, Research Director/Directeur de Recherche, Mucosal Inflammation and Immunity Group, Institut Pasteur & Institut Cochin
- Hiroshi Miyamoto MD, PhD, Director of Genitourinary Pathology at the University of Rochester Medical Center.
- Sean Li PhD, Associate Professor, Departments of Surgery and Urology, Boston Children’s Hospital and Harvard Medical School
- Madhuri Koti DVM, MVSc, PhD Assistant Professor, Department of Biomedical and Molecular Sciences at Queen’s University
Written by: Valentina Grajales MD, MS, Urologic Oncology Fellow, Twitter: @ValGraj, with Professor Ashish Kamat, Professor of the Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Twitter: @UroDocAsh during the 2022 8th Annual Leo & Anne Albert Institute for Bladder Cancer Care and Research (AIBCCR) Friday Sept 16 – Saturday Sept 17, 2022
- Piasecka B, Duffy D, Urrutia A, Quach H, Patin E, Posseme C, Bergstedt J, Charbit B, Rouilly V, MacPherson CR, Hasan M, Albaud B, Gentien D, Fellay J, Albert ML, Quintana-Murci L; Milieu Intérieur Consortium. Distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges. Proc Natl Acad Sci U S A. 2018 Jan 16;115(3):E488-E497. doi: 10.1073/pnas.1714765115. Epub 2017 Dec 27. PMID: 29282317; PMCID: PMC5776984.
- Ide H, Inoue S, Mizushima T, Jiang G, Chuang KH, Oya M, Miyamoto H. Androgen Receptor Signaling Reduces Radiosensitivity in Bladder Cancer. Mol Cancer Ther. 2018 Jul;17(7):1566-1574. doi: 10.1158/1535-7163.MCT-17-1061. Epub 2018 May 2. PMID: 29720561.
- Miyamoto H, Yao JL, Chaux A, Zheng Y, Hsu I, Izumi K, Chang C, Messing EM, Netto GJ, Yeh S. Expression of androgen and oestrogen receptors and its prognostic significance in urothelial neoplasm of the urinary bladder. BJU Int. 2012 Jun;109(11):1716-26. doi: 10.1111/j.1464-410X.2011.10706.x. Epub 2012 Jan 5. PMID: 22221549.
- Chenard S, Jackson C, Vidotto T, Chen L, Hardy C, Jamaspishvilli T, Berman D, Siemens DR, Koti M. Sexual Dimorphism in Outcomes of Non-muscle-invasive Bladder Cancer: A Role of CD163+ Macrophages, B cells, and PD-L1 Immune Checkpoint. Eur Urol Open Sci. 2021 Jun 3;29:50-58. doi: 10.1016/j.euros.2021.05.002. PMID: 34337534; PMCID: PMC8317911.
Session: T1 Bladder Cancer
(UroToday.com) The second session of the 8th Annual Leo & Anne Albert Institute for Bladder Cancer Care and Research (AIBCCR) Symposium was chaired by Dr Trinity Bivalacqua (University of Pennsylvania), who set the scene for T1 bladder cancer, where up to 50% of patients continue to develop disease recurrence despite BCG intravesical treatment. He highlighted the importance of preclinical modelling which can help interrogate the heterogenous cell types implicated in bladder cancer to help better understand the disease.
Dr Sima Porten (University of California San Francisco) delivered the second talk on clinical outcomes and current treatment strategies for T1 bladder cancer. She highlighted the conundrum patients and physicians face regarding bladder preservation therapy, where patients receiving intravesical BCG treatment risking disease progression versus early radical cystectomy with quality of life implications. Historic reports of the natural history of high grade (HG) T1 tumors reported a 53% risk of disease progression, 36% radical cystectomy rate and cancer specific mortality of 34% at 15 years. 1 However, more contemporary series of patients treated with adequate BCG suggest a freedom of high-grade recurrence of 74% and progression-free survival of 92% at 5 years. 2 Dr Porten highlighted several studies to support early radical cystectomy for HG T1 bladder cancer. Retrospective analysis of patients with HG pT1 bladder cancer report that deferred radical cystectomy resulted in a poorer 10-year cancer specific survival compared to patients receiving early radical cystectomy (51% vs 78%, p<0.01). 3 Further, 8% of patients with HG T1 patients were found to have lymph node positive disease at radical cystectomy, with 15% of patients upstaged to muscle-invasive bladder cancer (MIBC). 4 She stressed limitations of accurate disease staging by transurethral resection of bladder tumor (TURBT), clinical parameters, imaging and the need for better biomarkers and understanding in tumor biology. Dr Porten highlighted work from UCSF on Fibroblast activation protein inhibitor (FAPI)-PET/CT which may better assist in the identification of bladder cancer patients with occult nodal disease. FAPI which is excreted in urine limits the ability for accurate local staging, but early phase studies suggest that FAPI-PET/CT is better at identifying lymph node metastasis compared to fluorodeoxyglucose (FDG) PET/CT.
In the second talk which was on molecular and genetic aberrations on T1 bladder cancer was delivered by Dr Hikmat Al-Ahmadie (Memorial Sloan Kettering Cancer Center). He highlighted significant anatomical variation in histological landmarks where the lamina propria can be multiple folds thicker in the bladder dome compared to the trigone. 5 He pointed out limitations in pathological reporting and processing. TURBT represents a piece meal resection of tumor where lamina propria might be missed by the reporting pathologist in the sea of superficial papillary tissue. Haphazard orientation of TURBT chips by the fixation during processing can also limit the depth of tumor infiltration measurement. While sub-staging of lamina propria is recommended, there remains a lack of consensus on how this should be done. Binary classification such as focal versus extensive lamina propria invasion may provide important clinically relevant information and would allow for easy clinical adoption. Dr Al-Ahmadie concluded that genomic characterization of variant histology, tumor mutational burden and DNA damage repair genes may help compliment traditional clinical and histopathological classification.
Dr Cathy Mendelsohn (Columbia University) delivered the next talk on the investigation of luminal-basal plasticity in high grade T1 urothelial carcinoma. She presented work from her group on how chronic injury and inflammation can activate basal progenitor cells leading to bladder cancer development. Genomic classification suggested that PPAR gamma may be actively suppressed in basal/ squamous tumors which suggested that a loss of signaling may promote bladder cancer formation via MEK pathway. 6 Preclinical studies suggested that PPAR gamma mutation resulted in upregulation of NFKβ signaling resulting in squamous metaplasia. 7 She hypothesized that PPAR gamma signaling and MEK inhibition can reduce tumor growth. Her group has previously shown that utilizing mouse models, treatment with rosiglitazone (PPAR gamma agonist) and trametinib (MEK inhibitor) eradicates basal tumors in a N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model. 7
Dr John Sfakianos (Mount Sinai) then discussed the immune landscape of T1 urothelial carcinoma. He emphasized the significant disease heterogeneity in T1 bladder cancer and the upregulation of inflammatory markers in HG T1 tumors. His group utilized spatial sequencing, which allows for colocalization of gene expression, and reported that BCG naive tumors have a lower HLA-E expression and T/ NK infiltration. 8 BCG treatment then resulted in a dramatic increase in HLA-E expression. This is of relevance in BCG unresponsive tumors where despite recruitment of NK and T cells via the production of CXCL9/10/11, immune exhaustion may be responsible for treatment failure. He postulated that in patients with high levels of inflammatory cellular infiltrate, chemotherapy may be more effective than BCG. Further, priming tumors with chemotherapy prior to treatment BCG may improve BCG efficacy as second line treatment.
A) Visium spots labelled based on high expression of combination gene scores for NK, T and tumor cell markers. B) Magnified expression heatmaps within the shaded red box of combined NK, T or tumor cell markers and HLA-E. C) NK and T-cell markers by lineage showing upregulation of NK and T cell markers in the immune subtype, suggesting that along with upregulated checkpoints we see upregulated infiltration of immune markers in those tumor nests.
The final talk of the session was by Roger Li (Moffitt Cancer Center) on biomarkers for bladder sparing therapy in T1 bladder cancer. He highlighted the differences in predictive, prognostic and both predictive and prognostic biomarkers. Dr Li provided a comprehensive review of biomarkers in the T1 arena. He presented data on a 12-gene progression score to predict risk of NMIBC progression to MIBC which was an independent of clinical and histopathological risk factors. 9 Further work on transcriptomic profiling of T1 tumors had also identified 5 subtypes with variable response following BCG. 10 T1-Myc and T1-Early tumors had the highest risk of recurrence (58% at 24 months) with T1-TLum tumors observing the fewest recurrence (15% at 24 months) following BCG treatment. 10 Other studies he summarized include the CyPRIT cytokine urinary assay, basal versus luminal subclassification. 11, 12 He concluded that bladder cancer represents the cancer with the highest burden of copy number variation and would represent an area for future research.
Presented by: Dr Trinity Bivalacqua, MD, PhD, Director of Urologic Oncology, University of Pennsylvania; Dr Hikmat Al-Ahmadie, MD , Pathologist, Memorial Sloan Kettering Cancer Center; Dr Sima Porten, MD, MPH, Associate Professor of Urology, University of California San Francisco; Dr Cathy Mendelsohn, PhD, Professor of Urological Sciences, Pathology & Cell Biology, Columbia University; Dr John Sfakianos, MD, Assistant Professor of Urology, Mount Sinai; Roger Li, MD, Urologic oncologist, Moffitt Cancer Center,
Written by: Wei Shen Tan MBBCh, PhD, FRCS (Urol), Urologic Oncology Fellow, Department of Urology, MD Anderson Cancer Center, Twitter: @drtanws during the 2022 8th Annual Leo & Anne Albert Institute for Bladder Cancer Care and Research (AIBCCR) Friday Sept 16 – Saturday Sept 17, 2022References:
- Cookson MS, Herr HW, Zhang ZF, et al. The treated natural history of high risk superficial bladder cancer: 15-year outcome. J Urol 1997;158(1):62-7.
- Matulay JT, Li R, Hensley PJ, et al. Contemporary Outcomes of Patients with Nonmuscle-Invasive Bladder Cancer Treated with bacillus Calmette-Guérin: Implications for Clinical Trial Design. J Urol 2021;205(6):1612-21.
- Denzinger S, Fritsche HM, Otto W, et al. Early versus deferred cystectomy for initial high-risk pT1G3 urothelial carcinoma of the bladder: do risk factors define feasibility of bladder-sparing approach? Eur Urol 2008;53(1):146-52.
- Bruins HM, Skinner EC, Dorin RP, et al. Incidence and location of lymph node metastases in patients undergoing radical cystectomy for clinical non-muscle invasive bladder cancer: results from a prospective lymph node mapping study. Urol Oncol 2014;32(1):24.e13-9.
- Lopez-Beltran A, Cheng L. Stage T1 bladder cancer: diagnostic criteria and pitfalls. Pathology 2021;53(1):67-85.
- Liu C, Tate T, Batourina E, et al. Pparg promotes differentiation and regulates mitochondrial gene expression in bladder epithelial cells. Nat Commun 2019;10(1):4589.
- Tate T, Xiang T, Wobker SE, et al. Pparg signaling controls bladder cancer subtype and immune exclusion. Nat Commun 2021;12(1):6160.
- Ranti D, Wang Y, Daza J, et al. PD12-05 SPATIAL TRANSCRIPTOMICS PROVIDES EVIDENCE FOR ALTERNATIVE CHECKPOINT AXES IN BCG-TREATED NMIBC. Journal of Urology 2022;207(Supplement 5):e196.
- Dyrskjøt L, Reinert T, Algaba F, et al. Prognostic Impact of a 12-gene Progression Score in Non-muscle-invasive Bladder Cancer: A Prospective Multicentre Validation Study. Eur Urol 2017;72(3):461-69.
- Robertson AG, Groeneveld CS, Jordan B, et al. Identification of Differential Tumor Subtypes of T1 Bladder Cancer. Eur Urol 2020;78(4):533-37.
- Kamat AM, Briggman J, Urbauer DL, et al. Cytokine Panel for Response to Intravesical Therapy (CyPRIT): Nomogram of Changes in Urinary Cytokine Levels Predicts Patient Response to Bacillus Calmette-Guérin. Eur Urol 2016;69(2):197-200.
- Choi W, Porten S, Kim S, et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 2014;25(2):152-65.