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

2020 ◽  
pp. 1-11
Author(s):  
Joshua J. Meeks ◽  
Gottfrid Sjödahl ◽  
Seth P. Lerner ◽  
Arighno Das ◽  
David J. McConkey ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Immune Cell ◽  
Response To Therapy ◽  
Genomic Diversity ◽  
Intrinsic Resistance ◽  
Making Sense ◽  
Search Terms ◽  
Muscle Invasive ◽  
Next Generation Sequencing Ngs ◽  
Descriptive Feature

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 53-like signature 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.

MDSC clinical assay for cancer detection and monitoring in urothelial carcinoma.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. TPS110-TPS110
Author(s):  
Arnab Basu ◽  
Ali Rafatnia ◽  
Hugh Manoli ◽  
Genevieve Danenberg ◽  
Alan L. Epstein ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Urothelial Carcinoma ◽  
Outcome Measures ◽  
Response To Therapy ◽  
Urine Samples ◽  
Secondary Outcome ◽  
Clinical Assay ◽  
Metastatic Bladder Cancer ◽  
Blood And Urine Samples ◽  
Muscle Invasive

TPS110 Background: Human Myeloid Derived Suppressor Cells (MDSCs) have gained recognition as a significant population of cells that arise in cancer patients to mediate immune tolerance. Some studies have shown MDSC concentrations to be associated with overall survival and response to therapy in urothelial carcinoma. MDSCs comprise a heterogenous population that are yet to be fully characterized. We have identified a set of biomarkers uniquely expressed by the suppressive human MDSC phenotype and have developed an assay targeted to these markers. MDSCs are potentially a relatively cheap and easily performed screening and monitoring tool in cancers. This study will examine how a proprietary clinical assay works in detecting and monitoring MDSCs in blood and urine samples from patients with or without localized or metastatic bladder cancer. Methods: The pilot research trial will enroll 63 subjects in a 1:1:1 ratio in three groups, normal controls over age 40 without evidence of any malignancy, patients with metastatic disease and localized muscle invasive disease prior to cystectomy. This sample size provides 80% power to detect a 1SD difference in MDSC concentrations in these groups on an F test. Blood and urine samples will be drawn at baseline and at 4 months for comparison. The percent CD33+ HLA-DRlow HIF1a+, CD33+ HLADRlow C/EBPb+, CD11b+ HLA-DRlow HIF1a+, and CD11b+ HLA-DRlow C/EBPb+cells as a fraction of PBMC will be determined. Primary Outcome Measures will be 1. Change in MDSC levels in patients with known localized, muscle-invasive bladder cancer who undergo neoadjuvant and surgical treatment. 2. Change in MDSC level in patients with known metastatic bladder cancer who undergo systemic treatment and 3. The direction and magnitude of the changes compared with radiographically assessed tumor burden. Secondary outcome measures are to assess MDSC level measurements in urine cytology analysis at baseline and after treatment to determine whether the two tests correlate in any of the 3 groups of patients defined in this study. Conclusion: This pilot study will examine if a MDSC clinical assay works in detecting and monitoring MDSCs. Recruitment is open to patients at the USC Cancer center and LAC+USC medical center. Clinical trial information: NCT02735512.

Genomic characterization of variant histology muscle invasive bladder cancer (MIBC) to predict response to therapy.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. e24290-e24290
Author(s):  
Shilpa Gupta ◽  
Badrinath R. Konety ◽  
Elai Davicioni ◽  
Ewan Gibb
Keyword(s):  
Bladder Cancer ◽  
Response To Therapy ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Genomic Characterization ◽  
Variant Histology ◽  
Muscle Invasive

Pembrolizumab and chemoradiotherapy for muscle invasive bladder cancer: The ANZUP 1502 PCR-MIB trial.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS531-TPS531 ◽  
Author(s):  
Andrew James Weickhardt ◽  
Farshad Foroudi ◽  
Shomik Sengupta ◽  
Laura Galletta ◽  
Alan Herschtal ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Molecular Genetic ◽  
Response To Therapy ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Bladder Preservation ◽  
Immunological Parameters ◽  
Muscle Invasive

TPS531 Background: Pembrolizumab leads to responses in ~20% of metastatic bladder cancer patients. Irradiation of bladder cancer cells in-vitro and in-vivo leads to upregulation of PD-L1, and in immunocompetent mouse models blockade of PD-L1 leads to delayed tumour growth following irradiation. Randomised data from PACIFIC trial in NSCLC shows the addition of PD-L1 inhibition to chemoradiation significantly prolongs PFS. A trial of chemoradiotherapy with pembrolizumab will assess safety and synergy of the combination in localised bladder cancer. Methods: This pilot study enrols patients with maximally resected non-metastatic muscle invasive bladder cancer, who either wish for bladder preservation or are ineligible for cystectomy. This study will assess the safety and feasibility of combining pembrolizumab with chemoradiotherapy in ECOG 0-1 patients without contraindications to pembrolizumab. The study has enrolled 4 of a planned 30 patients. All patients treated with 64Gy of radiation therapy in 32 fractions over 6 weeks, 2 days. Cisplatin 35mg/m2 IV concurrently weekly for 6 doses with radiation. Pembrolizumab commences concurrently with radiation and is given 200mg IV q21 days for 7 doses. Surveillance cystoscopy is performed 12 & 24 weeks after the commencement of chemoradiotherapy to assess response to therapy. Patients will enter follow up with clinical assessment, cystoscopy and CT staging performed at intervals until close of study. The primary endpoint assessed will be safety, as defined by a satisfactorily low rate of unacceptable toxicity (G3-4 adverse events or failure of completion of planned chemotherapy and radiotherapy according to defined parameters). The secondary endpoint will be efficacy, as assessed by the proportion of patients achieving a best response of complete response based on the first two 12 and 24 week post chemoradiotherapy cystoscopic assessments. Exploratory analysis will include assessment of tumour histopathological, molecular, genetic and immunological parameters. It is expected that it will take two years to accrue the 30 patients across 5 Australian centres. NCT02662062. Clinical trial information: NCT02662062.

scholarly journals An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sia Viborg Lindskrog ◽  
Frederik Prip ◽  
Philippe Lamy ◽  
Ann Taber ◽  
Clarice S. Groeneveld ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Chromosomal Instability ◽  
Prognostic Value ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Invasive Bladder Cancer ◽  
Immune Cell Infiltration ◽  
Muscle Invasive Bladder Cancer ◽  
Omics Analysis ◽  
Muscle Invasive

AbstractThe molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC (n = 834). Transcriptomic analysis identifies four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provide independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations are significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration is associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirms the higher infiltration of class 2b tumors and demonstrates an association between higher immune cell infiltration and lower recurrence rates. Finally, the independent prognostic value of the transcriptomic classes is documented in 1228 validation samples using a single sample classification tool. The classifier provides a framework for biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.

scholarly journals An integrated multi-omics analysis identifies clinically relevant molecular subtypes of non-muscle-invasive bladder cancer

2020 ◽  
Author(s):  
Sia Viborg Lindskrog ◽  
Frederik F. Prip ◽  
Philippe Lamy ◽  
Ann Taber ◽  
Clarice S. Groeneveld ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Chromosomal Instability ◽  
Prognostic Value ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Invasive Bladder Cancer ◽  
Immune Cell Infiltration ◽  
Muscle Invasive Bladder Cancer ◽  
Omics Analysis ◽  
Muscle Invasive

AbstractThe molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we performed a large integrative multi-omics analysis of patients diagnosed with NMIBC (n=834). Transcriptomic analysis identified four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provided independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations were significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration was associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirmed the higher infiltration of class 2b tumors and demonstrated an association between higher immune cell infiltration and lower recurrence rates. Finally, a single-sample classification tool was built and the independent prognostic value of the transcriptomic classes was documented in 1306 validation samples. The classifier provides a framework for novel biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.

Programmed death-ligand 1 (PD-L1) characterization of circulating tumor cells (CTCs) and white blood cells (WBCs) in muscle invasive and metastatic bladder cancer patients.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 446-446 ◽  
Author(s):  
Archana Anantharaman ◽  
Terence W. Friedlander ◽  
David Lu ◽  
Rachel Krupa ◽  
Gayatri Premasekharan ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Checkpoint Inhibitors ◽  
White Blood Cells ◽  
Response To Therapy ◽  
Therapeutic Monitoring ◽  
Healthy Donors ◽  
Algorithmic Analysis ◽  
Muscle Invasive

446 Background: Recent studies indicate that PD-1 and PD-L1 checkpoint inhibitors have activity in chemotherapy refractory patients with muscle invasive (MIBC) and metastatic (mBCa) bladder cancer. PD-L1 expression on tumor cells or lymphocytes may correlate with response to therapy. To identify potential patients who may benefit from PD-1/PD-L1 targeted immunotherapeutics, we utilized a non-invasive blood test to evaluate PD-L1 protein expression in CTCs and WBCs of bladder cancer patients. Methods: Whole blood from 20 patients with MIBC or mBCa were collected and shipped to Epic Sciences. All nucleated cells were plated onto glass slides and subjected to immunofluorescent (IF) staining and CTC identification using scanners and algorithmic analysis. CTCs, defined as traditional (CK+ CD45- w/ intact DAPI+ nuclei and morphologically distinct) or CK- (CK-, CD45-, DAPI+, intact and distinct) were identified. PD-L1 biomarker characterization was assessed by IF staining. UroVysion FISH testing was used to assess genomic abnormalities in a subset of patient samples. Additionally, WBCs (CD45+ cells) were assessed for PD-L1 expression, relative to healthy controls. Results: Eighty percent of patients had mBCa and 20% had MIBC, 70% percent were men, and themedian age was 67 years, (range 43 to 88). Traditional CTCs were detected in 11/20 (55%) patients. Seven out of 20 (35%) patients had PD-L1+ cells, 4 of these patients had exclusively CK-/PD-L1+ CTCs, a subset of which were confirmed as malignant via FISH. CK- CTCs were detected in 14/20 (70%) patients. Five patients had greater than 4-fold PD-L1 positivity in WBCs as compared to healthy donors. Conclusions: Patients with MIBC and mBCa patients have detectable, heterogeneous CTCs with a population of CK-/PD-L1+ CTCs. Utilization of a liquid biopsy to identify patients with PD-L1+ CTCs and PD-L1+ WBCs may enable patient selection or short term therapeutic monitoring for measuring therapeutic efficacy. Further work will investigate association of PD-L1+ CTCs and WBCs with clinical response to PD-1 checkpoint immunotherapy.

scholarly journals Single-Cell Proteomic Analysis Dissects the Complexity of Tumor Microenvironment in Muscle Invasive Bladder Cancer

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5440
Author(s):  
Chao Feng ◽  
Xi Wang ◽  
Yuting Tao ◽  
Yuanliang Xie ◽  
Zhiyong Lai ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Tumor Microenvironment ◽  
Single Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Invasive Bladder Cancer ◽  
Mass Cytometry ◽  
Muscle Invasive Bladder Cancer ◽  
Precision Therapy ◽  
Muscle Invasive

Muscle invasive bladder cancer (MIBC) is a malignancy with considerable heterogeneity. The MIBC tumor microenvironment (TME) is highly complex, comprising diverse phenotypes and spatial architectures. The complexity of the MIBC TME must be characterized to provide potential targets for precision therapy. Herein, an integrated combination of mass cytometry and imaging mass cytometry was used to analyze tumor cells, immune cells, and TME spatial characteristics of 44 MIBC patients. We detected tumor and immune cell clusters with abnormal phenotypes. In particular, we identified a previously overlooked cancer stem-like cell cluster (ALDH+PD-L1+ER-β−) that was strongly associated with poor prognosis. We elucidated the different spatial architectures of immune cells (excluded, infiltrated, and deserted) and tumor-associated collagens (curved, stretched, directionally distributed, and chaotic) in the MIBC TME. The present study is the first to provide in-depth insight into the complexity of the MIBC TME at the single-cell level. Our results will improve the general understanding of the heterogeneous characteristics of MIBC, potentially facilitating patient stratification and personalized therapy.

scholarly journals Defining the microenvironment landscape of bladder cancer using highly multiplexed spatial genomic and proteomic analysis

2019 ◽  
Author(s):  
Jason W Reeves ◽  
Zhaojie Zhang ◽  
Zachary K Norgaard ◽  
Denise M Zhou ◽  
JingJing Gong ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cell ◽  
Immune Cell ◽  
Cell Types ◽  
Primary Resistance ◽  
Stromal Compartment ◽  
Spatial Profiling ◽  
Signaling Axis ◽  
Ffpe Tissues ◽  
Muscle Invasive

AbstractMuscle-invasive bladder cancer (MIBC) is an aggressive disease with limited therapeutic options. PD-1 pathway targeting immunotherapies have been approved to treat advanced bladder cancer, but most patients exhibit primary resistance, suggesting that immune evasion mechanisms exist. The PPARγ pathway has been identified as a potential therapeutic target in MIBC that is associated with reduced CD8+ T-cell infiltration and increased resistance to immunotherapies. We comprehensively profiled the tumor microenvironment (TME) in formalin-fixed, paraffin-embedded (FFPE) tissues from a cohort of PPARγhigh (n=13) and PPRARγlow (n=12) MIBC, integrating bulk gene expression, targeted mutation sequencing, immunohistochemistry and multiplex spatial profiling of RNA and protein expression on the GeoMx™ Digital Spatial Profiling (DSP) platform. Molecular subtyping was consistent between traditional methods and GeoMx profiling, and, in this cohort, we observed little evidence of spatial heterogeneity in tumor subtyping. The previously characterized T-cell exclusion phenotype of PPARγhigh MIBC was recapitulated on the GeoMx platform and was further extended to show that this is a general phenomenon across immune cell types, supporting potential combination of PPARγ inhibition with ICIs. Furthermore, we found that while immune cells were excluded from PPARγhigh tumors, the stromal compartment from these tumors was not significantly different than those PPARγlow tumors. By preserving spatial relationships during the GeoMx analysis, we also identify a novel association between lower immune cell expression in the tumors and higher expression of β-catenin in the stroma, and differential expression of other WNT pathway members associated with PPARγ activity.One Sentence SummaryA new method for capturing tumor-immune signaling in FFPE tissues explores how the PPARG signaling axis is associated with immune cell exclusion in bladder cancer.

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