Transcriptomic classification of non-muscle invasive bladder cancer and its clinical and prognostic implication

非肌层浸润性膀胱癌的转录组学分类及其临床和预后意义

基本信息

批准号：
10693811
负责人：
Marilyn L Kwan
金额：
$ 128.98万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10693811
关键词：
Acceleration Address Adjuvant Therapy Adverse effects BCG Live Bacillus Calmette-Guerin Therapy Biological Assay Cancer Patient Classification Clinical Clinical Management Consensus Data Demographic Factors Diagnosis Disease Early treatment Ethnic Origin Etiology Event Failure Generations Genes Goals Healthcare Systems Heterogeneity Immune Individual Intravesical Administration Investigation Knowledge Life Style Malignant Neoplasms Malignant neoplasm of urinary bladder Modeling Molecular Molecular Profiling Muscle Nature Newly Diagnosed Occupational Outcome Pathologic Patient-Focused Outcomes Patients Prospective cohort Race Recurrence Recurrent Malignant Neoplasm Recurrent disease Research Research Priority Risk Risk Factors Sample Size Smoking Specimen Survival Rate System Taxonomy Therapeutic Translating Translations Treatment outcome Tumor Subtype Validation aggressive therapy cancer care cancer epidemiology cancer heterogeneity cancer recurrence cancer subtypes clinical care clinical practice clinical translation cohort cost effective therapy environmental chemical exposure follow-up health care delivery high risk immunogenic improved individualized medicine intravesical meetings molecular marker molecular subtypes nano-string non-muscle invasive bladder cancer population based predicting response predictive modeling predictive tools prevent primary outcome prognostic prognostic value response risk prediction model risk stratification sex tool transcriptome transcriptomics treatment response tumor tumor progression

项目摘要

This study addresses the unmet clinical needs for management of non-muscle invasive bladder cancer (NMIBC). NMIBC represents ~75% of bladder cancer cases and has a favorable five-year survival rate, but typically recurs (50-70% in 5 years) and progresses to muscle-invasive disease (MIBC, 10-30%). Intravesical Bacillus Calmette-Guerin (BCG) is the most effective therapy to prevent NMIBC recurrence and progression, yet BCG has a 30% failure rate, with various adverse effects leading to intolerance. Two critical needs exist: 1) a risk stratification tool to identify patients at high risk of recurrence and progression for early and aggressive treatment, and 2) a response prediction tool to identify patients who are unresponsive or intolerant to BCG for other treatment options. Our goal is to develop and validate risk-stratification and BCG-response tools by incorporating molecular signatures into the current pathological system for optimal clinical care of NMIBC. Transcriptome analysis is powerful to identify genes, and importantly, to define cancer molecular subtypes associated with different therapeutic and prognostic outcomes. This approach has been applied in bladder cancer but primarily focused on MIBC. Research on NMIBC is an unmet need. Building on the Bladder Cancer Epidemiology, Wellness, and Lifestyle Study (Be-Well), one of the largest prospective cohorts of NMIBC patients, we propose to conduct a comprehensive transcriptomic analysis of NMIBC and examine the utility of molecular subtypes with additional prognostic genes in predicting NMIBC treatment response and prognostic outcomes. Our central hypothesis is that molecular signatures (i.e., molecular subtypes and/or other genes) could unveil NMIBC heterogeneity and thus improve the current pathological classification system for tailored NMIBC care. We will: Aim 1. Develop a risk stratification tool for NMIBC prognostic outcomes by incorporating molecular subtypes, genes, clinicopathological and demographic factors. Primary outcomes will be disease recurrence and progression, with survival explored. We will define molecular subtypes and identify genes by NMIBC prognostic outcomes (1a), build risk prediction models in Be-Well (n=928) (1b), validate molecular signatures and the risk-stratification tool in an independent validation cohort (n=959) (1c), and explore the tool in sex and race specific groups in the pooled cohorts (1d). Aim 2. Develop a response prediction tool for BCG outcomes by incorporating molecular subtypes, immune signatures, genes, clinicopathological and demographic factors. Primary outcomes will be BCG unresponsive with BCG intolerant explored. Given the high immunogenic nature of bladder cancer and BCG therapy, we will develop the BCG- response prediction tool with further consideration of immune signatures in patients who received BCG in Be- Well (n=426) and a validation cohort (n=691). We will explore characterization of molecular subtypes by sex, race/ethnicity, and etiological risk factors. Clinical translation will be accelerated given the generation of NMIBC-specific molecular signatures using NanoString in a large health care delivery system setting.

这项研究解决了未满足的非肌肉浸润性膀胱癌的临床需求（NMIBC）。 NMIBC占膀胱癌病例的75％，五年生存率，但通常复发（5年内为50-70％），并发展为肌肉侵入性疾病（MIBC，10-30％）。静脉内芽孢杆菌Calmette-Guerin（BCG）是防止NMIBC复发和进展的最有效疗法，然而，BCG的失败率为30％，各种不良影响导致不宽容。存在两个关键需求：1）一种风险分层工具，以识别早期和积极进展的高风险和进展的患者治疗和2）一种反应预测工具，可以识别出对BCG的反应或不宽容的患者其他治疗选择。我们的目标是通过将分子特征纳入当前的病理系统，以最佳的NMIBC临床护理。转录组分析非常有力地识别基因，重要的是，定义癌症分子亚型与不同的治疗和预后结局有关。这种方法已在膀胱中应用癌症，但主要集中于MIBC。 NMIBC的研究是未满足的需求。建立在膀胱癌流行病学，健康和生活方式研究（BE-WELL），NMIBC的前瞻性人群之一患者，我们建议对NMIBC进行全面的转录组分析，并检查在预测NMIBC治疗反应和预后方面具有其他预后基因的分子亚型结果。我们的中心假设是分子特征（即分子亚型和/或其他基因）可以公布NMIBC的异质性，从而改善当前的病理分类量身定制的NMIBC护理系统。我们将：目标1。为NMIBC预后开发风险分层工具通过纳入分子亚型，基因，临床病理和人口统计学因素的结果。基本的结果将是疾病复发和进展，并探讨了生存。我们将定义分子亚型和通过NMIBC预后结果识别基因（1A），在Be-Well中建立风险预测模型（n = 928）（1b），验证分子特征和独立验证队列中的风险分层工具（n = 959）（1C），并探索合并队列中的性别和种族特定组中的工具（1D）。目标2。开发一个通过结合分子亚型，免疫特征，基因，，临床病理和人口统计学因素。 BCG不耐受的主要结果将是BCG无反应的探索。鉴于膀胱癌和BCG治疗的高免疫原性，我们将发展BCG- 反应预测工具，并进一步考虑接受BCG的患者的免疫特征好（n = 426）和验证队列（n = 691）。我们将通过性别探索分子亚型的特征，种族/种族和病因风险因素。鉴于产生的临床翻译将加速在大型医疗保健输送系统设置中，使用纳米弦设置NMIBC特异性分子特征。