MULTIPLEXED PROTEIN BIOMARKER-BASED ASSAY FOR THE DETECTION OF BLADDER CANCER

项目摘要/摘要 背景镜检血尿(尿血)可能发生在高达10%的普通人群中，并且 结果进行了昂贵的评估，以确保它不会产生任何后果，即自 血尿通常是BCA的首发症状。此外，75%的新诊断的BCA患者没有 肌肉侵袭性疾病(NMIBC)，复发率非常高(&gt；70%)。正因为如此，它是 建议患者采用卡介苗(BCG)佐剂膀胱内灌注以减少 这种风险。尽管接受了卡介苗治疗，高达50%的患者没有反应，20%的患者进展为肌肉侵袭 膀胱癌(MIBC)需要更彻底的治疗(即，膀胱切除-切除膀胱)。 此外，根治性治疗的延迟可能会对存活率产生负面影响，因此，这项测试可以预测 对膀胱内注射卡介苗的治疗反应，确保正确的患者，在正确的时间得到正确的治疗 急切需要。到目前为止，还没有这样的测试。临床上对可靠的生物标志物的需求尚未得到满足。 A)排除哪些镜检血尿患者不需要进一步评估，以及b)预测 患者会对卡介苗有反应。假设我们的中心假设是存在一个分子轮廓，即 具体地与BCA相关，a)可用于指示非侵袭性中BCA的存在 获得的尿样和b)可用于预测对卡介苗的反应。这一假设将通过以下方式检验 完成以下具体目标：1)验证多重免疫分析检测牛血清白蛋白 出现镜检血尿的受试者，2)评估成本效益、成本效用和成本 血尿和BCA肿瘤病史患者多重免疫分析的有效性 监测和3)前瞻性地验证基于尿液的多重免疫分析来预测卡介苗反应 在中/高风险NMIBC受试者中。这项研究的意义将为改进打开大门 检测BCA并预测治疗反应的非侵入性方法本身将具有 对病人护理的显著影响。方法我们的团队开发并测试了一种多重免疫分析 走向BCA签名，在评估肉眼血尿和 BCA对肿瘤监测的病史。在目前的提案中，我们现在寻求在两个阶段测试多重测试 其他独立队列：中危/高危患者(AUA镜检血尿指南2020) 以镜下血尿为表现的早期BCA和中高危NMIBC患者 用卡介苗膀胱内注射预测治疗效果。此外，我们将生成马尔可夫模型和 使用从母公司R01收集的数据来评估成本效益、成本效用和成本效益 多重免疫分析。预期结果多重免疫分析的验证将减少对 使大量没有BCA的患者频繁、不适和昂贵 膀胱镜检查。具体地说，我们预计每年膀胱镜检查的数量将减少 500 000，这将转化为每年节省2.25亿美元的费用。

Project Summary/Abstract Background Microscopic hematuria (blood in urine) may occur in up to 10% of the general population and results in costly evaluation to ensure it is of no consequence, i.e., no bladder cancer (BCa) is present since hematuria is typically the initial sign of BCa. Furthermore, 75% of patients with newly diagnosed BCa have non- muscle-invasive disease (NMIBC), which has a very high recurrence rate (>70%). Because of this, it is recommended that the patients have adjuvant intravesical bacillus Calmette-Guerin (BCG) instillation to reduce this risk. Despite BCG treatment, up to 50% of patients fail to respond and 20% progress to muscle invasive bladder cancer (MIBC) mandating more radical treatment (i.e., cystectomy - removal of the urinary bladder). Moreover, the delay in radical treatment can negatively impact survival rates, hence, a test that could predict treatment response to intravesical BCG, ensuring the right patient, gets the right treatment at the right time is urgently required. To date, no such test is available. There exists an unmet clinical need for reliable biomarkers to a) ‘rule out’ which patients with microscopic hematuria do not require further evaluation and b) predict which patients will respond to BCG. Hypothesis Our central hypothesis is that a molecular profile exists that is specifically associated with BCa that a) can be utilized to indicate the presence of BCa in non-invasively obtained urine samples and b) can be utilized to predict response to BCG. This hypothesis will be tested by completing the following Specific Aims: 1) To validate the multiplex immunoassay for BCa detection in subjects presenting with microscopic hematuria, 2) To evaluate the cost benefit, cost utility and cost effectiveness of the multiplex immunoassay in subjects with hematuria and a history of BCa on tumor surveillance and 3) To validate prospectively the urine-based multiplex immunoassay to predict BCG response in subjects with intermediate/high risk NMIBC. Significance This research will open the door for improving on the non-invasive methods for detecting BCa and predicting treatment response as such it will have a marked impact on patient care. Methodology Our group has developed and tested a multiplex immunoassay towards a BCa signature with extremely encouraging results in subjects evaluated for gross hematuria and a history of BCa on tumor surveillance. In the current proposal, we now seek to test the multiplex assay in two additional independent cohorts: intermediate/high-risk patients (AUA microscopic hematuria guidelines 2020) presenting with microscopic hematuria for early BCa detection and patients with intermediate/high risk NMIBC treated with intravesical BCG to predict treatment response. Furthermore, we will generate Markov models and using data collected from the parent R01 to assess cost benefit, cost utility and cost effectiveness of the multiplex immunoassay. Expected Results The validation of the multiplex immunoassay will reduce the need to subject large numbers of patients who do not have BCa to frequent, uncomfortable and expensive cystoscopic examinations. Specifically, we would anticipate a reduction in the number of cystoscopies/year by 500,000, which would translate into cost savings of $225 million/year.