Determining the clinical impact of gene expression testing in localized prostate cancer

该项目的长期目标是同时减少治疗相关的发病率， 过度治疗局限性前列腺癌（PCa）的男性，同时通过最大限度地减少治疗不足来治愈更多的男性， 治疗前列腺癌高危男性。在这个建议中，我们的目标是确定是否组织基础基因表达 分类器（GEC）可用于改善局部化男性患者的癌症控制和生活质量（QOL）。 PCa。这一目标将通过三个具体目标来实现。在目标1中，我们将制定一个通用风险评分 它结合了遗传、临床和病理变量，以一种不可知的方式， 使用市售GEC测试。这将通过聚集一大批人来完成， 同一前列腺肿瘤病灶的靶向MRI/超声融合活检，并分析单个肿瘤， 三个测试中的每一个。然后，我们将开发一种转换方法，将每个GEC分数与新的 通用评分，我们将其应用于1000名新诊断的前列腺癌患者的队列， 在我们全州范围内的潜在登记中这些数据将用于验证我们最近开发的临床- 基因组风险分组系统，将其扩大到包括所有GEC测试，并将其集中在适当的 潜在适合于主动监测的有利风险前列腺癌分层。我们假设 普遍整合的临床-基因组风险组将提供比标准更好的区分， 临床类别，并将扩大积极监测合格患者的库。在目标2中，我们将进行 有史以来第一个前瞻性随机试验的临床效用和临床影响的GEC测试在有利的风险 局部前列腺癌，利用两个全州范围内的合作，包括60多个泌尿科和放射科， 肿瘤学实践。将患者随机分配至标准临床风险分层+/- GEC检测，以便 确定检测对治疗决策的影响（积极监测与根治性治疗），癌症 控制和QOL。我们假设GEC检测将减少主要治疗的使用，并增加 3年时的QOL，同时保持等级重新分类率和生化复发率 点目的3旨在确定GEC检测对治疗失败和患者报告的 前列腺切除术后复发高危男性的生活质量。这一目标利用了最近增加的G-MINOR 一项试验，将大约350名前列腺切除术后高风险失败的男性随机分为临床风险组 分层+/- GEC测试，以评估基于GEC测试的决策。通过扩大 在这项试验中，我们将确定GEC测试如何影响长期肿瘤控制和QOL。我们假设 在高风险患者中使用GEC将提供更准确的风险分层和有针对性的治疗决策， 从而改善癌症控制和QOL。这项工作有可能个性化治疗决策- 根据肿瘤的生物学特性为PCa患者制造，使一些男性避免昂贵和有毒的过度- 这将有助于提高治疗效果，同时减少因治疗不足而导致的疾病复发的负担。

The long-term goal of this project is to simultaneously decrease treatment-related morbidity from unnecessary over-treatment of men with localized prostate cancer (PCa) while curing more men by minimizing under- treatment of men with higher risk PCa. In this proposal we aim to determine if tissue based gene expression classifiers (GEC) can be utilized to improve both cancer control and quality of life (QOL) in men with localized PCa. This goal will be carried out through three specific aims. In Aim 1 we will develop a universal risk score that combines genetic, clinical, and pathologic variables in a manner that is agnostic to which of the three commercially available GEC tests used. This will be done through assembling a large cohort of men with targeted MRI/ultrasound fusion biopsies of the same prostate tumor focus and analyzing individual tumors with each of the three tests. We will then develop a conversion method aligning each GEC score with a new universal score, and we will apply this to a cohort of 1000 men with newly diagnosed prostate cancer followed in our statewide prospective registry. This data will be utilized to validate our recently developed clinical- genomic risk grouping system, broadening it to incorporate all GEC tests, and focusing it on appropriate stratification of favorable risk prostate cancer potentially suitable for active surveillance. We hypothesize that the universal integrated clinical-genomic risk groups will provide improved discrimination compared to standard clinical categories and will expand the pool of active surveillance-eligible patients. In Aim 2 we will conduct the first ever prospective randomized trial of the clinical utility and clinical impact of GEC testing in favorable risk localized prostate cancer, leveraging two statewide collaboratives containing over 60 urology and radiation oncology practices. Patients will be randomized to standard clinical risk stratification +/- GEC testing in order to determine the impact of testing on treatment decisions (active surveillance versus radical treatment), cancer control, and QOL. We hypothesize that GEC testing will decrease the use of primary therapy and increase QOL at 3 years, while maintaining rates of grade reclassification and biochemical recurrence at the same time point. Aim 3 seeks to determine the clinical impact of GEC testing on treatment failure and patient-reported QOL in men at high risk of recurrence post-prostatectomy. This aim leverages the recently accrued G-MINOR trial that randomized approximately 350 men at high risk of failure after prostatectomy to clinical risk stratification +/- GEC testing to assess decision making based on GEC testing. By extending the follow-up of this trial, we will determine how GEC testing impacts long-term tumor control and QOL. We hypothesize that GEC use in higher risk patients will provide more accurate risk stratification and targeted treatment decisions, leading to improved cancer control and QOL. This work has the potential to personalize treatment decision- making for PCa patients based on their tumor’s biology, allowing some men to avoid costly and toxic over- treatment while also decreasing the burden of recurrent disease from inappropriate under-treatment.