The telomere biomarker as a tool to inform decision-making for aggressive salvage therapy in men with rising PSA post prostatectomy

端粒生物标志物可作为前列腺切除术后 PSA 升高的男性积极挽救治疗决策的工具

• 批准号: 10635291
• 负责人: Christopher M Heaphy
• 金额: $ 62.3万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-22 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10635291
• 关键词: Address; Age; Antiandrogen Therapy; Biochemical; Biological Markers; Biology; Boston; Cancer Therapy Evaluation Program; Categories; Cells; Cessation of life; Clinic; Clinical; Coupled; Cox Models; Decision Making; Diagnosis; Disease; Distant Metastasis; Event; Hospitals; Image; Image Analysis; Immunofluorescence Immunologic; Length; Malignant Neoplasms; Malignant neoplasm of prostate; Medical center; Neoplasm Metastasis; Operative Surgical Procedures; Pathology; Patients; Pattern; Placebos; Precision therapeutics; Prediction of Response to Therapy; Prognosis; Prognostic Marker; Prostatectomy; Race; Radiation; Radiation Therapy Oncology Group; Randomized; Recurrence; Salvage Therapy; Stains; Standardization; Stromal Cells; Subgroup; Surgical margins; System; Testing; Time; Tissue Microarray; Urology; Validation; Weight; cancer cell; cell type; clinical practice; cohort; first-in-human; innovation; man; men; practice setting; predictive marker; prognostic; prognostic indicator; prospective; quantitative imaging; radiation response; side effect; telomere; tool; treatment effect; treatment response; tumor; tumor behavior; unnecessary treatment

Men with biochemical recurrence after prostatectomy receiving salvage radiation (RT) may benefit from added anti-androgen therapy (AAT) by decreasing their likelihood of progressing to distant metastasis and death. However, in RTOG 9601, not all men benefitted. No predictive biomarker currently exists to identify who is more likely or less likely to benefit from aggressive salvage therapy (RT+AAT). To address this unmet need for precision treatment decision-making, we will evaluate the telomere biomarker as a predictive biomarker for treatment response in this setting. Our conceptually innovative hypothesis is that the telomere biomarker – the combination of cancer cell-to-cell variability in telomere length coupled with stromal cell telomere length – captures information about tumor behavior beyond currently used indicators and thus, identifies men who are more likely or less likely to benefit from aggressive salvage therapy. We discovered that the telomere biomarker is an independent prognostic marker for lethal disease in surgically-treated men, identifying 3 prognostic categories: good, intermediate, and poor. The telomere biomarker has not been tested as predictive of treatment response in any setting. We will address the aims in 2 complementary settings, trial and clinical practice, totaling 839 men and 165 metastatic events. In the trial setting, we will use RTOG 9601, in which men were randomized to RT+/-AAT. In the clinical practice setting, we use cohorts who received RT+/-AAT at Johns Hopkins or Boston Medical Center and have tissue microarrays; in the analysis, we will weight by a propensity score to minimize bias due to patient and tumor factors. We will evaluate these aims stratified by the telomere biomarker: 1. In the standardized setting, test if rate of progression to metastasis and death from prostate cancer differs between RT+AAT and RT only. 2. In the clinical practice setting, test if rate of progression to metastasis and death from prostate cancer differs between RT+AAT and RT only. We will stain for telomeres and cell-type specific immunofluorescence markers and perform image capture and quantitative image analysis, and derive each man’s telomere biomarker. We will stratify by biomarker category and use Cox models to estimate associations between RT+AAT and progression, and determine if the biomarker adds to predictive capability for response to RT+AAT beyond currently used post-biochemical recurrence prognostic indicators. In men with the biomarker category associated with intermediate prognosis, we hypothesize that the progression rate is lower in men who received RT+AAT compared to men who received RT only. In men with biomarker categories associated with good or poor prognosis, we hypothesize that the progression rate in men who received RT+AAT is similar to the rate in men who received RT only. In RTOG 9601, RT+AAT was more efficacious than RT only in some subgroups. For optimized decision-making, we will determine if the biomarker is predictive in subgroups. If our hypothesis is confirmed, next steps would be prospective validation and commercial partnership to generate a kit-based system for automated platforms.

接受挽救性放射 (RT) 的前列腺切除术后生化复发的男性可能会受益于额外的治疗 通过降低其进展为远处转移和死亡的可能性来进行抗雄激素治疗（AAT）。 然而，在 RTOG 9601 中，并非所有男性都受益。目前还没有预测性生物标志物可以识别谁是 更有可能或不太可能从积极挽救治疗（RT+AAT）中受益。为了解决这一未满足的需求 精准治疗决策，我们将评估端粒生物标志物作为预测生物标志物 在这种情况下的治疗反应。我们概念上的创新假设是端粒生物标志物—— 癌细胞间端粒长度变异性与基质细胞端粒长度的结合 – 捕获当前使用的指标之外的有关肿瘤行为的信息，从而识别出哪些男性 更有可能或不太可能从积极的挽救治疗中受益。我们发现端粒 生物标志物是接受手术治疗的男性致命疾病的独立预后标志物，可识别 3 预后类别：良好、中等和较差。端粒生物标志物尚未经过预测性测试 任何环境下的治疗反应。我们将在试验和临床这两个互补的环境中实现这些目标 实践中，共有 839 名男性和 165 例转移事件。在试验设置中，我们将使用 RTOG 9601，其中男性 被随机分配至 RT+/-AAT。在临床实践中，我们使用接受 RT+/-AAT 的队列 约翰·霍普金斯大学或波士顿医学中心并拥有组织微阵列；在分析中，我们将加权 倾向评分，以最大限度地减少患者和肿瘤因素造成的偏差。我们将按以下分层评估这些目标 端粒生物标志物： 1. 在标准化环境中，测试转移进展率和死亡率 前列腺癌在 RT+AAT 和仅 RT 之间存在差异。 2. 在临床实践中，测试是否 RT+AAT 和仅 RT 之间前列腺癌转移和死亡的进展有所不同。我们会染色 用于端粒和细胞类型特异性免疫荧光标记并进行图像捕获和定量 图像分析，并得出每个人的端粒生物标记。我们将按生物标​​志物类别和用途进行分层 Cox 模型估计 RT+AAT 与进展之间的关联，并确定生物标志物是否增加 对 RT+AAT 反应的预测能力超出了目前使用的生化后复发预后 指标。在具有与中期预后相关的生物标志物类别的男性中，我们假设 与仅接受 RT 的男性相比，接受 RT+AAT 的男性的进展率较低。在男性中 生物标志物类别与预后的好坏相关，我们假设男性的进展率 接受 RT+AAT 的男性与仅接受 RT 的男性的比率相似。在RTOG 9601中，RT+AAT更 仅在某些亚组中比 RT 有效。为了优化决策，我们将确定生物标志物是否 在亚组中具有预测性。如果我们的假设得到证实，下一步将是前瞻性验证和 商业合作伙伴关系，为自动化平台生成基于套件的系统。