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.

前列腺切除术后的生化复发男性接受打捞辐射（RT）可能会受益 抗雄激素治疗（AAT）通过降低其发展到遥远转移和死亡的可能性。 但是，在RTOG 9601中，并非所有男人都受益。目前尚无预测生物标志物来确定谁是 从积极的打捞疗法（RT+AAT）中受益的可能性更大或更可能。解决这个未满足的需求 精确治疗决策，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。我们从概念上创新的假设是端粒生物标志物 - 端粒长度中癌细胞对细胞变异性的结合以及基质细胞端粒长度的结合 - 捕获有关肿瘤行为的信息，超出了当前使用的指标，因此，确定了男性 从积极的打捞疗法中受益的可能性更大或更可能。我们发现端粒 生物标志物是手术治疗男性致死性疾病的独立预后标记，确定3 预后类别：良好，中级和贫穷。端粒生物标志物尚未被测试为预测 在任何情况下的治疗反应。我们将在2个完整的设置，试用和临床上解决目标 练习，总共有839名男性和165个转移事件。在试用环境中，我们将使用RTOG 9601，其中男人 被随机分为RT +/- AAT。在临床实践环境中，我们使用在AT 约翰·霍普金斯（Johns Hopkins）或波士顿医疗中心（Boston Medical Center），有纸巾微阵列；在分析中，我们将通过 倾向评分以最大程度地减少因患者和肿瘤因素而导致的偏差。我们将评估这些目标 端粒生物标志物：1。在标准化的环境中，测试向转移的进展速率以及死亡的死亡率 前列腺癌仅在RT+AAT和RT之间有所不同。 2。在临床实践设置中，测试率是否 RT+AAT和RT之间的转移和前列腺癌死亡的进展仅不同。我们将不锈钢 用于端粒和细胞类型特异性免疫荧光标记，并执行图像捕获和定量 图像分析，并得出每个人的端粒生物标志物。我们将按生物标​​志物类别进行分层并使用 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添加 为了预测能力以响应RT+AAT，超出了当前使用的生物化学复发进度 指标。在与中间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的男性的进度率较低。在有男人 生物标志物类别与良好或不良的预后相关，我们假设男性的进展率 收到RT+AAT的人与仅接受RT的男性的价格相似。在RTOG 9601中，RT+AAT更多 仅在某些子组中比RT高效。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。如果确认我们的假设，下一步将是潜在的验证，并且 商业合作伙伴关系，为自动化平台生成基于套件的系统。