Molecular Biomarkers of Long-Term Response to Androgen Deprivation Therapy and Radiation in Prostate Cancer

在去年美国死于前列腺癌的33，330名男性中， 表现为局部疾病。因此，大多数PCa患者在潜在可治愈阶段被诊断 并且通常用根治性膀胱切除术（RP）治疗。RP后，侵袭性疾病患者面临 前列腺癌复发的风险，表现为持续升高或增加的血清PSA。而 挽救性放射治疗（RT）是术后复发的标准治疗选择，它导致 只有30-40%的患者能长期控制疾病。因此，手术后复发状态呈现出多重 通过解决三个关键挑战来改善患者护理的机会：（1）确定哪些患者将 从雄激素剥夺治疗（ADT）中获益，（2）确定哪些患者接受RT治疗 和ADT将需要进一步的治疗强化，以及（3）确定适当的治疗强化 RT和ADT治疗患者的策略。由于雄激素导向疗法代表了 治疗PCa（通过局部治疗进展）RTOG 96-01和RTOG 05-34 III期 临床试验代表了一个独特的资源库的前列腺切除术队列的患者， 是否存在ADT治疗。对于临床和病理特征 他们死于PCa的风险最高，这些具有里程碑意义的试验通过显示 与单独的RT相比，在RT中加入ADT导致患者存活率的显著改善。这 为开发和验证预测和预后生物标志物提供了前所未有的机会， 在手术后的患者护理过程中，存在多种未满足的临床需求。Aim 1将专注于使用高通量 DNA和RNA测序，以开发预测分类器，用于识别哪些患者将从ADT中获益 使用来自RTOG 96-01和05-34的患者。在目标2中，我们将开发和验证一个预后分类器， 整合了接受RT+ADT治疗的PCa患者的基因组和临床病理学数据， 强化治疗。目标3将侧重于识别需要强化治疗的RT+ADT患者， 使用RTOG 05-34的患者接受盆腔淋巴结放射治疗可能会受益。拟议 研究将通过开发和优化预后和预测生物标志物产生重大影响， 可能具有巨大的潜力，用于快速临床翻译，以个性化治疗和改变 术后PCa患者的管理。

Of the 33,330 men who died from prostate cancer in United States last year, over 80% of these patients presented with localized disease. Thus, a majority of PCa patients are diagnosed at a potentially curable stage and are often treated with radical prostatectomy (RP). Following RP, patients with aggressive disease face the risk of prostate cancer recurrence, which manifests as persistently elevated or increasing serum PSA. While salvage radiation therapy (RT) represents a standard treatment option for post-surgical recurrences, it results in long-term disease control in only 30-40% of patients. Thus, the post-surgical recurrence state presents multiple opportunities to improve patient care by addressing three critical challenges: (1) determining which patients will benefit from the addition of androgen deprivation therapy (ADT), (2) identifying which patients treated with RT and ADT will require further treatment intensification, and (3) identifying the appropriate treatment intensification strategy for RT and ADT treated patients. Since androgen-directed therapies represent the backbone of treatment for PCa (that have progressed through local therapies) the RTOG 96-01 and RTOG 05-34 phase III clinical trials represent a unique resource of banked prostatectomy cohorts from patients that were randomized to the presence or absence of treatment with ADT. For patients whose clinical and pathologic features place them at highest risk of dying from PCa, these landmark trials have defined the standard of care by showing that the addition of ADT to RT resulted in significant improvements to patient survival compared to RT alone. This presents an unparalleled opportunity to develop and validate predictive and prognostic biomarkers addressing multiple unmet clinical needs throughout patient care following surgery. Aim 1 will focus on using high-throughput DNA and RNA sequencing to develop a predictive classifier for identifying which patients would benefit from ADT using patients from RTOG 96-01 and 05-34. In Aim 2 we will develop and validate a prognostic classifier that integrates genomic and clinicopathologic data for PCa patients treated with RT+ADT that may benefit from treatment intensification. Aim 3 will focus on identifying RT+ADT patients requiring treatment intensification that could benefit from receiving pelvic lymph node radiation therapy using patients from RTOG 05-34. The proposed study would have significant impact by developing and optimizing prognostic and predictive biomarkers that could have enormous potential for rapid clinical translation to personalize therapy and transform the management of PCa patients following surgery.