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

在美国去年死于前列腺癌的33,330名男性中，超过80%的患者 表现出局部疾病的。因此，大多数前列腺癌患者被诊断为处于潜在的可治愈阶段。 并经常接受根治性前列腺切除术(RP)。在RP之后，侵袭性疾病的患者将面临 前列腺癌复发的风险，表现为血清PSA持续升高或增加。而当 挽救放射治疗(RT)是手术后复发的标准治疗选择，它导致 只有30%-40%的患者可以长期控制疾病。因此，手术后复发状态呈现出多个 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 从雄激素剥夺疗法(ADT)的增加中获益，(2)确定哪些患者接受了RT 和ADT将需要进一步的强化治疗，以及(3)确定适当的强化治疗 RT和ADT治疗患者的策略。因为雄激素导向疗法代表了 前列腺癌的治疗(已通过局部治疗取得进展)RTOG 96-01和RTOG 05-34第三阶段 临床试验代表了来自随机分组患者的前列腺摘除队列的独特来源。 是否接受ADT治疗。适用于临床和病理特征为 他们死于前列腺癌的风险最高，这些里程碑式的试验通过表明 与单纯放疗相比，在放疗的基础上加用ADT可显著提高患者的生存率。这 提供了一个无与伦比的机会来开发和验证预测和预后生物标记物 在手术后的病人护理过程中，存在多种未得到满足的临床需求。目标1将专注于使用高吞吐量 DNA和RNA测序开发用于确定哪些患者将受益于ADT的预测性分类器 使用RTOG 96-01和05-34的患者。在目标2中，我们将开发并验证一个预测分类器 整合接受RT+ADT治疗的PCa患者的基因组和临床病理数据，这些患者可能受益于 强化治疗。目标3将重点确定需要强化治疗的RT+ADT患者 可以从使用RTOG 05-34的患者接受盆腔淋巴结放射治疗中受益。建议数 这项研究将通过开发和优化预测和预测生物标记物来产生重大影响 可能在快速临床翻译方面具有巨大的潜力，以实现个性化治疗和转变 术后PCa患者的处理。

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.