Comprehensive genomic profiling of aggressive hormone sensitive prostate cancer

尽管筛查率很高，导致174，650例新病例中的大多数被早期发现， 在美国，前列腺癌仍有约31，620例因转移性和治疗抗性疾病而死亡。 为了使样本的基因谱分析能够识别我们收集的预后和预测生物标志物， 来自988名独特患者的肿瘤样本，这些患者参加了两项已完成的III期试验： CHAARTED：化学激素治疗与雄激素消融治疗广泛性疾病的试验 前列腺癌Sweeney等人，N Eng J Med 2015，373（8）：737-46。 CRIMRC PR 08 STAMPEDE：在一线长期激素治疗中添加多西他赛、唑来膦酸或两者 前列腺癌治疗（STAMPEDE）：一个自适应、多臂、多阶段平台的生存结果 随机对照试验，James，N. D、等人Lancet 2016，387（10024）：1163-1177。 这提供了一个非常独特的机会，研究基因谱，并确定生物标志物与良好的 与转移性激素敏感性前列腺癌（mHSPC）对激素治疗的不良反应相比。这5- R 01年的应用重点是评估与肿瘤抑制基因改变相关的基因组谱 导致p53、PTEN和RB 1功能丧失。临床前和临床数据支持以下假设： 这些肿瘤抑制基因突变的存在与ADT的不良反应相关。的 这两项试验的样本首次提供了前瞻性评估一种或多种药物是否有效的机会。 更多的这些突变可以在开始治疗之前识别出注定要有不良预后的患者。 对ADT的回应反过来，这些突变中的一个或多个的存在可能会识别出受益的患者。 早期加用多西他赛。这可以允许准确的患者选择和备用患者谁没有 早期受益于多西他赛这种化疗药物的副作用。 我们将首先进行肿瘤和生殖系DNA的全外显子组测序， 使用来自CHAARTED试验的Affyandroid平台进行有效和全面的询问 基因组然后，我们将开发临床基因组学模型，以确定是否更准确的预测， 早期多西他赛获益的预测可以通过外显子组变量的组合来实现 突变和/或基因表达谱（GEP）和/或临床因素。在锁定模型后，我们将 然后尝试验证STAMPEDE样本中的预后和预测模型。 同样值得强调的是，这种具有全外显子组测序和GEP的广泛方法也将允许 我们询问和其他探索其他假设的基础上出现的临床前和临床数据， 与DNA损伤修复基因有关的基因（例如BRCA 2）。这项工作也可能导致识别 靶向途径，以预防ADT耐药性的出现并改善mHSPC男性患者的生存率。

Despite a high rate of screening resulting in early identification of most of the 174,650 new cases of prostate cancer in the USA, there are still about 31,620 deaths for metastatic and treatment resistant disease. To enable gene profiling of the samples to identify prognostic and predictive biomarkers we have collected tumor samples from 988 unique patients enrolled on two completed phase 3 trials:  E3805 CHAARTED: ChemoHormonal Therapy versus Androgen Ablation Trial for Extensive Disease in Prostate cancer. Sweeney et al, N Eng J Med 2015, 373(8):737-46.  MRC PR08 STAMPEDE: Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial, James, N. D., et al Lancet 2016, 387(10024):1163-1177. This offers a very unique opportunity to study gene profiles and identify biomarkers associated with a good versus poor response to hormonal therapy for metastatic hormone sensitive prostate cancer (mHSPC). This 5- year R01 application focuses on assessing genomic profiles related to alterations of tumor suppressor genes leading to loss of function of p53, PTEN and RB1. Preclinical and clinical data supports the hypothesis that the presence of mutations in these tumor suppressors genes are associated with a poor response to ADT. The samples from the two trials provide the opportunity for the first time to prospectively assess whether one or more of these mutations can identify patients prior to starting treatment who are destined to have a poor response to ADT. In turn, the presence of one or more of these mutations may identify patients who benefit from adding in docetaxel early. This may allow accurate patient selection and spare patients who did not benefit from early docetaxel the side effects of this chemotherapeutic. We will first perform whole exome sequencing of the tumor and germline DNA and comprehensive RNA profile using the Affymetrix platform from the CHAARTED trial to efficiently and comprehensively interrogate the genome. We will then develop clinicogenomic models to determine whether more accurate prognostication and prediction of benefit from early docetaxel can be achieved with a combination of variables from the exome mutation and/or gene expression profiles (GEP) and/or clinical factors. Having locked down models, we will then attempt to validate the prognostic and predictive models in the STAMPEDE samples. It is also worth highlighting, this broad approach with whole exome sequencing and GEP will also allow us to interrogate and other explore other hypotheses based on emerging preclinical and clinical data such as those pertaining to DNA Damage Repair genes (e.g. BRCA2). This work may also lead to identification of pathways to target to prevent emergence of resistance to ADT and improve the survival of men with mHSPC.