Prognostic and Predictive Digital Tissue Image Assay for Prostate Cancer

项目摘要：仅在美国，2020年就有超过34，000例PCA相关死亡。确定性治疗 包括根治性前列腺切除术（RP）或放射治疗（RT）与长期雄激素抑制治疗（ADT）。 这些已被证明是器官局限性PCa的有效治疗方法，并已被证明 降低PCa死亡风险。然而，在38-52%的病例中， 预后取决于组织病理学。最近的一些临床试验表明， 然而，关键是要确定那些PCa患者， 确定性治疗（手术或放疗）具有复发或转移的高风险，因此将受益于 辅助治疗与不愿接受辅助治疗的患者相比，因此可以避免治疗的发病率和费用。 认识到这种未满足的临床需求的重要性，2018年NCCN PCa指南 修改为包括解密评分，一种基于预后分子基因的测试，以确定 手术后转移。我们开发了自己的“综合风险评分”（IRiS）图像分类器， (npj Precison Onc，In Press 14）结合了计算机从H&E组织中提取的形态学腺体特征 肿瘤的切片IRiS根据至生化复发的时间对PCa患者（N>900，6个研究中心）进行分层 (BCR)低风险组和高风险组（p<0.001; HR=2.44）。此外，IRiS与术前PSA和 在N=173例患者中，Gleason分级在预测BCR方面优于Decipher（p<0.001; HR=3.23 vs HR=2.76）。 在本R 01中，我们将验证IRiS作为（1）BCR和转移风险的预后以及（2） 预测确定性治疗（手术或放疗）后额外化疗的额外获益 PCa。在最近发表在《临床癌症研究》上的一篇论文中，我们确定了非裔美国人IRIS的特异性预后特征， (AA)有PCa的人我们将在这些发现的基础上开发PCa的人群特异性IRiS模型。我们将 还通过包括（1）基质和筛状形态的特征，（2）开发群体， 针对不同种族群体的特异性IRiS模型，以及（3）补充具有临床病理特征的IRiS。到 验证IRIS作为辅助治疗获益的预测，我们需要获得随机临床试验组织载玻片 涉及仅接受确定性治疗（手术或ADT+放疗）和确定性治疗的PCa患者的图像 治疗+形容词化疗STAMPEDE和RTOG-0521试验符合这些标准;我们已获得批准， 获取这些试验的组织切片图像为了使该工具广泛使用，IRiS将被集成到 PathPresenter是一个数字病理学查看器和管理平台，目前在178个国家使用。这 伙伴关系将结合联合收割机的专业知识，（一）计算病理学的Madabhushi集团，（2）临床， 来自宾夕法尼亚大学的PCa病理学和生物标志物专业知识（Priti Lal博士）和（3）GU 来自克利夫兰诊所（Shilpa Gupta博士）的医学肿瘤学专业知识将IRiS转化为第一个组织非 针对PCa的破坏性预后和预测性负担得起的精准医学（APM）解决方案。

PROJECT SUMMARY: There were >34,000 PCa-related deaths in 2020 in the US alone. Definitive treatment includes Radical prostatectomy (RP) or radiotherapy (RT) with long term androgen-suppression therapy (ADT). These have been shown to be effective treatments for organ-confined PCa and have been demonstrated to reduce the risk of death from PCa. In 38-52% of cases, however, advanced disease with potentially poor prognosis is found on tissue pathology. A number of recent clinical trials have shown the benefit of adjuvant therapy in select PCa patients post-RP or RT. However, it is critical to identify those PCa patients who following definitive therapy (surgery or radiation) are at high-risk for recurrence or metastasis and thus will benefit from adjuvant therapy versus patients who will not and hence may be spared the morbidity and cost of therapy. Recognizing the significance of this unmet clinical need, in 2018 the NCCN guidelines for PCa were modified to include the Decipher Score, a prognostic molecular gene-based test to identify the likelihood of metastasis following surgery. We have developed our own "Integrated Risk Score" (IRiS) image classifier that (npj Precison Onc, In Press14) combines computer extracted morphologic glandular features from H&E tissue slides of the tumor. IRiS stratified PCa patients (N>900, 6 sites) based on their time to biochemical recurrence (BCR) into low- and high-risk groups (p<0.001; HR=2.44). Further, IRiS when combined with pre-op PSA and Gleason grade outperformed Decipher in predicting BCR in N=173 patients (p<0.001; HR=3.23 vs HR=2.76). In this R01, we will validate IRiS as (1) prognostic of BCR and risk of metastasis as well as (2) predictive of the added benefit of additional chemotherapy following definitive therapy (surgery or radiation) in PCa. In a recent paper in Clin Cancer Res, we identified IRiS specific prognostic features for African American (AA) men with PCa. We will build on these findings to develop population specific IRiS models for PCa. We will also further optimize IRiS by including (1) features of stromal and cribriform morphology, (2) develop population specific IRiS models for different ethnic groups, and (3) complement IRiS with clinico-pathological features. To validate IRiS as predictive of benefit of adjuvant therapy, we need access to randomized clinical trial tissue slide images involving PCa patients treated with definitive therapy alone (surgery or ADT+radiation) and definitive therapy+ adj. chemo. The STAMPEDE and RTOG-0521 trials fit these criteria; we have secured approval to access tissue slide images from these trials. To make the tool widely available, IRiS will be integrated into PathPresenter, a digital pathology viewer and management platform currently in use in 178 countries. This partnership will combine expertise in (a) computational pathology of the Madabhushi group, (2) clinical, pathological and biomarker expertise of PCa from the University of Pennsylvania (Drs. Priti Lal) and (3) GU medical oncology expertise from the Cleveland Clinic (Dr Shilpa Gupta) to translate IRiS as the first tissue non- destructive prognostic and predictive Affordable Precision Medicine (APM) solution for PCa.