Comparative Effectiveness of Genomics Assay for Active Surveillance Failure Prediction in African American Men: the impact of genetic ancestry and socioeconomic status.

 描述（由申请人提供）：前列腺癌（PCa）是男性最常见的恶性肿瘤，但过度治疗是一个主要的公共卫生问题。为此，Genomic Health Inc.与学术和军事医院合作，验证了17个基因的相对表达测定，以预测根治性乳腺癌切除术时不良病理特征的概率，以提高主动监测的安全性。他们的Oncotype DX（ODX）检测在活检时提高了超出标准临床参数的预后准确性。ODX GPS的范围为0-100，通过降低不良病理的预测试概率来增加被认为有资格进行主动监测的男性数量，并允许患者和提供者自信地选择主动监测，以避免前期治疗发病率。 ODX已在大部分欧洲裔美国人（EA）人群中得到验证，但尚未在高风险非洲裔美国人（AA）男性中进行充分评估。我们的总体假设是，肿瘤型DX的预后准确性因种族、社会经济地位和遗传祖先而异。这是重要的，因为AA具有PCa和PCa死亡率的最高风险，并且尽管有资格通过临床参数进行主动监测，但更可能在其前列腺中隐藏不良病理。基于社会经济因素（包括保险、教育和收入），AA男性的侵袭性PCa风险在研究中各不相同。此外，AA和EA前列腺肿瘤之间的基因表达差异显着。考虑到这一点，如果预测性能较差或在AA和EA之间或在具有临床局限性前列腺癌（CLPCa）的AA亚群之间存在显著差异，则ODX可能对AA是危险的。 为了评估ODX在伴有CLPCa的AA中的预测性能，我们提出以下具体目的：（1）比较ODX GPS作为来自100名患有CLPCa的AA和50名患有CLPCa的EA男性的存档标本的不良病理学预测的有效性;（2）比较GPS对来自150个AA的存档标本中不良病理学的预测性能与来自不同社会人口统计学的CLPCa（收入，教育，保险状况）背景;（3）评估GPS预测性能的变化，在100个以前招募的AA与CLPCa的遗传程度的欧洲或非洲血统。 如果这项比较有效性研究揭示了种族、社会经济地位或遗传血统的预测性能差异，则可以提供校准的GPS评分。或者，如果ODX检测不足以测量不良病理学的风险，我们将阻止其在非洲血统男性中的使用。在这两种情况下，我们提高了对高危PCa人群主动监测的安全性。

 DESCRIPTION (provided by applicant): Prostate Cancer (PCa) is the most common malignancy in men but overtreatment is a major public health concern. To address this, Genomic Health Inc. in collaboration with academic and military hospitals validated a 17-gene relative expression assay to predict the probability of adverse pathologic features at the time of radical prostatectomy to improve the safety of active surveillance. Their Oncotype DX (ODX) assay improves the prognostic accuracy beyond standard clinical parameters at the time of biopsy. The ODX GPS is scaled from 0-100 and increases the number of men deemed eligible for active surveillance by decreasing the pre-test probability of adverse pathology and allows patients and providers to confidently elect active surveillance to avoid upfront treatment morbidity. ODX has been validated in largely European American (EA) populations but has yet to be adequately assessed in high-risk African American (AA) men. Our overarching hypothesis is that the prognostic accuracy of Oncotype DX varies by race and by socioeconomic status and genetic ancestry among AAs. This is significant since AAs have the highest risk of PCa and PCa mortality and are more likely to harbor adverse pathology in their prostate despite being eligible for active surveillance by clinical parameters. Risk of aggressive PCa varies across studies in AA men based on socioeconomic factors including insurance, education and income. Moreover, gene expression varies significantly between AA and EA prostate tumors. Given this, ODX can be dangerous for AAs if prediction performance is poorer or differs significantly between AAs and EAs or between subpopulations of AAs with clinically localized prostate cancer (CLPCa). To assess the prediction performance of ODX in AAs with CLPCa, we propose the following Specific Aims: (1) to compare the effectiveness of the ODX GPS as a predictor of adverse pathology in archived specimen from 100 AA and 50 EA men with CLPCa; (2) to compare the prediction performance of the GPS for adverse pathology in archived specimen from 150 AAs with CLPCa from divergent socio-demographic (income, education, insurance status) backgrounds; (3) to assess for variation in GPS prediction performance in 100 previously recruited AAs with CLPCa by degree of genetic European or African ancestry. Should this comparative effectiveness study reveal variations in prediction performance by race, socioeconomic status or genetic ancestry, a calibrated GPS score could be provided. Alternatively, if the ODX assay inadequately measures risk of adverse pathology we prevent its use in men of African ancestry. In either scenario we improve the safety of active surveillance for a high-risk PCa population.