Genomic marker to distinguish aggressive and indolent prostate cancer

摘要 前列腺癌是男性中最常见的癌症，估计有268，490例新发病例， 美国2022年在前列腺癌活检时，病理学家使用肿瘤材料来确定等级 还有舞台主要治疗决定基于活检组织信息和PSA（前列腺特异性 抗原，血液测试）。大约80%的新诊断病例被认为是低风险的。由于大多数新 诊断，低风险前列腺癌病例的疾病是无痛的（~70%）和手术来与显着 对于许多患有前列腺癌的男性来说，一个独特的治疗选择是积极监测。有 迫切需要可以补充标准临床变量的生物标志物（即，Gleason评分，PSA，肿瘤 分期、阳性活检次数、患者年龄）来预测将成为侵袭性病例的肿瘤， 需要治疗和那些可以安全地选择主动监测。DNA拷贝数的签名 一种名为GEMCaP（前列腺转移癌基因组评估）的肿瘤，是由美国癌症研究所发现的。 首席研究员。GEMCaP在术后环境中得到了验证，以确定那些准备接受 生化复发和转移。GEMCaP最近在主动监测环境中进行了评估， 在低风险前列腺癌男性中， 由临床变量定义。GEMCaP独立预测了不良病理学， RNA风险预测因子。当与临床变量相结合时，GEMCaP改善了预测 与商业RNA测定相比，术后生化复发的能力。GEMCaP还显示 确定可以通过主动监测安全管理的病例，这在以前是没有实现的 通过商业上可获得的RNA竞争产品。生物标记公司的NIH SBIR第一阶段的目标 该项目的目标是使用活检组织和定制测序面板将GEMCaP商业化。活检 这项研究的生物标本将由金丝雀基金会的注释良好的主动监测提供 活检组织的生物样本收集以及相关的临床变量和结果数据。本研究将使用 商业RNA生物标志物测定作为比较物。本项目的目的是：1）确定GEMCaP是否 可以根据活检确定临床低风险患者队列中的侵袭性CaP，并比较 生物标记公司的专有算法在主动监视设置与二进制截止方法，2）测试 GEMCaP在识别低风险病例中可以安全地保持主动监测，3）比较GEMCaP的 与市售的RNA预测物相比的性能。在第二阶段，我们将在更大的队列中验证我们的发现， 使用目标1中确定的调用方法。成功的临床验证作为第二阶段和实施 GEMCaP将提高预测准确性，从而减少对惰性前列腺患者的过度治疗 癌

ABSTRACT Prostate cancer is the most commonly diagnosed cancer in men, with an estimated 268,490 new cases in the U.S. in 2022. At the time of a prostate cancer biopsy, pathologists use the tumor material to determine the grade and stage. Primary treatment decisions are based on the biopsy tissue information and the PSA (prostate specific antigen, blood test). About 80% of newly diagnosed cases are considered low-risk. Since in the majority of newly diagnosed, low-risk prostate cancer cases the disease is indolent (~70%) and surgery comes with significant adverse effects, a unique treatment option for many men with prostate cancer is Active Surveillance. There is an urgent need for biomarkers that could supplement standard clinical variables (i.e., Gleason score, PSA, tumor staging, number of positive biopsies, patient age) to predict tumors that will become aggressive cases that require treatment and those that can safely elect Active Surveillance. The DNA copy number signature of the tumor, called GEMCaP (Genomic Evaluators of Metastatic Cancer of the Prostate), was discovered by the Principal Investigator. GEMCaP was validated in the post-surgery setting to identify those cases poised for biochemical recurrence and metastasis. GEMCaP was recently evaluated in the Active Surveillance setting using archived surgical tissue, adjacent to where the biopsy was sampled, in men with low-risk prostate cancer as defined by clinical variables. GEMCaP independently predicted adverse pathology alongside a commercially available RNA risk predictor. When combined with clinical variables, GEMCaP resulted in improved predictive power of biochemical recurrence post-surgery compared to a commercial RNA assay. GEMCaP was also shown to identify cases that can safely be managed with Active Surveillance, which has not previously been achieved by commercially-available RNA competitor products. The goal of Biomarker Corporation’s NIH SBIR Phase I project is to work toward commercializing GEMCaP using biopsy tissue and a custom sequencing panel. Biopsy biospecimens for this study will be provided by the Canary Foundation’s well-annotated Active Surveillance biospecimen collection of biopsy tissue with associated clinical variables and outcome data. The study will use a commercial RNA biomarker assay as a comparator. The aims of this project are to 1) Determine if GEMCaP can identify aggressive CaP in a cohort of patients considered clinically low-risk based on biopsies and compare Biomarker Corp.’s proprietary algorithm in the Active Surveillance setting with the binary cut-off method, 2) Test GEMCaP in identifying low-risk cases who can safely stay on Active Surveillance, 3) Compare GEMCaP’s performance to a commercially available RNA predictor. In Phase II we will validate our findings in a larger cohort, using the calling method identified in Aim 1. Successful clinical validation as a Phase II and implementation of GEMCaP will improve prediction accuracy and thereby reduce overtreatment of men with indolent prostate cancer.