Predictive Epigenomic Biomarkers In Rectal Cancer Patients Receiving Treatment

描述（由申请人提供）：直到今天，原发性直肠癌患者的管理仍然受到发病率、局部复发和远处器官复发等重大问题的挑战。在大多数研究中，直肠癌与结肠癌混合，但临床治疗不同，分子上不同。原发性直肠肿瘤预测性生物标志物的开发和验证可以显著改善疾病结局，降低发病率，最重要的是改善原发性直肠肿瘤治疗分层。我们已经确定，在初步试点研究中，表观基因组畸变（启动子区甲基化）的非编码基因组重复序列和肿瘤相关基因的原发性直肠腺癌，局部和远处器官转移复发和疾病的结果预测生物标志物。我们建议在原发性直肠肿瘤中验证这些结果，这些结果来自两项大规模多中心III期临床试验，患者随机分为全直肠系膜切除术（TME）与放疗前TME（PRTME），随访13年（回顾性研究），以及前瞻性随机III期多中心RAPIDO临床试验，新辅助放化疗后TME。直肠癌生物标志物的发展可能会改善分层，更有效地控制原发性直肠肿瘤的微转移和无微转移。我们的目标是开发和验证一种预测性生物标志物面板，用于对患者进行分层治疗。我们将确定哪些原发性直肠癌患者可以从单独的TME与不同的新辅助治疗方法（包括单独的放疗或放化疗方案）中获益。目标如下：目标一：原发性直肠癌的表观基因组生物标志物预测TME或PRTME治疗患者的远处器官复发目的II：研究原发性直肠癌的表观基因组生物标志物，以预测TME或PRTME治疗患者的局部复发。目的III：预测新辅助放化疗后TME无病生存期的最佳表观基因组直肠癌生物标志物。该研究使用表观基因组预测生物标志物的新组合解决了原发性直肠癌的重要治疗问题。

DESCRIPTION (provided by applicant): To this day, primary rectal cancer patient management continues to be challenged by significant problems in morbidity, locoregional recurrence, and distant organ recurrence. In most studies, rectal cancer is commingled with colon cancer, yet it is clinically treated differently and molecularly distinct. Development and verification of predictive biomarkers of primary rectal tumors could significantly improve disease outcome, reduce morbidity, and most importantly improve primary rectal tumor treatment stratification. We have identified, in preliminary pilot studies, epigenomic aberrations (promoter region methylation) of non-coding genomic repeat sequences and tumor-related genes in primary rectal adenocarcinoma that are predictive biomarkers for locoregional and distant organ metastasis recurrence and disease outcome. We propose to validate these findings in primary rectal tumors from two large-scale multicenter phase III clinical trials of patients randomized between Total Mesorectal Excision surgery(TME) versus Pre-Radiotherapy followed by TME (PRTME) in a 13 yr follow-up (retrospective study), and the prospective randomized Phase III multicenter RAPIDO clinical trial of neoadjuvant chemoradiation followed by TME. Development of rectal cancer biomarkers may improve stratification into more efficient control of primary rectal tumors with and without micrometastasis. Our objective is to develop and validate a predictive biomarker panel for utility in stratifying patients for treatment. We will identify primry rectal cancer patients who could benefit from TME alone versus different approaches of neoadjuvant treatments that include radiation alone or chemoradiation regimens. The Aims are as follows: Aim I: Validate epigenomic biomarkers of primary rectal cancer to predict distant organ recurrence in TME or PRTME treated patients. Aim II: Validate epigenomic biomarkers of primary rectal cancer to predict locoregional recurrence in TME or PRTME treated patients. Aim III: Validate optimal epigenomic rectal cancer biomarkers to predict disease-free survival in neoadjuvant chemoradiation followed by TME. The study addresses an important treatment problem of primary rectal cancer using a novel combination of epigenomic predictive biomarkers.