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、局部复发和远端器官复发等重大问题的挑战。在大多数研究中，直肠癌与结肠癌合并，但临床治疗不同，分子也不同。直肠原发肿瘤的预测性生物标志物的开发和验证可以显著改善疾病转归，降低发病率，最重要的是改善直肠原发肿瘤的分层治疗。在初步的试点研究中，我们已经确定了原发性直肠腺癌中非编码基因组重复序列和肿瘤相关基因的表观基因组畸变（启动子区甲基化），这些基因是局部区域和远处器官转移复发和疾病结局的预测性生物标志物。我们建议通过两项大规模多中心III期临床试验，在13年随访（回顾性研究）中随机选择全直肠系膜切除术（TME）与术前放疗后TME (PRTME)，以及新辅助放化疗后TME的前瞻性随机III期多中心RAPIDO临床试验，来验证原发性直肠肿瘤的这些发现。直肠癌生物标志物的发展可能会改善分层，从而更有效地控制有或没有微转移的原发性直肠肿瘤。我们的目标是开发和验证一种预测性生物标志物面板，用于分层患者的治疗。我们将确定单纯TME与不同新辅助治疗方法（包括单纯放疗或放化疗方案）相比可以获益的原发性直肠癌患者。目的1：验证原发性直肠癌的表观基因组生物标志物，以预测TME或PRTME治疗患者的远端器官复发。目的II：验证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：验证最佳的表观基因组直肠癌生物标志物，以预测新辅助放化疗后TME的无病生存。该研究利用一种新的表观基因组预测生物标志物组合解决了原发性直肠癌的一个重要治疗问题。

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.