Predictive Epigenomic Biomarkers In Rectal Cancer Patients Receiving Treatment

描述(由申请人提供)：直到今天，原发直肠癌患者的治疗仍然受到发病率、局部区域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在一起，然而它在临床上得到了不同的治疗，并且在分子上是不同的。开发和验证原发直肠肿瘤的预测生物标志物可以显著改善疾病结局，降低发病率，最重要的是改善原发直肠肿瘤的治疗分层。在初步的初步研究中，我们已经确定，在原发性直肠腺癌中，非编码基因组重复序列和肿瘤相关基因的表观基因组异常(启动子区域甲基化)是预测局部和远处器官转移、复发和疾病预后的生物标志物。我们建议在两个大规模的多中心III期临床试验中验证这些发现，这些临床试验的患者随机分为全直肠系膜切除术(TME)和放疗前TME(PRTME)，随访13年(回溯性研究)，以及前瞻性随机III期多中心Rapido临床试验新辅助化疗后TME。直肠癌生物标志物的开发可能会改善分层，从而更有效地控制有和没有微转移的原发直肠肿瘤。我们的目标是开发和验证一种预测性生物标志物小组，用于对患者进行分层治疗。我们将确定可以单独从TME中受益的原始直肠癌患者，以及不同的新辅助治疗方法，包括单独的放射治疗或化疗方案。研究目的如下：目的一：验证表观基因组生物标志物对TME或PRTME治疗患者远处器官复发的预测作用。目的II：验证表观基因组生物标志物对TME或PRTME治疗患者局部复发的预测作用。目的III：验证最佳表观基因组直肠癌生物标记物在新辅助化疗后TME中预测无瘤生存率。这项研究使用一种新的表观基因组预测生物标记物组合来解决原发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.