Predicting Risk of Recurrence After Colorectal Cancer Surgery in the United States: An Analysis of a Special Commission on Cancer National Study.
- 作者列表："Zafar SN","Hu CY","Snyder RA","Cuddy A","You YN","Lowenstein LM","Volk RJ","Chang GJ
BACKGROUND:Several factors can affect the risk of recurrence after curative resection of colorectal cancer (CRC). We aimed to develop a risk model for recurrence after definitive treatment of Stage I-III CRC using data from a nationally representative database and to develop an individualized web-based risk calculator. METHODS:A random sample of patients who underwent resection for Stage I-III CRC between 2006 and 2007 at Commission on Cancer (CoC) accredited centers were included. Primary data regarding first recurrence was abstracted from medical records and merged with the National Cancer Database. Multivariable cox regression analysis was used to test for factors associated with cancer recurrence, stratified by stage. Model performance was tested by c statistic and calibration plots. Hazard Ratios were utilized to develop an individualized web-based recurrence prediction tool. RESULTS:A total of 8249 patients from 1175 CoC centers were included. Of these, 1656 (20.1%) patients had a recurrence during 5 years of follow-up. Median time to recurrence was 16 months. The final predictive models displayed excellent discrimination and calibration with concordance indexes of 0.7. The online calculator included 12 variables, including tumor site, stage, time since surgery, and surveillance intensity. Output is displayed numerically and graphically with an icon array. CONCLUSIONS:Using primarily abstracted recurrence data from a random sample of patients treated for CRC at CoC accredited centers across the United States, we successfully created an individualized CRC recurrence risk assessment tool. This web-based calculator can be used by physicians and patients in shared decision making to guide management discussions. TRIAL REGISTRATION:ClinicalTrials.gov Registration Number: NCT02217865.
背景: 多种因素可影响结直肠癌 (CRC) 根治性切除术后的复发风险。我们旨在利用全国代表性数据库中的数据，开发 I-III 期 CRC 确定性治疗后复发的风险模型，并开发基于网络的个体化风险计算器。 方法: 随机抽样纳入 2006年和 2007 年在癌症委员会 (CoC) 认证中心接受 I-III 期 CRC 切除术的患者。从病历中提取首次复发的主要数据，并与国家癌症数据库合并。采用多变量 cox 回归分析检验与癌症复发相关的因素，按阶段分层。通过 c 统计图和校准图检验模型性能。利用风险比开发个体化的基于网络的复发预测工具。 结果: 共纳入来自 8249 个 CoC 中心的 1175 例患者。其中，1656 例 (20.1%) 患者在 5 年的随访中复发。中位复发时间为 16 个月。最终的预测模型显示了良好的区分度和校准，一致性指数为 0.7。在线计算器包括 12 个变量，包括肿瘤部位、分期、手术时间和监测强度。输出以数字和图形方式显示，并带有图标数组。 结论: 使用来自美国 CoC 认证中心接受 CRC 治疗的患者随机样本的主要抽象复发数据，我们成功创建了个体化 CRC 复发风险评估工具。这个基于网络的计算器可以由医生和患者在共享决策中使用，以指导管理讨论。 试用注册: ClinicalTrials.gov 注册号: nct02217865。
METHODS::Aims: Radiotherapy is predominantly used as one of the treatment modalities to treat local tumor in colorectal cancer (CRC). Hindrance in disease treatment can be attributed to radio-tolerance of cancer stem cells (CSCs) subsistence in the tumor. Understanding the radio-resistant property of CSCs might help in the accomplishment of targeted radiotherapy treatment and increased disease-free survival. Telomeric RAP1 contributes in modulation of various transcription factors leading to aberrant cell proliferation and tumor cell migration. Therefore, we investigated the role of RAP1 in maintaining resistance phenotype and acquired stemness in radio-resistant cells.Main Methods: Characterization of HCT116 derived radio-resistant cell (HCT116RR) was performed by cell survival and DNA damage profiling. RAP1 silenced cells were investigated for DNA damage and expression of CSC markers through western blotting and Real-time PCR post-irradiation. Molecular docking and co-immunoprecipitation study were performed to investigate RAP1 and KLF4 interaction followed by RAP1 protein status profiling in CRC patient.Key findings: We established radio-resistant cells, which showed tolerance to radiotherapy and elevated expression of CSC markers along with RAP1. RAP1 silencing showed enhanced DNA damage and reduced expression of CSC markers post-irradiation. We observed strong physical interaction between RAP1 and KLF4 protein. Furthermore, higher RAP1 expression was observed in the tumor of CRC patients. Dataset analysis also revealed that high expression of RAP1 expression is associated with poor prognosis.Significance: We conclude that higher expression ofRAP1 implicates its possible role in promoting radio-resistance in CRC cells by modulating DNA damage and CSC phenotype.
METHODS::Cancer stem-like cells are rare immortal cells within tumor, which are thought to play important roles in ionizing radiation (IR) therapy-resistance. Quercetin is a natural flavonoid with potential anti-cancer properties without significant cytotoxicity in normal tissues. In this study, we demonstrated that quercetin-IR combination treatment exhibited more dramatic anti-cancer effect than either quercetin or IR treatment alone via targeting colon cancer stem cells (CSCs) and inhibiting the Notch-1 signaling. These effects were further verified by in vivo studies which showed remarkable decrease of the CSCs markers and the expression of Notch-1 signaling proteins in human colon cancer xenografts in nude mice. Co-treatment with quercetin and low dose of radiation significantly reduced the expressions of all five proteins of γ-secretase complex in HT-29 and DLD-1 cells. In addition, ectopic expression of the Notch intracellular domain (NICD) partly reversed the inhibition effects by the combination therapy. In conclusion, our results indicated that the combination of quercetin (20 μM) and IR (5Gy) might be a promising therapeutic strategy for colon cancer treatment by targeting colon cancer stem-like cells and inhibiting the Notch-1 signaling. In future studies, we intend to further explore the potential therapeutic efficacy of the quercetin-radiation combination treatment in clinical trials.
METHODS:OBJECTIVES:Long-term prevention of metastatic disease remains a challenge in locally advanced rectal cancer, and robust pretreatment prognostic factors for metastatic progression are lacking. We hypothesized that detecting circulating tumor-specific DNA (ctDNA) based on hypermethylation of the neuropeptide Y gene (meth-ctDNA) could be a prognostic marker in the neoadjuvant setting; we examined this in a secondary, explorative analysis of a prospective trial. MATERIALS AND METHODS:Serum samples were prospectively collected in a phase III trial for locally advanced rectal cancer. Positivity for and fractional abundance of meth-ctDNA in baseline samples were estimated. Overall survival (OS) and the rate of distant metastases were compared between meth-ctDNA positive and negative patients; other prognostic factors were controlled for in multivariate Cox regression. Importance of quantitative load was examined by considering the fractional abundance of meth-ctDNA relative to total circulating DNA. RESULTS:Baseline serum samples were available for 146 patients. In total, 30 patients had presence of meth-ctDNA, with no correlation with cT (P=0.8) or cN (P=0.6) stages. Median follow-up was 10.6 years for OS and 5.1 years for freedom from distant metastases. Patients with meth-ctDNA had significantly worse 5-year OS (47% vs. 69%), even when controlling for other prognostic factors (hazard ratio=2.08; 95% confidence interval, 1.23-1.51). This seemed mainly driven by disparity in the rate of distant metastases (55% vs. 72% at 5 y, P=0.01); hazard ratio=2.20 (95% confidence interval, 1.19-4.07, P=0.01) in multivariate analysis. Increased quantitative load was highly significant for worse outcomes. CONCLUSIONS:Meth-ctDNA could be a potential prognostic marker in the neoadjuvant setting and may, if validated, identify patients at increased risk of distant metastases.