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Prognostic Value of Serum NPY Hypermethylation in Neoadjuvant Chemoradiotherapy for Rectal Cancer: Secondary Analysis of a Randomized Trial.

血清 NPY 高甲基化在直肠癌新辅助放化疗中的预后价值: 一项随机试验的二次分析。

  • 影响因子:2.46
  • DOI:10.1097/COC.0000000000000609
  • 作者列表:"Appelt AL","Andersen RF","Lindebjerg J","Jakobsen A
  • 发表时间:2020-01-01
Abstract

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.

摘要

目的: 局部晚期直肠癌转移性疾病的长期预防仍然是一个挑战,并且缺乏针对转移进展的稳健的预处理预后因素。我们假设基于神经肽 Y 基因 (meth-ctDNA) 超甲基化检测循环肿瘤特异性 DNA (ctDNA) 可能是新辅助治疗环境中的预后标志物; 我们在一项前瞻性试验的二次探索性分析中对此进行了检查。 材料和方法: 在局部晚期直肠癌的 III 期试验中前瞻性收集血清样本。估计基线样本中 meth-ctDNA 的阳性和分数丰度。比较 meth-ctDNA 阳性和阴性患者的总生存率 (OS) 和远处转移率; 在多因素 Cox 回归中控制其他预后因素。通过考虑 meth-ctDNA 相对于总循环 DNA 的分数丰度来检验定量负荷的重要性。 结果: 146 例患者的基线血清样本可用。总共有 30 例患者存在 meth-ctDNA,与 cT (P = 0.8) 或 cN (P = 0.6) 分期无相关性。OS 的中位随访时间为 10.6 年,无远处转移为 5.1 年。Meth-ctDNA 患者的 5 年 OS 明显恶化 (47% vs. 69%),即使控制其他预后因素 (风险比 = 2.08; 95% 置信区间,1.23-1.51)。这似乎主要是由远处转移率的差异 (55% vs. 5 y 时 72%,P = 0.01); 多变量分析中风险比 = 2.20 (95% 置信区间,1.19-4.07,P = 0.01)。定量负荷增加对于较差的结局非常显著。 结论: Meth-ctDNA 可能是新辅助治疗中潜在的预后标志物,如果验证,可能会识别远处转移风险增加的患者。

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翻译标题与摘要 下载文献
影响因子:2.46
发表时间:2020-01-01
DOI:10.1097/COC.0000000000000609
作者列表:["Appelt AL","Andersen RF","Lindebjerg J","Jakobsen A"]

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.

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