未经治DLBCL患者ctDNA和CT监测 一个相关生物标志物的研究

检验之星

　　一项新的研究结果表明，对于具有高复发风险的弥漫性大B细胞淋巴瘤患者，在未表现出明显临床症状前通过循环监控（Surveillance circulating）循环肿瘤DNA(ctDNA)，或可一定程度上减轻此类患者因疾病复发而带来的负担。而采用的临时性监控（Interim circulating）循环肿瘤DNA对于具有高治疗失败风险的弥漫性大B细胞淋巴瘤患者来说或是一种很有前途的生物标志物。该项研究在线发表于4月分的柳叶刀.肿瘤学杂志（The Lancet Oncology）上。

　　弥漫性大B细胞淋巴瘤是一种可治愈的疾病，可一旦发生治疗失败，临床结局相当不尽人意。虽然目前借助影像学手段可帮助识别具有高治疗失败风险的患者，但放射性物质的暴露本身就是一个潜在的健康安全问题。

　　为评估弥漫性大B细胞淋巴瘤患者的血清中是否可检测到循环肿瘤DNA编码克隆免疫球蛋白基因序列，从而用来预测经一线治疗后该类患者复发发生的情况。来自美国马里兰州贝塞斯达国家癌症研究所癌症研究中心恶性淋巴组织肿瘤科的 Mark Roschewski 博士等人进行了一项相关研究。

　　研究人员使用下一代DNA测序技术回顾分析1993年5月8日至2013年6月6日期间分配到三种治疗协议之一的患者的游离肿瘤DNA情况。符合条件的患者为患弥漫性大B细胞淋巴瘤而无患惰性淋巴瘤证据且截至目前未经治疗的患者。研究人员获得了大多数治疗周期的系列血清样本及同期CT扫描结果及长达5年的随访资料。对预处理血清样本中免疫球蛋白受体基因重排VDJ基因片段进行扩增和测序，并定量血清循环肿瘤DNA编码的VDJ基因重排。

　　研究人员从126例随访中位数时间为11年(IQR 6.8–14.2)的患者的预处理标本中识别出肿瘤克隆型。108例患者在治疗结束前两个周期进行的临时性监控（Interim monitoring  ）循环肿瘤DNA显示，对于可检测到循环肿瘤DNA的患者来说预知5年疾病进展的几率为41.7% (95% CI 22.2–60.1)而对于未能检测到循环肿瘤DNA的患者来说为80.2% (69.6–87.3)(p<0.0001)。可检测到肿瘤循环DNA的临时性监测的阳性预测值为62.5% (95% CI 40.6–81.2)阴性预测值为 79.8% (69.6–87.8)。

　　107例获得完全缓解的患者进行了循环监控（Surveillance monitoring）循环肿瘤DNA，Cox比例风险模型显示临床疾病进展的危险比为228（95％CI为51-1022）对于监测期间可检测到循环肿瘤DNA的患者跟检测不到循环肿瘤DNA的患者相比较（P <0.0001），循环监控循环肿瘤DNA的阳性预测值为88.2％（95％CI为63.6-98.5）阴性预测值为97.8％（92.2-99.7），在弥漫性大B细胞淋巴瘤表现出临床证据前确定临床疾病复发风险的中位时间为3.5个月（范围0-200）。

　　研究最后认为对于具有高复发风险的弥漫性大B细胞淋巴瘤患者，在未表现出明显临床症状前通过循环监控循环肿瘤DNA，或可一定程度上减轻此类患者因疾病复发而带来的负担。而采用的临时性监控循环肿瘤DNA对于具有高治疗失败风险的弥漫性大B细胞淋巴瘤患者来说或是一种很有前途的生物标志物。


英文原文   

Circulating tumour DNA and CT monitoring in patients with untreated diffuse large B-cell lymphoma: a correlative biomarker study


Summary

Background：Diffuse large-B-cell lymphoma is curable, but when treatment fails, outcome is poor. Although imaging can help to identify patients at risk of treatment failure, they are often imprecise, and radiation exposure is a potential health risk. We aimed to assess whether circulating tumour DNA encoding the clonal immunoglobulin gene sequence could be detected in the serum of patients with diffuse large-B-cell lymphoma and used to predict clinical disease recurrence after frontline treatment.

Methods：We used next-generation DNA sequencing to retrospectively analyse cell-free circulating tumour DNA in patients assigned to one of three treatment protocols between May 8, 1993, and June 6, 2013. Eligible patients had diffuse large-B-cell lymphoma, no evidence of indolent lymphoma, and were previously untreated. We obtained serial serum samples and concurrent CT scans at specified times during most treatment cycles and up to 5 years of follow-up. VDJ gene segments of the rearranged immunoglobulin receptor genes were amplified and sequenced from pretreatment specimens and serum circulating tumour DNA encoding the VDJ rearrangements was quantitated.

Findings：Tumour clonotypes were identified in pretreatment specimens from 126 patients who were followed up for a median of 11 years (IQR 6·8–14·2). Interim monitoring of circulating tumour DNA at the end of two treatment cycles in 108 patients showed a 5-year time to progression of 41·7% (95% CI 22·2–60·1) in patients with detectable circulating tumour DNA and 80·2% (69·6–87·3) in those without detectable circulating tumour DNA (p<0·0001). Detectable interim circulating tumour DNA had a positive predictive value of 62·5% (95% CI 40·6–81·2) and a negative predictive value of 79·8% (69·6–87·8). Surveillance monitoring of circulating tumour DNA was done in 107 patients who achieved complete remission. A Cox proportional hazards model showed that the hazard ratio for clinical disease progression was 228 (95% CI 51–1022) for patients who developed detectable circulating tumour DNA during surveillance compared with patients with undetectable circulating tumour DNA (p<0·0001). Surveillance circulating tumour DNA had a positive predictive value of 88·2% (95% CI 63·6–98·5) and a negative predictive value of 97·8% (92·2–99·7) and identified risk of recurrence at a median of 3·5 months (range 0–200) before evidence of clinical disease.

Interpretation ：Surveillance circulating tumour DNA identifies patients at risk of recurrence before clinical evidence of disease in most patients and results in a reduced disease burden at relapse. Interim circulating tumour DNA is a promising biomarker to identify patients at high risk of treatment failure.


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