Circulating Tumor DNA Analyses as Markers of Recurrence Risk and Benefit of Adjuvant Therapy for Stage III Colon Cancer
Circulating Tumor DNA Analyses as Markers of Recurrence Risk and Benefit of Adjuvant Therapy for Stage III Colon Cancer
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DOI：
10.1001/jamaoncol.2019.3616
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发表时间：
2019-12-01
期刊：
影响因子：
28.4
通讯作者：
Gibbs, Peter
中科院分区：
文献类型：
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作者：
Tie, Jeanne;Cohen, Joshua D.;Gibbs, Peter
重要性III期结肠癌患者的辅助化疗通过根除微小残留病变来预防复发。然而，目前还不能确定哪些患者在完成标准辅助治疗后仍有高复发风险。术后循环肿瘤DNA(CtDNA)分析可以发现微小的残留病变，并与结直肠癌的复发有关。目的探讨术后和化疗后连续检测ctDNA是否能实时反映III期结肠癌的辅助治疗效果。设计、设置和参与者这项多中心、澳大利亚、基于人群的队列生物标记物研究招募了100名连续100名新诊断的III期结肠癌患者，计划从2014年11月1日至2017年5月31日进行24周的辅助化疗。排除在最近3年内诊断为其他恶性肿瘤的患者。中位随访时间为28.9个月(11.6~46.4个月)。医生对ctDNA结果视而不见。对2018年12月10日至2019年6月23日的数据进行了分析。连续采集手术后和化疗后的血浆样本。通过对结直肠癌中常见的15个突变基因进行大规模平行测序，确定了单个患者肿瘤中的体细胞突变。设计了个性化的检测方法来量化ctDNA。主要结果和指标检测ctDNA和无复发间期(RFI)。结果经4次排除后，符合条件的患者96例，中位年龄(26~82岁)，男性49例(51%)。在所有96名可评估的患者的肿瘤组织中至少发现了1个体细胞突变。在96例术后样本中有20例(21%)可检测到循环肿瘤DNA，并且与较低的无复发生存率有关(风险比[HR]，3.8；95%可信区间，2.4-21.0；P<；.001)。在88例化疗后样本中有15例(17%)可检测到循环肿瘤DNA。化疗后可检测到ctDNA的3年估计RFI为30%，未检测到ctDNA的为77%(HR，6.8；95%CI，11.0-157.0；P<；.001)。在调整已知的临床病理危险因素后，术后ctDNA状态仍然与RFI独立相关(HR，7.5；95%CI，3.5-16.1；P<；.001)。结论和相关性结果表明，术后ctDNA分析是III期结肠癌有希望的预后标志物。化疗后ctDNA分析可以确定尽管完成了标准辅助治疗但仍有高复发风险的患者亚群。这一高危人群为探索其他治疗方法提供了一个独特的机会。这项多中心队列研究评估了手术后和化疗后对循环肿瘤DNA水平的连续分析是否可以为III期结肠癌患者的辅助治疗效果提供实时指示。问题：循环肿瘤DNA水平的连续分析是否可以为III期结肠癌患者的辅助化疗效果提供实时指示？在这项对96例III期结肠癌患者进行的多中心队列研究中，在手术后可检测到的循环肿瘤DNA水平与未检测到的循环肿瘤DNA水平的患者中，观察到三年无复发间隔的显著差异(47%对76%)和完成化疗后(30%对77%)。这意味着，尽管完成了标准的辅助治疗，但手术后和化疗后的循环肿瘤DNA分析可能会识别出复发风险较高的患者，这为探索其他治疗方法提供了独特的机会。
Importance Adjuvant chemotherapy in patients with stage III colon cancer prevents recurrence by eradicating minimal residual disease. However, which patients remain at high risk of recurrence after completing standard adjuvant treatment cannot currently be determined. Postsurgical circulating tumor DNA (ctDNA) analysis can detect minimal residual disease and is associated with recurrence in colorectal cancers. Objective To determine whether serial postsurgical and postchemotherapy ctDNA analysis could provide a real-time indication of adjuvant therapy efficacy in stage III colon cancer. Design, Setting, and Participants This multicenter, Australian, population-based cohort biomarker study recruited 100 consecutive patients with newly diagnosed stage III colon cancer planned for 24 weeks of adjuvant chemotherapy from November 1, 2014, through May 31, 2017. Patients with another malignant neoplasm diagnosed within the last 3 years were excluded. Median duration of follow-up was 28.9 months (range, 11.6-46.4 months). Physicians were blinded to ctDNA results. Data were analyzed from December 10, 2018, through June 23, 2019. Exposures Serial plasma samples were collected after surgery and after chemotherapy. Somatic mutations in individual patients' tumors were identified via massively parallel sequencing of 15 genes commonly mutated in colorectal cancer. Personalized assays were designed to quantify ctDNA. Main Outcomes and Measures Detection of ctDNA and recurrence-free interval (RFI). Results After 4 exclusions, 96 eligible patients were eligible; median patient age was 64 years (range, 26-82 years); 49 (51%) were men. At least 1 somatic mutation was identified in the tumor tissue of all 96 evaluable patients. Circulating tumor DNA was detectable in 20 of 96 (21%) postsurgical samples and was associated with inferior recurrence-free survival (hazard ratio [HR], 3.8; 95% CI, 2.4-21.0; P < .001). Circulating tumor DNA was detectable in 15 of 88 (17%) postchemotherapy samples. The estimated 3-year RFI was 30% when ctDNA was detectable after chemotherapy and 77% when ctDNA was undetectable (HR, 6.8; 95% CI, 11.0-157.0; P < .001). Postsurgical ctDNA status remained independently associated with RFI after adjusting for known clinicopathologic risk factors (HR, 7.5; 95% CI, 3.5-16.1; P < .001). Conclusions and Relevance Results suggest that ctDNA analysis after surgery is a promising prognostic marker in stage III colon cancer. Postchemotherapy ctDNA analysis may define a patient subset that remains at high risk of recurrence despite completing standard adjuvant treatment. This high-risk population presents a unique opportunity to explore additional therapeutic approaches.This multicenter cohort study assesses whether serial postsurgical and postchemotherapy analyses of circulating tumor DNA levels could provide a real-time indication of adjuvant therapy efficacy in patients with stage III colon cancer.Question Can serial analysis of circulating tumor DNA levels provide a real-time indication of adjuvant chemotherapy efficacy in patients with stage III colon cancer? Findings In this multicenter cohort study of 96 patients with stage III colon cancer, a significant difference in 3-year recurrence-free interval was observed in patients with detectable vs undetectable levels of circulating tumor DNA after surgery (47% vs 76%) and after completion of chemotherapy (30% vs 77%). Meaning Postsurgical and postchemotherapy circulating tumor DNA analyses may identify patients at high risk of recurrence despite completing standard adjuvant treatment, presenting a unique opportunity to explore additional therapeutic approaches.