Department of General and Breast Surgery, Cork University Hospital, Cork, Ireland.
Cork Breast Research Centre, University College Cork, Cork, Ireland.
JAMA Netw Open. 2020 Nov 2;3(11):e2026921. doi: 10.1001/jamanetworkopen.2020.26921.
Fragmented DNA is continuously released into the circulation following apoptosis and necrosis of both cancerous and noncancerous cells; when it is released by cancer cells, it is specifically known as circulating tumor DNA (ctDNA). Previous studies have suggested that ctDNA can reflect tumor burden and guide potential therapeutic targets.
To determine the association of ctDNA with breast cancer disease-free survival (DFS) and progression-free survival in early, locally advanced, and metastatic breast cancer.
An electronic search was conducted using the Cochrane Library, ScienceDirect, PubMed, and Embase from July 30, 2019, to October 31, 2019; all languages were included. The following search terms were used: ctDNA OR circulating tumor DNA OR liquid biopsy AND breast cancer OR breast carcinoma OR breast tumor AND prognosis OR survival. All titles were screened, and the appropriate abstracts were reviewed. If any data were missing, the authors contacted the study authors for permission to access data and extrapolate hazard ratios (HRs).
To be included in the analysis, the studies had to meet the following prespecified inclusion criteria: (1) a ctDNA blood sample was measured; (2) DFS, progression-free survival, or relapse-free survival was reported as an HR; and (3) the patient population only had breast cancer. Retrospective and prospective observational cohort studies were included.
Two authors (C.C. and C.F.) independently reviewed the literature. All data were recorded independently by both authors and were compared at the end of the reviewing process to limit selection bias. Duplicates were removed and any disparities were clarified. Data were pooled using a fixed-effects or random-effects model according to the study heterogeneity. This study adhered to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE).
The primary outcome was the association of ctDNA with DFS or relapse-free survival in breast cancer. Secondary outcomes focused on subgroup analysis in the setting of early breast cancer and metastatic breast cancer.
From a total of 263 publications found using the predefined search terms, data from 8 studies (3.0%) reporting on 739 patients in total were suitable for inclusion. Circulating tumor DNA gene variation detection (both before and after treatment) was statistically significantly associated with shorter DFS (HR, 4.44; 95% CI, 2.29-8.61; P < .001). Detection of ctDNA was statistically significantly associated with a reduction in DFS in both the early breast cancer subgroup (HR, 8.32; 95% CI, 3.01-22.99; P < .001) and the metastatic or locally advanced subgroup (HR, 1.91; 95% CI, 1.35-2.71; P < .001). Pretreatment and posttreatment plasma sample collection was analyzed in both early and metastatic groups. The posttreatment group encompassed both surgical and oncologic therapy. Pretreatment plasma detection of ctDNA was statistically significantly associated with reduced DFS (HR, 3.30; 95% CI, 1.98-5.52; P < .001). Posttreatment sampling of ctDNA failed to achieve statistical significance (HR, 8.17; 95% CI, 1.01-65.89; P = .05).
In this systematic review and meta-analysis, elevated plasma ctDNA was associated with a high risk of relapse. This finding suggests that plasma ctDNA may provide an excellent method to stratify risk and personalize patient follow-up.
重要性：细胞凋亡和坏死会导致癌症和非癌症细胞不断向循环系统释放碎片化的 DNA；当这些 DNA 由癌细胞释放时，它们被特别称为循环肿瘤 DNA（ctDNA）。之前的研究表明，ctDNA 可以反映肿瘤负担，并指导潜在的治疗靶点。
目的：确定 ctDNA 与早期、局部晚期和转移性乳腺癌的无病生存（DFS）和无进展生存之间的关系。
数据来源：从 2019 年 7 月 30 日至 2019 年 10 月 31 日，使用 Cochrane Library、ScienceDirect、PubMed 和 Embase 进行了电子搜索，涵盖所有语言。使用了以下搜索词：ctDNA 或循环肿瘤 DNA 或液体活检和乳腺癌或乳腺癌或乳腺肿瘤和预后或生存。筛选了所有标题，并审查了适当的摘要。如果任何数据缺失，作者会联系研究作者，请求允许访问数据并推断危险比（HR）。
研究选择：为了进行分析，研究必须符合以下预先指定的纳入标准：（1）测量了 ctDNA 血样；（2）报告了 DFS、无进展生存或无复发生存作为 HR；（3）患者人群仅患有乳腺癌。纳入了回顾性和前瞻性观察队列研究。
数据提取和综合：两位作者（C.C. 和 C.F.）独立审查了文献。所有数据均由两位作者独立记录，并在审查过程结束时进行比较，以限制选择偏倚。删除了重复项，并澄清了任何差异。根据研究的异质性，使用固定效应或随机效应模型对数据进行汇总。本研究遵循系统评价和荟萃分析的首选报告项目（PRISMA）和观察性研究荟萃分析（MOOSE）的指南。
主要结果和测量：主要结局是 ctDNA 与乳腺癌的 DFS 或无复发生存之间的关系。次要结局集中在早期乳腺癌和转移性乳腺癌的背景下进行亚组分析。
结果：从使用预定义搜索词找到的 263 篇出版物中，共有 8 项研究（3.0%）的数据适合纳入，共涉及 739 名患者。循环肿瘤 DNA 基因变异检测（治疗前后）与较短的 DFS 显著相关（HR，4.44；95%CI，2.29-8.61；P<.001）。在早期乳腺癌亚组（HR，8.32；95%CI，3.01-22.99；P<.001）和转移性或局部晚期亚组（HR，1.91；95%CI，1.35-2.71；P<.001）中，检测到 ctDNA 与 DFS 降低显著相关。在早期和转移性组中均分析了治疗前和治疗后血浆样本的采集。后处理组包括手术和肿瘤治疗。治疗前血浆 ctDNA 检测与 DFS 降低显著相关（HR，3.30；95%CI，1.98-5.52；P<.001）。治疗后取样 ctDNA 未能达到统计学意义（HR，8.17；95%CI，1.01-65.89；P=.05）。
结论和相关性：在这项系统评价和荟萃分析中，升高的血浆 ctDNA 与高复发风险相关。这一发现表明，血浆 ctDNA 可能提供一种极好的风险分层和个体化患者随访的方法。
