The incorporation of circulating tumor DNA (ctDNA) into the management of operable breast cancer (BC) has been hampered by the heterogeneous results from different studies. We aimed to assess the prognostic value of ctDNA in patients with operable (non metastatic) BC. A systematic search of databases (PubMed/Medline, Embase, and CENTRAL) and conference proceedings was conducted to identify studies reporting the association of ctDNA detection with disease-free survival (DFS) and overall survival (OS) in patients with stage I-III BC. Log-hazard ratios (HRs) were pooled at each timepoint of ctDNA assessment (baseline, after neoadjuvant therapy, and follow-up). ctDNA assays were classified as primary tumor-informed and non tumor-informed. Of the 3174 records identified, 57 studies including 5779 patients were eligible. In univariate analyses, ctDNA detection was associated with worse DFS at baseline [HR 2.98, 95% confidence interval (CI) 1.92-4.63], after neoadjuvant therapy (HR 7.69, 95% CI 4.83-12.24), and during follow-up (HR 14.04, 95% CI 7.55-26.11). Similarly, ctDNA detection at all timepoints was associated with worse OS (at baseline: HR 2.76, 95% CI 1.60-4.77; after neoadjuvant therapy: HR 2.72, 95% CI 1.44-5.14; and during follow-up: HR 9.19, 95% CI 3.26-25.90). Similar DFS and OS results were observed in multivariate analyses. Pooled HRs were numerically higher when ctDNA was detected at the end of neoadjuvant therapy or during follow-up and for primary tumor-informed assays. ctDNA detection sensitivity and specificity for BC recurrence ranged from 0.31 to 1.0 and 0.7 to 1.0, respectively. The mean lead time from ctDNA detection to overt recurrence was 10.81 months (range 0-58.9 months). ctDNA detection was associated with worse DFS and OS in patients with operable BC, particularly when detected after treatment and using primary tumor-informed assays. ctDNA detection has a high specificity for anticipating BC relapse.

中文翻译：

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循环肿瘤 DNA 用于预测可手术乳腺癌患者的复发：系统评价和荟萃分析

由于不同研究结果的异质性，循环肿瘤 DNA (ctDNA) 纳入可手术乳腺癌 (BC) 的治疗受到了阻碍。我们的目的是评估 ctDNA 对可手术（非转移性）BC 患者的预后价值。对数据库（PubMed/Medline、Embase 和 CENTRAL）和会议记录进行系统检索，以确定报告 ctDNA 检测与 I-III 期患者无病生存 (DFS) 和总生存 (OS) 之间关系的研究公元前。在 ctDNA 评估的每个时间点（基线、新辅助治疗后和随访）汇总对数风险比 (HR)。 ctDNA 检测分为原发性肿瘤相关检测和非肿瘤相关检测。在已确定的 3174 条记录中，有 57 项研究（包括 5779 名患者）符合资格。在单变量分析中，ctDNA 检测与基线 [HR 2.98，95% 置信区间 (CI) 1.92-4.63]、新辅助治疗后（HR 7.69，95% CI 4.83-12.24）和随访期间较差的 DFS 相关（ HR 14.04，95% CI 7.55-26.11)。同样，所有时间点的 ctDNA 检测均与较差的 OS 相关（基线时：HR 2.76，95% CI 1.60-4.77；新辅助治疗后：HR 2.72，95% CI 1.44-5.14；随访期间：HR 9.19，95 % CI 3.26-25.90）。在多变量分析中观察到类似的 DFS 和 OS 结果。当新辅助治疗结束时或随访期间以及原发性肿瘤相关检测中检测到 ctDNA 时，合并的 HR 数值更高。 ctDNA 检测 BC 复发的灵敏度和特异性分别为 0.31 至 1.0 和 0.7 至 1.0。从 ctDNA 检测到明显复发的平均时间为 10.81 个月（范围 0-58.9 个月）。 ctDNA 检测与可手术 BC 患者较差的 DFS 和 OS 相关，特别是在治疗后并使用原发性肿瘤相关检测进行检测时。 ctDNA 检测对于预测 BC 复发具有高度特异性。