The use of circulating tumor DNA (ctDNA) concentration for metastatic cancer surveillance is promising, but uncertainty remains about cut-offs with clinical validity. This observational study recruited 136 subjects with advanced metastatic breast cancer (irrespective of /hormone receptor status) for sequencing of their primary tumor in search for hotspot variants amenable for monitoring by droplet digital PCR (ddPCR). The study analyzed 341 on-treatment samples from 19 patients with variants H1047R or E545K enrolled for long-term (median 85 weeks, range 13-125 weeks), frequent (every 3-5 weeks, median of 14 time points per subject, range 2-29) blood sampling for ctDNA quantification by ddPCR, orthogonally validated by deep sequencing. The diagnostic accuracy of ctDNA versus cancer antigen 15-3 (CA15-3) concentrations to predict disease progression within 12 weeks was investigated using receiver operating characteristic (ROC) analysis. Likelihood ratios were used for rational selection of ctDNA result intervals. ctDNA [area under the ROC curve (AUC) 0.848, 95% confidence interval (CI) 0.791-0.895] showed superior diagnostic performance than CA15-3 (AUC 0.670, 95% CI 0.601-0.735, < 0.001) to predict clinical progression within 12 weeks. ctDNA levels below 10 mutant allele copies/ml had high negative predictive value (88%), while levels above 100 copies/ml detected 64% of progressions 10 weeks earlier versus standard of care. Logistic regression analysis indicated complementary value of ctDNA and the presence of two consecutive CA15-3 rises, resulting in a model with 86% (95% CI 74% to 93%) positive predictive value and a clinically meaningful result in 89% of blood draws. Intensive ctDNA quantification improves metastatic breast cancer surveillance and enables individualized risk-based scheduling of clinical care.

中文翻译：

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合理设定循环肿瘤 DNA 浓度阈值以改善转移性乳腺癌监测

使用循环肿瘤 DNA (ctDNA) 浓度进行转移性癌症监测是有前景的，但临床有效性的截止值仍然存在不确定性。这项观察性研究招募了 136 名晚期转移性乳腺癌受试者（无论激素受体状态如何）对其原发肿瘤进行测序，以寻找适合通过液滴数字 PCR (ddPCR) 监测的热点变异。该研究分析了来自 19 名 H1047R 或 E545K 变异患者的 341 份治疗样本，这些患者的入组时间为长期（中位 85 周，范围 13-125 周）、频繁（每 3-5 周，每个受试者中位 14 个时间点，范围） 2-29) 通过 ddPCR 进行血液采样以进行 ctDNA 定量，并通过深度测序进行正交验证。使用受试者工作特征 (ROC) 分析研究了 ctDNA 与癌症抗原 15-3 (CA15-3) 浓度的诊断准确性，以预测 12 周内疾病进展。似然比用于合理选择 ctDNA 结果区间。ctDNA [ROC 曲线下面积 (AUC) 0.848，95% 置信区间 (CI) 0.791-0.895] 在预测临床进展方面表现出优于 CA15-3（AUC 0.670，95% CI 0.601-0.735，< 0.001）的诊断性能12周。ctDNA 水平低于 10 个突变等位基因拷贝/ml 具有较高的阴性预测值 (88%)，而高于 100 个拷贝/ml 的水平与标准护理相比，可提前 10 周检测到 64% 的进展。Logistic 回归分析表明 ctDNA 的互补价值和两次连续 CA15-3 升高的存在，导致模型具有 86%（95% CI 74% 至 93%）的阳性预测值，并且 89% 的抽血结果具有临床意义。强化 ctDNA 定量可改善转移性乳腺癌监测，并实现基于风险的个性化临床护理安排。