Department of Laboratory Medicine, AZ Delta General Hospital, Roeselare; Department of Biomolecular Medicine, Ghent University, Ghent.
Department of Oncology, AZ Delta General Hospital, Roeselare.
ESMO Open. 2024 Feb;9(2):102235. doi: 10.1016/j.esmoop.2024.102235. Epub 2024 Feb 5.
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 ERBB2/hormone receptor status) for sequencing of their primary tumor in search for PIK3CA hotspot variants amenable for monitoring by droplet digital PCR (ddPCR). The study analyzed 341 on-treatment samples from 19 patients with PIK3CA 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, P < 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.
循环肿瘤 DNA（ctDNA）浓度用于转移性癌症监测具有很大的潜力，但具有临床有效性的截断值仍存在不确定性。
本观察性研究招募了 136 名晚期转移性乳腺癌患者（无论 ERBB2/激素受体状态如何），对其原发肿瘤进行测序，以寻找可通过液滴数字 PCR（ddPCR）监测的 PIK3CA 热点变异。该研究分析了 19 名携带 PIK3CA 变异 H1047R 或 E545K 的患者的 341 个治疗中样本，这些患者接受了长期（中位时间 85 周，范围 13-125 周）、频繁（每 3-5 周一次，中位每个患者 14 个时间点，范围 2-29 个）的血液采样，通过 ddPCR 定量 ctDNA，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 ctDNA 与癌抗原 15-3（CA15-3）浓度预测 12 周内疾病进展的诊断准确性。使用似然比为 ctDNA 结果区间的合理选择提供依据。
ctDNA [ROC 曲线下面积（AUC）0.848，95%置信区间（CI）0.791-0.895]在预测 12 周内临床进展方面的诊断性能优于 CA15-3（AUC 0.670，95%CI 0.601-0.735，P<0.001）。ctDNA 水平低于 10 个突变等位基因拷贝/ml 具有高阴性预测值（88%），而水平高于 100 拷贝/ml 则比标准护理提前 10 周检测到 64%的进展。逻辑回归分析表明 ctDNA 和连续两次 CA15-3 升高的互补价值，从而建立了一个具有 86%（95%CI 74%-93%）阳性预测值的模型，在 89%的血液采集中有临床意义的结果。
密集型 ctDNA 定量提高了转移性乳腺癌的监测能力，并使基于风险的临床护理计划成为可能。
