Department of Medicine, Division of Oncology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA.
Sci Rep. 2022 Oct 22;12(1):17732. doi: 10.1038/s41598-022-20928-8.
Circulating tumor DNA (ctDNA) in peripheral blood has been used to predict prognosis and therapeutic response for triple-negative breast cancer (TNBC) patients. However, previous approaches typically use large comprehensive panels of genes commonly mutated across all breast cancers. Given the reduction in sequencing costs and decreased turnaround times associated with panel generation, the objective of this study was to assess the use of custom micro-panels for tracking disease and predicting clinical outcomes for patients with TNBC. Paired tumor-normal samples from patients with TNBC were obtained at diagnosis (T0) and whole exome sequencing (WES) was performed to identify somatic variants associated with individual tumors. Custom micro-panels of 4-6 variants were created for each individual enrolled in the study. Peripheral blood was obtained at baseline, during Cycle 1 Day 3, at time of surgery, and in 3-6 month intervals after surgery to assess variant allele fraction (VAF) at different timepoints during disease course. The VAF was compared to clinical outcomes to evaluate the ability of custom micro-panels to predict pathological response, disease-free intervals, and patient relapse. A cohort of 50 individuals were evaluated for up to 48 months post-diagnosis of TNBC. In total, there were 33 patients who did not achieve pathological complete response (pCR) and seven patients developed clinical relapse. For all patients who developed clinical relapse and had peripheral blood obtained ≤ 6 months prior to relapse (n = 4), the custom ctDNA micro-panels identified molecular relapse at an average of 4.3 months prior to clinical relapse. The custom ctDNA panel results were moderately associated with pCR such that during disease monitoring, only 11% of patients with pCR had a molecular relapse, whereas 47% of patients without pCR had a molecular relapse (Chi-Square; p-value = 0.10). In this study, we show that a custom micro-panel of 4-6 markers can be effectively used to predict outcomes and monitor remission for patients with TNBC. These custom micro-panels show high sensitivity for detecting molecular relapse in advance of clinical relapse. The use of these panels could improve patient outcomes through early detection of relapse with preemptive intervention prior to symptom onset.
外周血循环肿瘤 DNA（ctDNA）已被用于预测三阴性乳腺癌（TNBC）患者的预后和治疗反应。然而，之前的方法通常使用广泛的基因综合面板，这些基因在所有乳腺癌中普遍发生突变。鉴于测序成本的降低和与面板生成相关的周转时间的减少，本研究的目的是评估使用定制微面板来跟踪疾病并预测 TNBC 患者的临床结果。在诊断时（T0）获得了患有 TNBC 的患者的肿瘤-正常配对样本，并进行全外显子组测序（WES）以鉴定与个体肿瘤相关的体细胞变异。为研究中纳入的每位个体创建了 4-6 个变体的定制微面板。在基线时、第 1 周期第 3 天、手术时以及手术后 3-6 个月时获得外周血，以评估疾病过程中不同时间点的变异等位基因分数（VAF）。将 VAF 与临床结果进行比较，以评估定制微面板预测病理反应、无病间隔和患者复发的能力。评估了 50 名个体的队列，最长可达 TNBC 诊断后 48 个月。共有 33 名患者未达到病理完全缓解（pCR），7 名患者发生临床复发。对于所有发生临床复发且在复发前≤6 个月获得外周血的患者（n=4），定制 ctDNA 微面板在临床复发前平均 4.3 个月识别出分子复发。定制 ctDNA 面板结果与 pCR 中度相关，以至于在疾病监测期间，只有 11%的 pCR 患者发生分子复发，而 47%的无 pCR 患者发生分子复发（卡方检验；p 值=0.10）。在这项研究中，我们表明，4-6 个标志物的定制微面板可有效地用于预测 TNBC 患者的结局并监测缓解情况。这些定制微面板在临床复发前具有很高的灵敏度，可以提前检测到分子复发。通过在症状出现前进行预防性干预，尽早发现复发，这些面板的使用可以改善患者的预后。
