Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, P.R. China.
Department of Anesthesiology, Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, P.R. China.
Cancer Res Commun. 2023 May 30;3(5):933-942. doi: 10.1158/2767-9764.CRC-22-0363. eCollection 2023 May.
Currently, approximately 30%-55% of the patients with non-small cell lung cancer (NSCLC) develop recurrence due to minimal residual disease (MRD) after receiving surgical resection of the tumor. This study aims to develop an ultrasensitive and affordable fragmentomic assay for MRD detection in patients with NSCLC. A total of 87 patients with NSCLC, who received curative surgical resections (23 patients relapsed during follow-up), enrolled in this study. A total of 163 plasma samples, collected at 7 days and 6 months postsurgical, were used for both whole-genome sequencing (WGS) and targeted sequencing. WGS-based cell-free DNA (cfDNA) fragment profile was used to fit regularized Cox regression models, and leave-one-out cross-validation was further used to evaluate models' performance. The models showed excellent performances in detecting patients with a high risk of recurrence. At 7 days postsurgical, the high-risk patients detected by our model showed an increased risk of 4.6 times, while the risk increased to 8.3 times at 6 months postsurgical. These fragmentomics determined higher risk compared with the targeted sequencing-based circulating mutations both at 7 days and 6 months postsurgical. The overall sensitivity for detecting patients with recurrence reached 78.3% while using both fragmentomics and mutation results from 7 days and 6 months postsurgical, which increased from the 43.5% sensitivity by using only the circulating mutations. The fragmentomics showed great sensitivity in predicting patient recurrence compared with the traditional circulating mutation, especially after the surgery for early-stage NSCLC, therefore exhibiting great potential to guide adjuvant therapeutics.
The circulating tumor DNA mutation-based approach shows limited performance in MRD detection, especially for landmark MRD detection at an early-stage cancer after surgery. Here, we describe a cfDNA fragmentomics-based method in MRD detection of resectable NSCLC using WGS, and the cfDNA fragmentomics showed a great sensitivity in predicting prognosis.
目前，约 30%-55%的非小细胞肺癌 (NSCLC) 患者在接受肿瘤切除术后因微小残留病灶 (MRD) 而复发。本研究旨在开发一种超敏且经济实惠的片段组学检测方法，用于检测 NSCLC 患者的 MRD。共有 87 名接受根治性手术切除的 NSCLC 患者（23 名在随访期间复发）入组本研究。共采集了 163 份术后 7 天和 6 个月的血浆样本，用于全基因组测序 (WGS) 和靶向测序。基于 WGS 的循环游离 DNA (cfDNA) 片段谱用于拟合正则化 Cox 回归模型，进一步采用留一法交叉验证评估模型性能。该模型在检测高复发风险患者方面表现出优异的性能。术后 7 天，我们的模型检测到的高危患者复发风险增加了 4.6 倍，而术后 6 个月时风险增加到 8.3 倍。与术后 7 天和 6 个月的靶向测序循环突变相比，这些片段组学确定的风险更高。使用术后 7 天和 6 个月的片段组学和突变结果检测复发患者的总敏感性为 78.3%，而仅使用循环突变的敏感性为 43.5%。与传统的循环突变相比，片段组学在预测患者复发方面具有更高的敏感性，尤其是在早期 NSCLC 手术后，因此具有指导辅助治疗的巨大潜力。
基于循环肿瘤 DNA 突变的方法在 MRD 检测中的表现有限，尤其是在手术后早期癌症的里程碑式 MRD 检测中。在这里，我们描述了一种使用 WGS 检测可切除 NSCLC 中 MRD 的 cfDNA 片段组学方法，cfDNA 片段组学在预测预后方面表现出很高的敏感性。
