Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China; Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
Burning Rock Biotech, Guangzhou, China.
Ann Oncol. 2023 May;34(5):486-495. doi: 10.1016/j.annonc.2023.02.010. Epub 2023 Feb 26.
BACKGROUND: Early detection of cancer offers the opportunity to identify candidates when curative treatments are achievable. The THUNDER study (THe UNintrusive Detection of EaRly-stage cancers, NCT04820868) aimed to evaluate the performance of enhanced linear-splinter amplification sequencing, a previously described cell-free DNA (cfDNA) methylation-based technology, in the early detection and localization of six types of cancers in the colorectum, esophagus, liver, lung, ovary, and pancreas. PATIENTS AND METHODS: A customized panel of 161 984 CpG sites was constructed and validated by public and in-house (cancer: n = 249; non-cancer: n = 288) methylome data, respectively. The cfDNA samples from 1693 participants (cancer: n = 735; non-cancer: n = 958) were retrospectively collected to train and validate two multi-cancer detection blood test (MCDBT-1/2) models for different clinical scenarios. The models were validated on a prospective and independent cohort of age-matched 1010 participants (cancer: n = 505; non-cancer: n = 505). Simulation using the cancer incidence in China was applied to infer stage shift and survival benefits to demonstrate the potential utility of the models in the real world. RESULTS: MCDBT-1 yielded a sensitivity of 69.1% (64.8%-73.3%), a specificity of 98.9% (97.6%-99.7%), and tissue origin accuracy of 83.2% (78.7%-87.1%) in the independent validation set. For early-stage (I-III) patients, the sensitivity of MCDBT-1 was 59.8% (54.4%-65.0%). In the real-world simulation, MCDBT-1 achieved a sensitivity of 70.6% in detecting the six cancers, thus decreasing late-stage incidence by 38.7%-46.4%, and increasing 5-year survival rate by 33.1%-40.4%, respectively. In parallel, MCDBT-2 was generated at a slightly low specificity of 95.1% (92.8%-96.9%) but a higher sensitivity of 75.1% (71.9%-79.8%) than MCDBT-1 for populations at relatively high risk of cancers, and also had ideal performance. CONCLUSION: In this large-scale clinical validation study, MCDBT-1/2 models showed high sensitivity, specificity, and accuracy of predicted origin in detecting six types of cancers.
背景：癌症的早期检测提供了在可行的治疗方法下识别候选者的机会。THUNDER 研究（THe UNintrusive Detection of EaRly-stage cancers，NCT04820868）旨在评估增强型线性分裂扩增测序的性能，这是一种以前描述的基于游离 DNA（cfDNA）甲基化的技术，用于早期检测和定位结直肠、食管、肝、肺、卵巢和胰腺的六种癌症。
患者和方法：通过公共和内部（癌症：n=249；非癌症：n=288）甲基组数据分别构建和验证了定制的 161984 个 CpG 位点的面板。从 1693 名参与者（癌症：n=735；非癌症：n=958）的 cfDNA 样本中回顾性收集数据，用于训练和验证两种用于不同临床场景的多癌种检测血液检测（MCDBT-1/2）模型。在年龄匹配的 1010 名参与者的前瞻性和独立队列中验证了模型（癌症：n=505；非癌症：n=505）。使用中国的癌症发病率进行模拟，以推断分期转移和生存获益，以证明模型在现实世界中的潜在效用。
结果：MCDBT-1 在独立验证集中的灵敏度为 69.1%（64.8%-73.3%），特异性为 98.9%（97.6%-99.7%），组织起源准确性为 83.2%（78.7%-87.1%）。对于早期（I-III 期）患者，MCDBT-1 的灵敏度为 59.8%（54.4%-65.0%）。在现实世界的模拟中，MCDBT-1 在检测六种癌症中的灵敏度为 70.6%，从而降低了晚期发病率 38.7%-46.4%，并分别提高了 5 年生存率 33.1%-40.4%。同时，MCDBT-2 的特异性略低，为 95.1%（92.8%-96.9%），但灵敏度为 75.1%（71.9%-79.8%），适用于癌症风险较高的人群，也具有理想的性能。
结论：在这项大规模的临床验证研究中，MCDBT-1/2 模型在检测六种癌症时表现出高灵敏度、特异性和预测起源的准确性。
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