LBA3 - Early detection and localization of multiple cancers using a blood-based methylation assay (ELSA-seq)

Background

Early detection of cancer can potentially offer clinical benefits, particularly for those without effective screening methods. The PREDICT study (NCT 04383353) is a prospective, multi-center, longitudinal study that aims to identify multiple cancers non-invasively in early stages. As a pilot project, the THUNDER (THe UNintrusive Detection of Early-stage canceR) study is designed for development and validation of ELSA-seq, a sensitive targeted methylation sequencing assay that interrogates epigenetic alterations from circulating cell-free DNA (cfDNA). Herein we report results from the second THUNDER sub study (THUNDER-II), which focused on malignancies developed in liver, colon/rectum, esophagus, pancreas, lung and ovary.

Methods

THUNDER-II comprises four independent steps: marker discovery, model training, validation, and single-blind test. By combining data generated in-house and from public sources, a targeted methylation panel was designed. A total of 625 patients and 483 non-cancer controls were enrolled and divided into a training set (274 cancer and 195 non-cancer) and an independent validation set (351 cancer and 288 non-cancer).

Results

The cancer patients and non-cancer controls were generally comparable with respect to age, gender, and smoking status. Various stages were represented in the cancer group, and 79.5% patients were diagnosed at early stages (I-III). At 99.5% training specificity (95%CI: 96.7-100%), the cross-validated sensitivity was 79.9% (95%CI: 74.6-84.4%). The results were consistent in the validation set, with 98.3% specificity (95%CI: 95.8-99.4%) and 80.6% (76.0-84.6%) sensitivity across stages and cancer types. In terms of tracking diseased organ(s), the classifier returned a tissue-of-origin (TOO) result in 98.6% cases, and 81.0% (95%CI: 77.2-84.3%) of these predictions were correct.

Conclusions

Results from the THUNDER-II study demonstrated that early cancer signals could be identified by ELSA-seq with high specificity. This method also enabled accurate prediction of TOO, offering guidance for subsequent diagnostic work-up. Together these findings highlight the potential implementation of this sensitive and robust assay as a multi-cancer detection test.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Burning Rock Biotech.

Disclosure

B. Li: Shareholder/Stockholder/Stock options, Full/Part-time employment: Burning Rock Biotech. S. Cai, J. Xu, C. Wang, S. Fang, F. Qiu, J. Su, F. Xu, X. Wen, Y. Zhang, G. Wang: Full/Part-time employment: Burning Rock Biotech. H. Liu, Z. Zhang: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: Burning Rock Biotech.