Cancers lacking standard screening (LSS) options account for approximately 70% of cancer-related deaths due to late-stage diagnosis. Circulating tumor DNA (ctDNA) is a promising biomarker for multi-cancer early detection. We previously developed SPOT-MAS, a multimodal ctDNA-based assay analyzing methylation and fragmentomic profiles, effective in detecting common cancers (breast, colorectal, liver, lung and gastric). This study extends the analysis to five LSS cancers: endometrial, esophageal, head and neck, ovarian and pancreatic.

The emergence of multicancer early detection (MCED) tests holds promise for improving early cancer detection and public health outcomes. However, positive MCED test results require confirmation through recommended cancer diagnostic imaging modalities. To address these challenges, we have developed a consultation and work-up protocol for definitive diagnostic results post MCED testing, named SPOT-MAS. Developed through circulating tumor DNA (ctDNA) analysis and in line with professional guidelines and advisory board consensus, this protocol standardizes information to aid general practitioners in accessing, interpreting and managing SPOT-MAS results. Clinical effectiveness is demonstrated through a series of identified cancer cases. Our research indicates that the protocol could empower healthcare professionals to confidently interpret circulating tumor DNA test results for 5 common types of cancer, thereby facilitating the clinical integration of MCED tests.

This study exploited hepatocellular carcinoma (HCC)-specific circulating DNA methylation profiles to improve the accuracy of a current screening assay for HCC patients in high-risk populations.

Population-specific profiling of mutations in cancer genes is of critical importance for the understanding of cancer biology in general as well as the establishment of optimal diagnostics and treatment guidelines for that particular population.

We have demonstrated that our TSMA in combination with other cfDNA features can improve TOO detection in low-depth cfDNA samples.

This study provides insights into the early detection of malignancies with noninvasive methods by developing a framework, which assesses methylation, CNA, and other genomic features. They established a solid model in discriminating malignancies from healthy controls, as well as the ability to distinguish tumor of origin. This important study will demonstrate its practical impacts in the clinic and other researchers of the field.