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Aim: 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. Methods: SPOT-MAS was applied to profile cfDNA methylation and fragmentomic patterns in 739 healthy individuals and 135 LSS cancer patients. Results: We identified 347 differentially methylated regions and observed genome-wide hypomethylation across all five LSS cancers. Esophageal and head and neck cancers showed an enrichment of short cfDNA fragments (<150 bp). Eleven 4-mer end motifs were consistently altered in cfDNA fragments across all LSS cancers. Many significant signatures were consistent with previous observations in common cancers. Notably, SPOT-MAS achieved 96.2% specificity and 74.8% overall sensitivity, with a lower sensitivity of 60.7% in early-stage cancers. Conclusion: This proof-of-concept study demonstrates that SPOT-MAS a non-invasive test trained on five common cancer types, could detect a number of LSS cancer cases, potentially complementing existing screening programs. Plain Language Summary Many cancers do not have standard tests, so they are often found too late, which leads to about 70% of cancer deaths. We've created a blood test that can help find cancer early. This test has already worked well for common cancers like breast and lung cancer, and now we're testing it on five harder-to-detect cancers: endometrial, esophageal, head and neck, ovarian and pancreatic cancers. In our study, we tested our blood test on 739 healthy people and 135 patients with these difficult cancers. Our method correctly identified healthy people 96.2% of the time and found cancer cases 74.8% of the time. This new test could help with screening for types of cancer that do not have good tests right now. Article highlights Approximately 70% of cancer deaths result from late-stage diagnoses in cancers lacking standard-of-care screening (LSS). The SPOT-MAS test is a ctDNA-based assay designed to detect five common cancers (breast, lung, colorectal, gastric and liver) and has been extended to five additional LSS cancers: endometrial, esophageal, head and neck, ovarian and pancreatic. The assay analyzed cfDNA methylation and fragmentomic patterns in 135 LSS cancer patients and 739 healthy individuals. It identified 347 differentially methylated regions and specific fragmentomic alterations. SPOT-MAS achieved 96.2% specificity and 74.8% overall sensitivity, with 60.7% sensitivity for early-stage detection. This study suggests that SPOT-MAS could serve as a non-invasive method for detecting LSS cancers. [ABSTRACT FROM AUTHOR]