This study shows that circulating tumor DNA (ctDNA) can accurately reflect the genetic profile of appendiceal cancer, which is crucial for surgical decision-making.

• ctDNA from plasma matched tumor genomic profiling with 98.4% concordance overall and 85.7% for actionable mutations.
• Key mutations found: KRAS (41%), GNAS (30%), TP53 (30%), and SMAD4 (29%).
• High-grade tumors are linked to TP53, SMAD4, and other mutations; GNAS is prevalent in low-grade tumors.

Integrating ctDNA analysis into clinical pathways can enhance patient selection and outcome predictions.

• cfDNA concentration can serve as a prognostic biomarker for disease-specific survival and progression.