Genomic subtype significantly impacts recurrence patterns and survival in resampled ampullary adenocarcinoma, suggesting a need for tailored therapy.

• Genomic classification indicates that colorectal subtype has a recurrence-free survival of 55.5 months, compared to 18.3 months for pancreatic/distal bile duct subtype (p=0.022).
• Distant recurrence occurred more frequently in the pancreatic/distal bile duct subtype (44% vs. 21%; p=0.005).
• Adjuvant chemotherapy improved overall survival (HR 0.52; p=0.008), while the addition of radiation showed no benefit for recurrence-free survival.

Surgeons should consider genomic classification when discussing prognosis and adjuvant therapy options with patients.