Three Molecular Developmental Pathways of Remnant Pancreatic Cancer After Resection: A Nationwide Project Study of Japan Pancreas Society

Objective: To clarify the molecular mechanism of remnant pancreatic cancer (PC) development after primary PC resection. Background: Molecular mechanisms of the development of remnant PCs after primary PC resection are largely unknown. Methods: Forty-three patients undergoing remnant PC resection after primary PC resection between 2001 and 2017 at 26 institutes were retrospectively analyzed. Clinicopathologic features and molecular alterations detected by targeted amplicon sequencing of 36 PC-associated genes were evaluated. Results: These patients showed significantly lower body mass indices and higher hemoglobin A1c values at remnant PC resection than at primary PC resection. A comparison of the molecular features between primary and remnant PCs indicated that remnant PCs were likely to develop through 3 different molecular pathways: successional, showing identical and accumulated alterations (n = 14); phylogenic, showing identical and distinct alterations (n = 26); and distinct, showing independent distinctive alterations (n = 3). The similarity of gene alterations was associated with time to the remnant PC development (r = 0.384, P = 0.0173). Phylogenic pathways were significantly associated with the intraductal spread of carcinoma (P = 0.007). Patient survival did not differ significantly depending on these molecular pathways. Conclusions: Molecular profiling uncovered 3 pathways for the development of remnant PCs, namely, successional, phylogenic, and distinct pathways. The vast majority of remnant PCs are likely to be molecularly associated with primary PCs either in the successional or phylogenic way. This information could impact the design of a strategy for monitoring and treating remnant PCs.