Alkylating-induced hypermutation in pancreatic neuroendocrine tumours

Pancreatic neuroendocrine tumours (PanNET) represent the most chemosensitive subtype of NET, with alkylating agents being the mainstay treatment for advanced-stage disease. However, disease progression remains inevitable and presents significant clinical challenges. Advances in tumour molecular profiling have facilitated a deeper understanding of the genomic landscape of PanNET, with the aim of guiding therapeutic strategies. Although actionable mutations and elevated tumour mutational burden (TMB) are exceedingly rare in PanNET, they may offer novel therapeutic opportunities. Emerging evidence suggests that treatment with alkylating agents can induce a hypermutator phenotype in a subset of PanNET, characterised by a marked increase in TMB. This genomic evolution may enhance neoantigen load and thereby potentiate responsiveness to immune checkpoint inhibition. This mini review explores hypermutation in PanNET, with a focus on alkylating-induced changes, and considers the potential of immunotherapy in this context.