The evolutionary history of metastatic pancreatic neuroendocrine tumors reveals a therapy driven route to high-grade transformation (A03)

Introduction: Tumor evolution with acquisition of more aggressive disease characteristics is a
hallmark of disseminated cancer. Metastatic pancreatic neuroendocrine tumors (PanNETs) in particular,
show frequent progression from a low/intermediate to a high-grade disease.

Aim(s): To understand the molecular mechanisms underlying metastatic progression as well as transformation from a low/intermediate to a high-grade PanNET. Materials and methods: We performed multi-omics analysis (genome/exome sequencing, total RNA-sequencing and methylation array) of 32 longitudinal samples from six patients with metastatic low/intermediate grade PanNET. Findings were validated in post-alkylating chemotherapy samples from 24 PanNET patients using targeted next generation sequencing.

Results: Bioinformatics analyses of the multi-omics dataset confirmed the current PanNET
evolutionary model with early MEN1 inactivation. This was followed by pronounced genetic diversity on
both spatial and temporal levels, with parallel and convergent tumor evolution involving the ATRX/DAXX and mTOR pathways. Following alkylating chemotherapy treatment, some PanNETs developed
mismatch repair deficiency and acquired a hypermutator phenotype. This was validated among 16
PanNET patients that had high-grade progression after alkylating chemotherapy, of whom 8 had a
tumor mutational burden >50 (50%). In comparison, among the 8 patients that did not show high-grade
progression, 0 had a tumor mutational burden >50 (0%, (Odds ratio “infinite” (95% confidence interval
1.8-“infinite” p=0.02).

Conclusion: Our findings contribute to broaden the understanding of
metastatic/high-grade PanNETs and suggests that therapy driven disease evolution is an important
hallmark of this disease.

Keywords: pancreatic neuroendocrine tumor, tumor evolution, alkylating
chemotherapy, treatment resistance