Treatment-driven changes can lead to more aggressive forms of metastatic pancreatic neuroendocrine tumors (PanNETs), according to a recent study.
Post-treatment samples revealed Mismatch Repair Deficiency (dMMR) in several patients, suggesting that chemotherapy may induce genetic vulnerabilities that promote aggressive tumor behavior. The study identified mutations in key mismatch repair genes—including MSH6—associated with this deficiency.
Notably, patients with a tumor mutational burden (TMB) greater than 50 had a significantly higher likelihood of progressing to high-grade tumors compared to those with lower TMBs. The researchers noted that this finding underscores the potential role of TMB as a biomarker for monitoring disease progression and tailoring therapeutic strategies.
The study published in The Journal of Pathology examined the transition from low/intermediate to high-grade tumors, a shift often associated with poor patient outcomes. Based on the multi-omics analysis conducted on 32 longitudinal samples from 6 patients, the study explored the molecular underpinnings of metastatic progression in PanNETs and highlighted the role of systemic therapies in shaping tumor evolution and the emergence of aggressive disease characteristics.
The researchers outlined the complex evolution of PanNETs including the inactivation of the MEN1 gene which occurred early in tumor development and additional diverse genetic changes including alterations in the ATRX/DAXX genes and the mechanistic target of the rapamycin (mTOR) pathway. Patients treated with alkylating chemotherapy tended to exhibit significant increases in TMB.
The study's findings could lead to future biomarker-driven research and therapeutic strategies. The authors advocate for the inclusion of TMB analysis in clinical settings, especially for patients experiencing high-grade progression post-chemotherapy.
The authors declared no conflicts of interest.