The Evolutionary Origins of Recurrent Pancreatic Cancer

Area of Science:

• Genomics and Molecular Oncology
• Cancer Biology

Background:

• Surgery offers the only cure for early-stage pancreatic cancer (stages I/II).
• However, most patients experience disease recurrence post-surgery, leading to mortality.
• The genomic landscape and vulnerabilities of recurrent pancreatic cancer remain largely unknown.

Purpose of the Study:

• To investigate the genomic features of recurrent pancreatic cancer.
• To identify potential therapeutic targets for managing disease recurrence.
• To understand the clonal origins and heterogeneity of recurrent tumors.

Main Methods:

• Whole-exome or targeted sequencing was performed on 10 resected primary pancreatic cancers.
• Matched intrapancreatic recurrences or distant metastases were analyzed alongside primary tumors.
• Genomic alterations, mutational burden, and signaling pathway activation were assessed.

Main Results:

• Recurrent pancreatic cancer exhibits a significantly increased mutational burden compared to treatment-naïve disease.
• Genetic alterations activating MAPK/ERK and PI3K-AKT signaling pathways are enriched in recurrent tumors.
• Recurrence can arise from monophyletic or polyphyletic origins, with evidence of intermetastatic seeding and subclonal heterogeneity.

Conclusions:

• Recurrent pancreatic cancer possesses a distinct genomic landscape characterized by higher mutational burden and pathway activation.
• Intermetastatic genetic heterogeneity and diverse clonal origins contribute to disease progression.
• Routine post-treatment tumor sampling may offer valuable insights for managing recurrent pancreatic cancer.