Tumor Mutational Burden in Real-World Patients With Pancreatic Cancer: Genomic Alterations and Predictive Value for...

Area of Science:

• Oncology
• Genomics
• Immunotherapy

Background:

• Pancreatic ductal adenocarcinoma (PDAC) is generally considered non-immunogenic.
• A small subset of PDAC patients exhibit high tumor mutational burden (TMB), deficient mismatch repair, or high microsatellite instability.
• These genomic features may indicate potential response to immune checkpoint inhibitor (ICI) therapy.

Purpose of the Study:

• To analyze the clinical outcomes of PDAC patients with high TMB.
• To investigate the association between high TMB, specific genomic alterations, and response to ICI therapy in PDAC.

Main Methods:

• Comprehensive genomic profiling (CGP) data from 21,932 PDAC patients were analyzed.
• Patients were categorized into high TMB (≥10 mutations/Mb) and low TMB groups.
• Clinical outcomes, including overall survival, were compared between patients receiving ICI and those not receiving ICI, stratified by TMB status.

Main Results:

• 1.3% of PDAC patients (n=293) had high TMB.
• High-TMB patients showed increased alterations in BRCA2, BRAF, PALB2, and mismatch repair pathway genes, but fewer KRAS alterations.
• Among patients receiving ICI (n=51), high-TMB patients had significantly longer median overall survival (25.7 months) compared to low-TMB patients (5.2 months).

Conclusions:

• High TMB is a predictive biomarker for ICI therapy efficacy in PDAC.
• Patients with high TMB receiving ICI demonstrated improved survival outcomes.
• Novel findings include higher rates of BRAF and BRCA2 mutations and lower rates of KRAS mutations in high-TMB PDAC.