Tumor Mutational Burden as a Potential Biomarker for Immunotherapy in Pancreatic Cancer: Systematic Review and Still-Open Questions

SIMPLE SUMMARY: Tumor mutational burden (TMB) represents the number of mutations per megabase (muts/Mb) harbored by tumor cells in a given neoplasm, and can be determined with next-generation sequencing. High values are an indicator of potential response to immunotherapy. With this systematic review, we assessed its role in pancreatic ductal adenocarcinoma (PDAC). Our main findings can be summarized as: (i) high-TMB can be found in about 1% of PDAC; (ii) it is associated with mucinous/colloid and medullary histology; (iii) high-TMB PDAC frequently harbor other actionable alterations, with microsatellite instability as the most common; (iv) immunotherapy has shown promising results in high-TMB PDAC. ABSTRACT: Tumor mutational burden (TMB) is a numeric index that expresses the number of mutations per megabase (muts/Mb) harbored by tumor cells in a neoplasm. TMB can be determined using different approaches based on next-generation sequencing. In the case of high values, it indicates a potential response to immunotherapy. In this systematic review, we assessed the potential predictive role of high-TMB in pancreatic ductal adenocarcinoma (PDAC), as well as the histo-molecular features of high-TMB PDAC. High-TMB appeared as a rare but not-negligible molecular feature in PDAC, being present in about 1.1% of cases. This genetic condition was closely associated with mucinous/colloid and medullary histology (p < 0.01). PDAC with high-TMB frequently harbored other actionable alterations, with microsatellite instability/defective mismatch repair as the most common. Immunotherapy has shown promising results in high-TMB PDAC, but the sample size of high-TMB PDAC treated so far is quite small. This study highlights interesting peculiarities of PDAC harboring high-TMB and may represent a reliable starting point for the assessment of TMB in the clinical management of patients affected by pancreatic cancer.