High Tumor Mutational Burden and ARID1A Mutations in Pancreatic Ductal Adenocarcinoma: A Case Report on the Efficacy of Pembrolizumab and Chemotherapy Combination Therapy
Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with poor prognosis, characterized by late-stage diagnosis and limited treatment options. It is currently the 3rd leading cause of cancer-related deaths in the United States and it is projected to become the 2nd leading cause of cancer-related deaths by 2030. Standard treatment for advanced PDAC includes chemotherapy regimens such as FOLFIRINOX and Gemzar/Abraxane, for advanced PDAC, but its effectiveness is often modest and accompanied by significant toxicity. Recently, immune checkpoint inhibitors, particularly pembrolizumab, have shown promise in treating tumors with high tumor mutational burden (TMB), which is associated with increased neoantigen presentation and immune response. However, the role of TMB as a predictive biomarker for immunotherapy in PDAC remains under investigation.
Case Report: A 61-year-old male with a history of type 2 diabetes, hypertension, and hyperlipidemia was diagnosed with locally advanced PDAC. After initial chemotherapy with FOLFIRINOX and later with Gemzar/Abraxane, disease progression was noted. Genetic testing revealed a high TMB of 29 mutations/me mega base, prompting the addition of pembrolizumab to the treatment regimen.
Subsequent imaging demonstrated a reduction in tumor size while serum CA 19-9 levels decreased from 654 to 29 U/mL. The patient tolerated the combination therapy well with no significant adverse effects.
Discussion: PDAC’s aggressive nature and low survival rates highlight the need for novel treatment strategies. While chemotherapy remains the cornerstone, immunotherapy with pembrolizumab has shown promise, particularly in tumors with high TMB. TMB correlates with better immune responses, including increased immune cell infiltration and upregulated T cell activity. The presence of ARID1A mutations, which contribute to genomic instability, further enhances the immunogenicity of TMB-high tumors, supporting the efficacy of immune checkpoint blockade. The usage of genetic markers in molding treatment strategies alongside conventional chemotherapy can be used to improve treatment outcomes and help guide personalized therapy.
