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Robust response to pembrolizumab in temozolomide-associated hypermutated and microsatellite instability-high
Udhayvir S Grewal1, Charles W Shi2, Saima Muzahir3
1Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA 30308, United States.
Abstract:
Pancreatic neuroendocrine tumors (PanNETs) are typically characterized by low tumor mutational burden and limited responsiveness to immune checkpoint inhibitors. Emerging evidence suggests that prior exposure to alkylating chemotherapeutic agents may be associated with a hypermutated phenotype (along with DNA mismatch repair dysfunction or DNA damage response gene alterations), potentially sensitizing tumors to immunotherapy. We present a case of a 68-year-old woman with metastatic functional PanNET (VIPoma) who developed a treatment-associated hypermutated, microsatellite instability-high phenotype following capecitabine-temozolomide therapy. Treatment with pembrolizumab resulted in a robust clinical, biochemical, and radiographic response. This case highlights dynamic genomic evolution in PanNETs and underscores the importance of serial molecular profiling in guiding therapeutic decisions.
Insights
Pancreatic neuroendocrine tumors (PanNETs) usually don't respond to immunotherapy. However, chemotherapy can induce a hypermutated state, making PanNETs responsive to immune checkpoint inhibitors (ICIs) like pembrolizumab.
Area of Science:
- Oncology
- Genomics
- Cancer Research
Background:
- Pancreatic neuroendocrine tumors (PanNETs) exhibit low tumor mutational burden (TMB) and poor response to immune checkpoint inhibitors (ICIs).
- Alkylating chemotherapy may induce a hypermutated phenotype, potentially sensitizing tumors to immunotherapy.
Purpose of the Study:
- To report a case of a metastatic functional PanNET that developed a hypermutated phenotype after chemotherapy.
- To demonstrate the efficacy of ICIs in a treatment-associated hypermutated PanNET.
Main Methods:
- Case report of a 68-year-old woman with metastatic functional PanNET (VIPoma).
- Analysis of genomic changes following capecitabine-temozolomide (CAPTEM) therapy.
- Treatment with pembrolizumab and assessment of response.
Main Results:
- The patient developed a hypermutated, microsatellite instability-high (MSIhigh) phenotype after CAPTEM therapy.
- Pembrolizumab treatment led to significant clinical, biochemical, and radiographic response.
- This indicates dynamic genomic evolution in PanNETs.
Conclusions:
- Chemotherapy can induce a hypermutated phenotype in PanNETs, enhancing immunotherapy response.
- Serial molecular profiling is crucial for guiding treatment decisions in PanNETs.
- This case highlights a potential strategy for improving PanNET treatment outcomes.
