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Genomic Profiling of Rare Undifferentiated Sarcomatoid Subtypes of Pancreatic Carcinomas: In Search of Therapeutic
Erik B Faber1, Harris B Krause2, Khalid Amin3
1Medical Scientist Training Program, University of Minnesota Medical School, Minneapolis, MN.
Purpose:
The highly aggressive undifferentiated sarcomatoid carcinoma (USC) subtype of pancreatic ductal adenocarcinoma (PDAC) remains poorly characterized because of its rarity. Previous case reports suggest that immune checkpoint inhibitors could be a promising treatment strategy, but the prevalence of established predictive biomarkers of response is largely unknown. The objective of this study was to leverage comprehensive genomic profiling of USC PDAC tumors to determine the prevalence of biomarkers associated with potential response to targeted therapies.
Methods:
USC tumors (n = 20) underwent central pathology review by a board-certified gastrointestinal pathologist to confirm the diagnosis. These samples were compared with non-USC PDAC tumors (N = 5,562). Retrospective analysis of DNA and RNA next-generation sequencing data was performed.
Results:
USC PDACs were more frequently PD-L1+ by immunohistochemistry than non-USC PDAC (63% v 16%, respectively, P < .001). Furthermore, USC PDAC had an increase in neutrophils (8.99% v 5.55%, P = .005) and dendritic cells (1.08% v 0.00%, q = 0.022) and an increased expression of PDCD1LG2 (4.6% v 1.3%, q = 0.001), PDCD1 (2.0% v 0.8%, q = 0.060), and HAVCR2 (45.9% v 21.7%, q = 0.107) than non-USC PDAC. Similar to non-USC PDAC, KRAS was the most commonly mutated gene (86% v 90%, respectively, P = 1).
Conclusion:
To our knowledge, this work represents the largest molecular analysis of USC tumors to date and showed an increased expression of immune checkpoint genes in USC tumors. These findings provide evidence for further investigation into immune checkpoint inhibitors in USC tumors.
Insights
Undifferentiated sarcomatoid carcinoma (USC) of pancreatic ductal adenocarcinoma (PDAC) shows increased immune checkpoint gene expression. This suggests potential efficacy of immune checkpoint inhibitors for treating this rare cancer subtype.
Area of Science:
- Oncology
- Genomics
- Immunotherapy
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is aggressive, with the undifferentiated sarcomatoid carcinoma (USC) subtype being rare and poorly understood.
- Immune checkpoint inhibitors show promise for cancer treatment, but predictive biomarkers for USC PDAC are largely unknown.
Purpose of the Study:
- To investigate the prevalence of biomarkers associated with targeted therapy response in USC PDAC.
- To perform comprehensive genomic profiling of USC PDAC tumors.
Main Methods:
- Central pathology review of 20 USC tumors to confirm diagnosis.
- Retrospective analysis of DNA and RNA next-generation sequencing data.
- Comparison with 5,562 non-USC PDAC tumors.
Main Results:
- USC PDAC demonstrated higher PD-L1 expression (63% vs. 16%) compared to non-USC PDAC.
- Increased neutrophils, dendritic cells, and expression of immune checkpoint genes (PDCD1LG2, PDCD1, HAVCR2) were observed in USC PDAC.
- KRAS mutations were common in both USC PDAC (86%) and non-USC PDAC (90%).
Conclusions:
- This study represents the largest molecular analysis of USC tumors to date.
- USC tumors exhibit increased expression of immune checkpoint genes.
- Findings support further investigation of immune checkpoint inhibitors for USC PDAC treatment.
