Immune-Based Therapies and the Role of Microsatellite Instability in Pancreatic Cancer

Abstract

Pancreatic cancer is one of the most aggressive malignancies with limited treatment options thus resulting in high morbidity and mortality. Among all cancers, with a five-year survival rates of only 2–9%, pancreatic cancer holds the worst prognostic outcome for patients. To improve the overall survival, an earlier diagnosis and stratification of cancer patients for personalized treatment options are urgent needs. A minority of pancreatic cancers belong to the spectrum of Lynch syndrome-associated cancers and are characterized by microsatellite instability (MSI). MSI is a consequence of defective mismatch repair protein functions and it has been well characterized in other gastrointestinal tumors such as colorectal and gastric cancer. In the latter, high levels of MSI are linked to a better prognosis and to an increased benefit to immune-based therapies. Therefore, the same therapies could offer an opportunity of treatment for pancreatic cancer patients with MSI. In this review, we summarize the current knowledge about immune-based therapies and MSI in pancreatic cancer.

Evaluation of Micro Satellite Instability and Mismatch Repair Status in Different Solid Tumors: A Multicenter Analysis in a Real World Setting

“…The crucial role of MMR/MSI analysis for ICI administration followed the FDA approval in 2017 of the anti-PD-1 immune checkpoint monoclonal antibody pembrolizumab for MSI-H/dMMR patients with unresectable or metastatic solid tumors, regardless of age and histotype [29,30]. However, beyond the clear role in the management of CRC patients, the efficacy of ICIs in other solid tumors featuring MSI-H/dMMR status, including ECs, OCs, PaCs, PrCs, and GCs, has been demonstrated [31][32][33][34][35][36][37][38][39][40][41][42]. Thus, it is pivotal that MSI-H/dMMR status in different types of solid tumors be evaluated.…”

“…In intraductal papillary mucinous neoplasm (IPMN) of the pancreas, the incidence of MSI-H/dMMR is lower, dropping to 6.9% [40]. The lowest incidence rates of MSI-H/dMMR status have, instead, been observed in prostatic (PrC, about 3%) and pancreatic (PaC, about 1%) cancers [41,42]. However, despite such low of 16 incidence, ICIs have proven highly effective in both PrC and PaC patients featuring an MSI-H/dMMR status [41,42].…”

Pan-Cancer Analysis of the Characteristics of LY96 in Prognosis and Immunotherapy Across Human Cancer

“…Microsatellite instability is the result of functional defects in mismatch repair proteins and is also well characterized in other gastrointestinal tumors such as colorectal cancer and gastric cancer. In the latter, higher levels of MSI were associated with better outcomes and increased benefits of immunotherapy ( Ghidini et al, 2020 ). Similarly, tumor mutational load predicts survival after immunotherapy across multiple cancer types ( Samstein et al, 2019 ).…”

Pancreatic Cancer: Pathogenesis, Screening, Diagnosis, and Treatment

“…149 There is also evidence suggesting that the CD40 agonist selicrelumab may modulate the tumor microenvironment in pancreatic cancer making it more immunologically active. 150 Ghidini et al 151 recently published a review of the current immune-based treatment approaches for patients with PDAC with regard to MSI. Although significant increases in overall survival have yet to be observed from these combinations, measurable changes in tumor immunogenicity indicate that further research in this area may lead to significantly improved immune therapies for pancreatic cancer.…”