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Case Reports
. 2024;16(13):853-858.
doi: 10.1080/1750743X.2024.2376516. Epub 2024 Jul 23.

Failure of immune checkpoint inhibitors for microsatellite instability-positive pancreatic adenocarcinoma with atypical pattern of short tandem repeat mutation

Anna Babayan  1 , Evgeny Ledin  1 , Alexandra Lebedeva  2   3 , Olesya Kuznetsova  2   4 , Daria Kravchuk  5 , Tatiana Grigoreva  2   3   6 , Ekaterina Belova  2   3   7 , Alexandra Kavun  2 , Vladislav Mileyko  2   3 , Alexey Tryakin  4 , Mikhail Fedyanin  4   5   8 , Maxim Ivanov  2   3   9
Affiliations
Case Reports

Failure of immune checkpoint inhibitors for microsatellite instability-positive pancreatic adenocarcinoma with atypical pattern of short tandem repeat mutation

Anna Babayan et al. Immunotherapy. 2024.

Abstract

Microsatellite instability (MSI) is an important biomarker in cancer. While routine methods can detect MSI in certain tumor types, in other tumor types the results may be incorrect due to differences in the MSI loci pattern. Here, we report the case of a patient with pancreatic adenocarcinoma, with confirmed MSI by two independent next-generation sequencing tests, but not by routine methods, who had progression on pembrolizumab. Comparison of the patient's MSI loci patterns with MSI+ colorectal adenocarcinoma samples showed a lower fraction of unstable loci, low resolution of a second peak in the repeat length spectrum of unstable short tandem repeats in the patient's sample, and a lower length of indels (3.7 vs 4.5 base pairs, p < 0.01).

Keywords: case report; immune checkpoint inhibitors; liquid biopsy; microsatellite instability; next generation sequencing.

Plain language summary

Microsatellite instability (MSI) is typically evaluated to select patients who will most likely benefit from the treatments to make immune system work better (immunotherapy). MSI is difficult to identify in cancer, because its patterns can vary in different tumors. In this article, we describe a case of a pancreatic cancer patient whose tumor, although MSI-positive, did not respond to immunotherapy. We conclude that this can be because the MSI pattern was different from those typically observed in other cancers.

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Conflict of interest statement

A Lebedev, T Grigoreva, O Kuznetsova, E Belova, A Kavun, M Ivanov, V Mileyko are employees of OncoAtlas LLC. Other authors report to conflict of interest. The authors have no other competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript apart from those disclosed.

Figures

Figure 1.
Figure 1.
Treatment timeline.
Figure 2.
Figure 2.
For each short tandem repeat manual validation of the next-generation sequencing microsatellite instability analysis was carried out based on the observed length spectrum of the mononucleotide tandem repeats (A & B) Each STR was classified as stable, unstable with unresolved second peak or unstable with resolved second peak based on the deviation from observed spectrum of the same STR analyzed in control samples with verified MSS status. Statistics on STR classes were collected for all sequenced samples of the PAAD patient’s tumor and LB samples (C) The same analysis was performed for archival CRC FFPE samples to compare the pattern of MSI of different tumor types. CRC: Colorectal cancer; LB: Liquid biopsy; MSI: Microsatellite instability; MSS: Microsatellite stable; NGS: Next-generation sequencing; PAAD: Pancreatic adenocarcinoma; STR: Short tandem repeat.
See this image and copyright information in PMC

References

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