Pancreatic Cancer Progression in a Patient With Lynch Syndrome Receiving Immunotherapy: A Cautionary Tale

View More View Less
  • 1 Department of Surgery, McGill University;
  • | 2 Research Institute of the McGill University Health Centre;
  • | 3 The Rosalind and Morris Goodman Cancer Research Centre, McGill University;
  • | 4 Canadian Centre for Computational Genomics, McGill University and Genome Quebec Innovation Center;
  • | 5 Department of Medical Oncology, Hôpital St-Eustache;
  • | 6 Department of Pathology, McGill University;
  • | 7 Molecular Diagnostics Laboratory, Sir Mortimer B. Davis-Jewish General Hospital; and
  • | 8 Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
Restricted access

Pancreatic ductal adenocarcinomas (PDACs) with DNA mismatch repair deficiency (MMRd) respond preferentially to immune checkpoint inhibitors (ICIs). However, a subset of MMRd PDACs does not respond to these agents. This report describes a patient with PDAC who experienced rapid disease progression suggestive of hyperprogressive disease. The case involved a 63-year-old man carrying a pathogenic germline PMS2 mutation who developed metastatic PDAC. His tumor showed isolated loss of PMS2 expression by immunohistochemistry (IHC). He was treated with pembrolizumab, but his disease rapidly progressed. Whole-genome and transcriptome sequencing of a liver metastasis biopsy, acquired at disease progression, showed a retained wild-type PMS2 allele and hallmarks of microsatellite stability, including low tumor mutational burden and low MSIsensor score. PCR-based microsatellite instability (MSI) testing of the treatment-naïve tumor showed microsatellite stability. The ICI-treated tumor had a lower density of CD8+ T-cell infiltration than the treatment-naïve tumor, which is contrary to the expected evolution with ICI responsiveness. Through this case and a review of the literature, we highlight the low penetrance of PMS2 germline mutations in PDAC and discuss pitfalls in ascertaining MMRd and MSI based on IHC testing alone. An orthogonal confirmatory assay is warranted in the presence of uncommon immunophenotypes, such as isolated PMS2 loss, to optimize selection of patients with PDAC for immunotherapy.

Submitted April 1, 2021; final revision received April 21, 2021; accepted for publication April 21, 2021.

Author contributions: Conceptualization: Wang, Zogopoulos. Methodology: Wang, Pacis, Marcus, Gao, Chong, Foulkes. Investigation: Cuggia, Boileau, Marcus, Gao, Chong, Foulkes, Zogopoulos. Software: Pacis. Formal analysis: Wang, Pacis. Resources: Boileau, Gao, Chong, Zogopoulos. Writing–original draft: Wang, Zogopoulos. Writing–review and editing: All authors. Supervision: Foulkes.

Disclosures: The authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: This work was supported by funding from the Fonds de Recherche du Québéc—Santé, the Canadian Institutes of Health Research Vanier Canada Graduate Scholarship, and the McGill University Surgical-Scientist Program (Dr. Wang); and the Cancer Research Society and the Quebec Cancer Consortium (Dr. Zogopoulos).

Correspondence: George Zogopoulos, MD, PhD, McGill University Health Centre, 1001 Decarie Boulevard, Room EM2.3210, Montreal, Quebec, Canada H4A 3J1. Email: george.zogopoulos@mcgill.ca
  • 1.

    Grant RC, Denroche R, Jang GH, et al. Clinical and genomic characterisation of mismatch repair deficient pancreatic adenocarcinoma [published online September 15, 2020]. Gut, doi: 10.1136/gutjnl-2020-320730

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017;357:409413.

  • 3.

    Matos I, Martin-Liberal J, García-Ruiz A, et al. Capturing hyperprogressive disease with immune-checkpoint inhibitors using RECIST 1.1 criteria. Clin Cancer Res 2020;26:18461855.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Wang Y, Park JYP, Pacis A, et al. A preclinical trial and molecularly annotated patient cohort identify predictive biomarkers in homologous recombination-deficient pancreatic cancer. Clin Cancer Res 2020;26:54625476.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Alpert L, Pai RK, Srivastava A, et al. Colorectal carcinomas with isolated loss of PMS2 staining by immunohistochemistry. Arch Pathol Lab Med 2018;142:523528.

  • 6.

    Hu ZI, Shia J, Stadler ZK, et al. Evaluating mismatch repair deficiency in pancreatic adenocarcinoma: challenges and recommendations. Clin Cancer Res 2018;24:13261336.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Tachon G, Frouin E, Karayan-Tapon L, et al. Heterogeneity of mismatch repair defect in colorectal cancer and its implications in clinical practice. Eur J Cancer 2018;95:112116.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Daly MB, Pal T, Berry MP, et al. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2021;19:77–102. To view the most recent version, visit NCCN.org

  • 9.

    Cohen R, Hain E, Buhard O, et al. Association of primary resistance to immune checkpoint inhibitors in metastatic colorectal cancer with misdiagnosis of microsatellite instability or mismatch repair deficiency status. JAMA Oncol 2019;5:551555.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Luchini C, Bibeau F, Ligtenberg MJL, et al. ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Ann Oncol 2019;30:12321243.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Champiat S, Dercle L, Ammari S, et al. Hyperprogressive disease is a new pattern of progression in cancer patients treated by anti-PD-1/PD-L1. Clin Cancer Res 2017;23:19201928.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Kim CG, Kim KH, Pyo KH, et al. Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer. Ann Oncol 2019;30:11041113.

  • 13.

    Sasaki A, Nakamura Y, Mishima S, et al. Predictive factors for hyperprogressive disease during nivolumab as anti-PD1 treatment in patients with advanced gastric cancer. Gastric Cancer 2019;22: 793802.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Kato S, Goodman A, Walavalkar V, et al. Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res 2017;23:42424250.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014;515:568571.

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 869 869 689
PDF Downloads 578 578 415
EPUB Downloads 0 0 0