Characterization of discordance between mismatch repair deficiency and microsatellite instability testing may prevent inappropriate treatment with immunotherapy.

Autor: Geurts BS; Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.; Oncode Institute, Utrecht, The Netherlands., Zeverijn LJ; Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.; Oncode Institute, Utrecht, The Netherlands., van Berge Henegouwen JM; Department of Clinical Genetics, Erasmus Medical Center, Leiden, The Netherlands., van der Wijngaart H; Department of Medical Oncology, GROW, Maastricht University Medical Center, Maastricht, The Netherlands., Hoes LR; Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.; Oncode Institute, Utrecht, The Netherlands., de Wit GF; Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.; Oncode Institute, Utrecht, The Netherlands., Spiekman IA; Department of Medical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands., Battaglia TW; Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.; Oncode Institute, Utrecht, The Netherlands., van Beek DM; Hartwig Medical Foundation, Amsterdam, The Netherlands., Roepman P; Hartwig Medical Foundation, Amsterdam, The Netherlands., Jansen AM; Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands., de Leng WW; Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands., Broeks A; Core Facility Molecular Pathology & Biobanking, Netherlands Cancer Institute, Amsterdam, The Netherlands., Labots M; Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands., van Herpen CM; Department of Medical Oncology, Radboud Medical Center, Nijmegen, The Netherlands., Gelderblom H; Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands., Verheul HM; Department of Medical Oncology, Erasmus Medical Center, Rotterdam, The Netherlands., Snaebjornsson P; Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.; Faculty of Medicine, University of Iceland, Reykjavik, Iceland., Voest EE; Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.; Oncode Institute, Utrecht, The Netherlands.
Jazyk: angličtina
Zdroj: The Journal of pathology [J Pathol] 2024 Jul; Vol. 263 (3), pp. 288-299. Date of Electronic Publication: 2024 May 15.
DOI: 10.1002/path.6279
Abstrakt: In the Drug Rediscovery Protocol (DRUP), patients with cancer are treated based on their tumor molecular profile with approved targeted and immunotherapies outside the labeled indication. Importantly, patients undergo a tumor biopsy for whole-genome sequencing (WGS) which allows for a WGS-based evaluation of routine diagnostics. Notably, we observed that not all biopsies of patients with dMMR/MSI-positive tumors as determined by routine diagnostics were classified as microsatellite-unstable by subsequent WGS. Therefore, we aimed to evaluate the discordance rate between routine dMMR/MSI diagnostics and WGS and to further characterize discordant cases. We assessed patients enrolled in DRUP with dMMR/MSI-positive tumors identified by routine diagnostics, who were treated with immune checkpoint blockade (ICB) and for whom WGS data were available. Patient and tumor characteristics, study treatment outcomes, and material from routine care were retrieved from the patient medical records and via Palga (the Dutch Pathology Registry), and were compared with WGS results. Initially, discordance between routine dMMR/MSI diagnostics and WGS was observed in 13 patients (13/121; 11%). The majority of these patients did not benefit from ICB (11/13; 85%). After further characterization, we found that in six patients (5%) discordance was caused by dMMR tumors that did not harbor an MSI molecular phenotype by WGS. In six patients (5%), discordance was false due to the presence of multiple primary tumors (n = 3, 2%) and misdiagnosis of dMMR status by immunohistochemistry (n = 3, 2%). In one patient (1%), the exact underlying cause of discordance could not be identified. Thus, in this group of patients limited to those initially diagnosed with dMMR/MSI tumors by current routine diagnostics, the true assay-based discordance rate between routine dMMR/MSI-positive diagnostics and WGS was 5%. To prevent inappropriate ICB treatment, clinicians and pathologists should be aware of the risk of multiple primary tumors and the limitations of different tests. © 2024 The Pathological Society of Great Britain and Ireland.
(© 2024 The Pathological Society of Great Britain and Ireland.)
Databáze: MEDLINE
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