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MSI testing

What’s new? What should be considered?

MSI-Testung

Was ist neu? Was ist zu beachten?

Abstract

Based on new trial data regarding immune checkpoint inhibitors (ICIs), the detection of high-grade microsatellite instability (MSI-H) or underlying deficient mismatch repair protein (dMMR) is now becoming increasingly important for predicting treatment response. For the first time, a PD‑1 ICI (pembrolizumab) has been approved by the European Medicines Agency (EMA) for first-line treatment of advanced (stage IV) dMMR/MSI‑H colorectal cancer (CRC). Further indications, such as dMMR/MSI‑H endometrial carcinoma (EC), have already succeeded (Dostarlimab, 2nd line treatment) and others are expected to follow before the end of 2021. The question of optimal testing in routine diagnostics should therefore be re-evaluated. Based on a consideration of the strengths and weaknesses of the widely available methods (immunohistochemistry and PCR), a test algorithm is proposed that allows quality assured, reliable, and cost-effective dMMR/MSI‑H testing. For CRC and EC, testing is therefore already possible at the primary diagnosis stage, in line with international recommendations (NICE, NCCN). The clinician is therefore enabled from the outset to consider not only the predictive but also the prognostic and predispositional implications of such a test when counseling patients and formulating treatment recommendations. As a basis for quality assurance, participation in interlaboratory comparisons and continuous documentation of results (e.g., QuIP Monitor) are strongly recommended.

Zusammenfassung

Aufgrund neuer Studiendaten mit Immuncheckpoint-Inhibitoren (ICI) gewinnt der Nachweis einer hochgradigen Mikrosatelliteninstabilität (MSI-H) bzw. der zugrunde liegenden Mismatch-Repair-Protein-Defizienz (dMMR) nun auch zur Prädiktion von Therapieansprechen zunehmend an Bedeutung. Aktuell wurde von der Europäischen Medizinischen Agentur (EMA) erstmals ein PD-1-ICI (Pembrolizumab) für die Erstlinientherapie des fortgeschrittenen (Stadium IV) dMMR/MSI‑H kolorektalen Karzinoms (KRK) zugelassen. Weitere Indikationen, wie z. B. für das metastastasierte dMMR/MSI-H-Endometriumkarzinom (EK) in der Zweitlinientherapie (Dostarlimab) sind bereits gefolgt, andere werden noch im laufenden Jahr 2021 erwartet. Dies erfordert eine Neubewertung der Frage nach der optimalen Testung in der Routinediagnostik. Auf Basis einer Abwägung von Stärken und Schwächen der in der Breite zur Verfügung stehenden Methoden (Immunhistochemie und PCR) wird ein Testalgorithmus vorgeschlagen, der qualitätsgesichert eine zuverlässige und kosteneffektive dMMR/MSI-H-Testung erlaubt. Für das KRK und EK ist damit analog internationaler Empfehlungen (NICE, NCCN) eine Testung bereits bei der Primärdiagnose möglich. Somit wird der Kliniker von vornherein in die Lage versetzt, neben den prädiktiven auch die prognostischen und prädispositionsbedingten Implikationen eines solchen Tests bei der Beratung von Patienten und Erarbeitung von Therapieempfehlungen zu berücksichtigen. Als Grundlage der Qualitätssicherung wird die Teilnahme an Ringversuchen und eine fortlaufende Ergebnisdokumentation (z. B. QuIP-Monitor) empfohlen.

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Correspondence to Josef Rüschoff.

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Conflict of interest

G. Baretton, H. Bläker, W. Dietmaier, M. Dietel, K. Jöhrens, T. Kirchner, S. Merkelbach-Bruse, P. Schirmacher, and K. Tiemann declare that they have no competing interests. Honoraria for lectures and advisory boards have been received by: MB from AstraZeneca, Roche, Novartis, GSK, MSD, Targos, Molecular Health, Merck. R. Büttner from AbbVie, AstraZeneca, Bayer, BMS, Boehringer-Ingelheim, Illumina, Lilly, MSD, Novartis, Qiagen, Pfizer, Roche. A. Hartmann from Abbvie, AstraZeneca, Biontech, BMS, Boehringer Ingelheim, Cepheid, Diaceutics, Illumina, Ipsen, Janssen, MSD, Nanostring, Novartis, Qiagen, QuIP GmbH, Roche, 3DHistotech. L.-C. Horn from Astra Zeneca, Roche, Dako, Novartis, Exact Sciences, GSK. D. Mayr from AstraZeneca, MSD, Roche, Novartis, BMS. R. Knüchel from MSD. J. Rüschoff from MSD/Merck, GSK, BMS, AstraZeneca, Roche, Exact Sciences, QuIP GmbH. H.-U. Schildhaus from MSD, BMS, Pfizer, Novartis Oncology, Roche Pharma, Molecular Health. M. Tiemann from BMS, MSD. W. Weichert from Roche, MSD, BMS, AstraZeneca, Pfizer, Merck, Lilly, Boehringer, Novartis, Takeda, Bayer, Amgen, Astellas, Illumina, Siemens, Agilent, GSK, ADC, Molecular Health. R. Büttner is co-founder and scientific advisor, J. Rüschoff co-founder and CMO, H.-U. Schildhaus: employee of Targos Mol. Path. Gmbh.

For this article no studies with human participants or animals were performed by any of the authors. All studies performed were in accordance with the ethical standards indicated in each case.

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W. Roth, Mainz

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Rüschoff, J., Baretton, G., Bläker, H. et al. MSI testing. Pathologe (2021). https://doi.org/10.1007/s00292-021-00948-3

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Keywords

  • DNA mismatch repair
  • Endometrial carcinoma
  • Immune checkpoint inhibitors
  • Microsatellite instability
  • Prognosis

Schlüsselwörter

  • DNA-Mismatch-Reparatur
  • Endometriumkarzinome
  • Immuncheckpoint-Inhibitoren
  • Mikrosatelliteninstabilität
  • Prognose
  • Endometriumkarzinome