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.
BACKGROUND
Cancers with a defective DNA mismatch repair (dMMR) system contain thousands of mutations most frequently located in monomorphic microsatellites and are thereby defined as having microsatellite instability (MSI). Therefore, MSI is a marker of dMMR. MSI/dMMR can be identified using immunohistochemistry to detect loss of MMR proteins and/or molecular tests to show microsatellite alterations. Together with tumour mutational burden (TMB) and PD-1/PD-L1 expression, it plays a role as a predictive biomarker for immunotherapy.


METHODS
To define best practices to implement the detection of dMMR tumours in clinical practice, the ESMO Translational Research and Precision Medicine Working Group launched a collaborative project, based on a systematic review-approach, to generate consensus recommendations on the: (i) definitions related to the concept of MSI/dMMR; (ii) methods of MSI/dMMR testing and (iii) relationships between MSI, TMB and PD-1/PD-L1 expression.


RESULTS
The MSI-related definitions, for which a consensus frame-work was used to establish definitions, included: 'microsatellites', 'MSI', 'DNA mismatch repair' and 'features of MSI tumour'. This consensus also provides recommendations on MSI testing; immunohistochemistry for the mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 represents the first action to assess MSI/dMMR (consensus with strong agreement); the second method of MSI/dMMR testing is represented by polymerase chain reaction (PCR)-based assessment of microsatellite alterations using five microsatellite markers including at least BAT-25 and BAT-26 (strong agreement). Next-generation sequencing, coupling MSI and TMB analysis, may represent a decisive tool for selecting patients for immunotherapy, for common or rare cancers not belonging to the spectrum of Lynch syndrome (very strong agreement). The relationships between MSI, TMB and PD-1/PD-L1 expression are complex, and differ according to tumour types.


CONCLUSIONS
This ESMO initiative is a response to the urgent questions raised by the growing success of immunotherapy and provides also important insights on the relationships between MSI, TMB and PD-1/PD-L1.
['Luchini|C|C|', 'Bibeau|F|F|', 'Ligtenberg|M J L|MJL|', 'Singh|N|N|', 'Nottegar|A|A|', 'Bosse|T|T|', 'Miller|R|R|', 'Riaz|N|N|', 'Douillard|J-Y|JY|', 'Andre|F|F|', 'Scarpa|A|A|']
D000074322:Antineoplastic Agents, Immunological D060890:B7-H1 Antigen D014408:Biomarkers, Tumor D053843:DNA Mismatch Repair D004252:DNA Mutational Analysis D005062:European Union D005820:Genetic Testing D059014:High-Throughput Nucleotide Sequencing D006801:Humans D007150:Immunohistochemistry D008495:Medical Oncology D053842:Microsatellite Instability D009154:Mutation D009369:Neoplasms D018579:Patient Selection D017410:Practice Guidelines as Topic D061026:Programmed Cell Death 1 Receptor D012955:Societies, Medical
immunotherapy microsatellite instability (MSI) tumour mutational burden (TMB) next-generation sequencing (NGS) tumour mutational load (TML)