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

Abstract

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 framework 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.

Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications

“…In fact, 14 different PCRs were described, with only 6 studies (26% of all PCR-based studies) using the standardised NCI/MSI PCR markers. 4 A similar situation was observed for IHC, with four different types of analyses and only seven studies (53.8%) using the standardised antibodies.…”

“…52 However, due to the strong association of these two PDAC variants with MSI/dMMR, for cases of medullary and mucinous/colloid histology, the final pathology report should be integrated with the assessment of MSI/dMMR status. This should be performed using IHC as first-line analysis, also following existing guidelines, 4 and, only in the case of doubtful or not reliable IHC results, MSI-based PCR should be executed. Considering the different advantages and limitations of the methods of MSI testing in PDAC (which have been summarised in table 2), NGS is recommended as first-line analysis in the case of limited tissue, and in the context of precision oncology.…”

“…However, regarding this point, the results of our meta-analysis cannot be considered definitive, because available data on this aspect are still limited and also because of their high heterogeneity; further studies are needed to address this important point. Indeed, although MSI/dMMR is a well-recognised prognostic moderator of some cancers, with a strong association to better prognosis such as in colorectal, gastric, duodenal and ampullary cancers, 4 in PDAC such survival improvement is not so clear. The morphological and genetic complexity of this tumour type and its high aggressiveness may explain only in part these findings, indicating the probable presence of other still unknown but important factors along this line.…”

“…Interestingly, this condition can be tested using immunohistochemistry (IHC) and molecular tests, including classic (PCR)-based microsatellite testing and novel next-generation sequencing (NGS) approaches. 4 MSI/dMMR occurs in a respectable proportion of colorectal cancers (about 15%), is associated with distinct biological behaviour and differential response to different therapies, and thus routine screening is advocated in guidelines. 4 For PDAC, however, its frequency varies largely among different studies and a complete definition of MSI/dMMR PDACs is still lacking.…”

“…4 MSI/dMMR occurs in a respectable proportion of colorectal cancers (about 15%), is associated with distinct biological behaviour and differential response to different therapies, and thus routine screening is advocated in guidelines. 4 For PDAC, however, its frequency varies largely among different studies and a complete definition of MSI/dMMR PDACs is still lacking. Therefore, with this systematic review, coupled with a comparative analysis with existing databases, we aim at clarifying the true frequency of MSI/dMMR in PDAC, also highlighting the specific histological, immunohistochemical and molecular features of this tumour subtype.…”