Dataset Information

How I treat MSI cancers with advanced disease.

ABSTRACT: Mismatch repair deficiency (dMMR) results in microsatellite instability (MSI) and is strongly associated with responsiveness to programmed death-1 receptor (PD-1)-blocking antibodies. Probably the main driver for the observed high efficacy of immune checkpoint inhibitors in dMMR tumours is the remarkably high tumour mutational burden. MSI can be detected using immunohistochemistry and/or PCR. In addition, next-generation sequencing is becoming increasingly available to clinical laboratories as a cost-effective and scalable method to evaluate multiple genetic aberrations including MSI. Efficacy of PD-1-blockade in MSI tumours is similar for patients with colorectal cancer (CRC; objective response rate (ORR) 36%) or a different cancer type (ORR 46% across 14 other cancer types). Based on these results, PD-1-blocking antibody pembrolizumab was the first tumour-agnostic treatment to be granted Food and Drug Administration approval based on the presence of MSI as a biomarker. Currently, there is no approved PD-1-blocking antibody for MSI cancers in Europe. Here, we present our experience with the screening for MSI and the treatment of patients with advanced disease of MSI CRC and non-CRC with immunotherapy.

SUBMITTER: Kok M

PROVIDER: S-EPMC6555602 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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How I treat MSI cancers with advanced disease.

Kok Marleen M Chalabi Myriam M Haanen John J

ESMO open 20190521 Suppl 2

Mismatch repair deficiency (dMMR) results in microsatellite instability (MSI) and is strongly associated with responsiveness to programmed death-1 receptor (PD-1)-blocking antibodies. Probably the main driver for the observed high efficacy of immune checkpoint inhibitors in dMMR tumours is the remarkably high tumour mutational burden. MSI can be detected using immunohistochemistry and/or PCR. In addition, next-generation sequencing is becoming increasingly available to clinical laboratories as a ...[more]

PMID: 31231574

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Project description:Microsatellite instability (MSI) has emerged as an important predictor of sensitivity for immunotherapy-based strategies. β-2-Microglobulin (B2M) contains microsatellites within the coding regions and is prone to somatic changes in MSI/mismatch repair deficiency (MSI/dMMR) tumors. To delineate prevalence and associations of B2M mutations in MSI-H/dMMR cancers, we investigated the mutational profile of B2M and clinical and pathological features in gastric cancer (GC), colorectal cancer (CRC), and endometrial cancer (EC) with a high incidence of microsatellite instability-high (MSI-H)/dMMR. Formalin-fixed paraffin-embedded (FFPE) tumor tissues along with matched normal tissues were collected from 108 MSI/dMMR patients with GC, CRC, and EC. Genomic profiling of tissue and blood samples were assessed next-generation sequencing (NGS). Immunohistochemistry (IHC) was used to examine the presence or absence of B2M protein. Alternations in the exonic microsatellite regions of B2M were observed at various but high frequencies (57.5% in CRC, 23.9% in GC, and 13.6% in EC) and in different forms. NGS assay revealed that genes involved in chromatin regulation, the PI3K pathway, the WNT pathway, and mismatch repair were extensively altered in the MSI-H cohort. Signature 6 and 26, 2 of 4 mutational signatures associated with defective DNA mismatch repair, featured with high numbers of small insertion/deletions (INDEL) dominated in all 3 types of cancer. Alternations in the exonic microsatellite regions of B2M were observed at various but high frequencies (57.5% in CRC, 23.9% in GC, and 13.6% in EC) and in different forms. Tumor mutational burden (TMB) was significantly higher in the patients carrying MSI-H/dMMR tumors with B2M mutation than that in patients with wild-type B2M (P = .026).The frame shift alteration occurring at the exonic microsatellite sties caused loss of function of B2M gene. In addition, a case with CRC carrying indels in B2M gene resisted the ICI treatment was reported. In conclusion, patients carrying MSI-H/dMMR tumors with B2M mutation showed significantly higher TMB. Prescription of ICIs should be thoroughly evaluated for these patients.

Dataset Information

How I treat MSI cancers with advanced disease.

Publications

How I treat MSI cancers with advanced disease.

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