Majority of <i>B2M</i>-Mutant and -Deficient Colorectal Carcinomas Achieve Clinical Benefit From Immune Checkpoint Inhibitor Therapy and Are Microsatellite Instability-High.
case_control · Level III
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- Record sourced from PubMed, PMID 31008436.
- Also identified by DOI 10.1200/PO.18.00321 and PMC identifier 6469719.
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Abstract
Microsatellite instability-high (MSI-H) colorectal carcinomas (CRCs) show high rates of response to immune checkpoint inhibitors (IOs). <i>B2M</i> mutations and protein loss have been proposed as causes of resistance to IOs, yet they are enriched in MSI-H CRC. We aimed to characterize <i>B2M</i>-mutant, IO-naive CRC. All CRCs with results for Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets, a next-generation sequencing assay that interrogates > 400 genes for mutations as well as MSI status, were surveyed for <i>B2M</i> mutations. All <i>B2M</i>-mutant CRCs were assessed for expression of <i>B2M</i>, major histocompatibility complex class I, and programmed death-1 ligand (PD-L1) via immunohistochemistry and average CD3<sup>+</sup> and CD8<sup>+</sup> tumor-infiltrating lymphocyte counts against a control group of MSI-H <i>B2M</i> wild-type CRCs. Fifty-nine (3.4%) of 1,751 patients with CRC harbored <i>B2M</i> mutations, with 84% (77 of 92) of the mutations predicted to be truncating. <i>B2M</i> mutations were significantly enriched in MSI-H CRCs, with 44 (24%) of 182 MSI-H CRCs harboring <i>B2M</i> mutations (<i>P</i> < .001). Thirty-two of 44 <i>B2M</i>-mutant CRCs with available material (73%) had complete loss of <i>B2M</i> expression, whereas all 26 CRCs with wild-type <i>B2M</i> retained expression (<i>P</i> < .001). <i>B2M</i> mutation status was not associated with major histocompatibility complex class I expression, <i>KRAS</i> or <i>BRAF</i> mutation, tumor-infiltrating lymphocyte level, or PD-L1 expression after adjustment for MSI status. Of 13 patients with <i>B2M</i>-mutant CRC who received programmed death-1 or PD-L1 IOs, 11 (85%) achieved clinical benefit, defined as stable disease or partial response using Response Evaluation Criteria in Solid Tumors criteria. <i>B2M</i> mutations occur in approximately 24% of MSI-H CRCs and are usually associated with loss of <i>B2M</i> expression. Most patients with <i>B2M</i>-mutant MSI-H CRC with loss of protein expression obtain clinical benefit from IOs.