Majority of B2M-mutant and -deficient colorectal carcinomas achieve clinical benefit from immune checkpoint inhibitor therapy and are microsatellite instability-high Journal Article


Authors: Middha, S.; Yaeger, R.; Shia, J.; Stadler, Z. K.; King, S.; Guercio, S.; Paroder, V.; Bates, D. D. B.; Rana, S.; Diaz, L. A. Jr; Saltz, L.; Segal, N.; Ladanyi, M.; Zehir, A.; Hechtman, J. F.
Article Title: Majority of B2M-mutant and -deficient colorectal carcinomas achieve clinical benefit from immune checkpoint inhibitor therapy and are microsatellite instability-high
Abstract: PURPOSE Microsatellite instability-high (MSI-H) colorectal carcinomas (CRCs) show high rates of response to immune checkpoint inhibitors (IOs). B2M 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 B2M-mutant, IO-naive CRC. PATIENTS AND METHODS 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 B2M mutations. All B2M-mutant CRCs were assessed for expression of B2M, major histocompatibility complex class I, and programmed death-1 ligand (PD-L1) via immunohistochemistry and average CD3(+) and CD8(+) tumor-infiltrating lymphocyte counts against a control group of MSI-H B2M wild-type CRCs. RESULTS Fifty-nine (3.4%) of 1,751 patients with CRC harbored B2M mutations, with 84% (77 of 92) of the mutations predicted to be truncating. B2M mutations were significantly enriched in MSI-H CRCs, with 44 (24%) of 182 MSI-H CRCs harboring B2M mutations (P < .001). Thirty-two of 44 B2M-mutant CRCs with available material (73%) had complete loss of B2M expression, whereas all 26 CRCs with wild-type B2M retained expression (P < .001). B2M mutation status was not associated with major histocompatibility complex class I expression, KRAS or BRAF mutation, tumor-infiltrating lymphocyte level, or PD-L1 expression after adjustment for MSI status. Of 13 patients with B2M-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. CONCLUSION B2M mutations occur in approximately 24% of MSI-H CRCs and are usually associated with loss of B2M expression. Most patients with B2M-mutant MSI-H CRC with loss of protein expression obtain clinical benefit from IOs. (C) 2019 by American Society of Clinical Oncology
Keywords: tumors; mismatch repair-deficient
Journal Title: JCO Precision Oncology
Volume: 3
ISSN: 2473-4284
Publisher: American Society of Clinical Oncology  
Date Published: 2019-01-01
Language: English
ACCESSION: WOS:000462216200001
DOI: 10.1200/po.18.00321
PROVIDER: wos
PMCID: PMC6469719
PUBMED: 31008436
Notes: Source: Wos
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MSK Authors
  1. Leonard B Saltz
    615 Saltz
  2. Neil Howard Segal
    115 Segal
  3. Zsofia Kinga Stadler
    159 Stadler
  4. Marc Ladanyi
    897 Ladanyi
  5. Jinru Shia
    475 Shia
  6. Rona Denit Yaeger
    82 Yaeger
  7. Ahmet Zehir
    164 Zehir
  8. Jaclyn Frances Hechtman
    113 Hechtman
  9. Sumit   Middha
    59 Middha
  10. Luis Alberto Diaz
    26 Diaz
  11. Satshil Rana
    4 Rana
  12. Sarah A King
    3 King
  13. David Dawson Bartlett Bates
    7 Bates