Mismatch Repair (MMR) Gene Alteration and BRAF V600E Mutation Are Potential Predictive Biomarkers of Immune Checkpoint Inhibitors in MMR-Deficient Colorectal Cancer

Ibrahim Halil Sahin, Subir Goyal, Yoanna Pumpalova, Mohamad B. Sonbol, Satya Das, Sigurdis Haraldsdottir, Daniel Ahn, Kristen K. Ciombor, Zhengjia Chen, Amber Draper, Jordan Berlin, Tanios Bekaii-Saab, Gregory B. Lesinski, Bassel F. El-Rayes, Christina Wu

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Immune checkpoint inhibitor (ICI) therapy is highly effective in metastatic mismatch repair-deficient (MMR-D) colorectal cancer (CRC). In this study, we evaluated molecular and clinical predictors of ICI response in MMR-D CRC. Materials and Methods: Patient databases at four cancer institutions were queried. The Fisher exact test was performed to test the association of clinical and molecular markers. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and compared by the log-rank test. Twelve- and 24-month PFS rates were compared by the Z test. Results: A total of 60 patients with CRC with MMR-D/microsatellite instability-high who previously received ICIs were identified. Patients with liver metastasis had a lower overall response rate as compared with other sites of metastasis (36.4% vs. 68.7%; p =.081). Patients with MLH1/PMS2 loss had worse 1-year and 2-year PFS rates compared with patients with MSH2/MSH6 loss (84.2% vs. 57.8% and 78.2% vs. 54.2%, respectively; p <.001). There were improved 1-year and 2-year PFS rates in patients with wild-type BRAF when compared with patients with BRAF V600E mutation (73.3% vs. 40%, and 73.3% vs. 26.7%; respectively; p <.001). Patients aged >65 had significantly worse PFS rates as compared with patients aged ≤65 (p <.001). Conclusion: BRAF V600E mutation, MLH1 and/or PMS2 loss, as well as age >65 years and liver metastasis, may be predictive of duration of ICI response in patients with MMR-D CRC. Larger cohorts are needed to confirm our findings. Implications for Practice: The results of this study reveal clinically important biomarkers that potentially predict immune checkpoint inhibitor response in patients with mismatch repair-deficient colorectal cancer.

Original languageEnglish (US)
JournalOncologist
DOIs
StateAccepted/In press - 2021

Keywords

  • BRAF
  • Colorectal cancer
  • Immune checkpoint inhibitors
  • Liver metastasis
  • MLH1
  • MSH2
  • MSH6
  • Microsatellite instability high
  • Mismatch repair-deficient
  • PMS2

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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