Effect of Microsatellite Instability and Tumor Mutational Burden on Outcome in First-Line Treatment of Metastatic Colorectal Cancer


Key Points

  • Higher tumor mutational burden was associated with improved overall survival.
  • Among patients with microsatellite instability–high tumors, those in the bevacizumab group had better survival vs those in the cetuximab group.

In an analysis of the phase III CALGB/SWOG 80405 trial reported in the Journal of Clinical Oncology, Innocenti et al found that tumor mutational burden and microsatellite instability status affected overall survival in patients receiving first-line chemotherapy plus bevacizumab or cetuximab for metastatic colorectal cancer. The trial showed no difference in overall survival between bevacizumab and cetuximab recipients.

The study involved analysis of primary tumor DNA from 843 patients in the trial (37% received bevacizumab, 38% received cetuximab, and 25% received both in addition to chemotherapy). Gene mutations were identified by polymerase chain reaction; microsatellite status was determined by genotyping of microsatellites; and tumor mutational burden was assessed by next-generation sequencing. Interactions of molecular alterations with the bevacizumab group and cetuximab groups were tested.

Factors Affecting Survival

Among all patients, those with high tumor mutational burden (> 8 mutations/Mb) had prolonged overall survival vs those with low tumor mutational burden (hazard ratio [HR] = 0.73, P = .02). Among patients with microsatellite instability–high tumors, those in the bevacizumab group had prolonged overall survival vs those in the cetuximab group (HR = 0.13, 95% confidence interval [CI] = 0.06–0.30; P < .001 for interaction between microsatellite status and the 2 treatment groups).

Patients with BRAF-mutant tumors (HR = 2.01, P < .001) and patients with extended RAS-mutant tumors (HR = 1.52, P < .001) had poorer overall survival vs those with wild-type tumors. Among patients with triple-negative tumors, those with tumors wild-type for NRAS, KRAS, and BRAF had better survival vs those with mutations in at least one of these genes (median = 35.9 months vs 22.2 months, P < .001).

The investigators concluded, “In patients with metastatic colorectal cancer treated in [the] first line, low tumor mutational burden and BRAF and RAS mutations are negative prognostic factors. Patients with microsatellite instability–high tumors benefited more from bevacizumab than from cetuximab, and studies to confirm this effect of microsatellite instability–high [status] are warranted.”

Federico Innocenti, MD, PhD, of the University of North Carolina at Chapel Hill Eshelman School of Pharmacy and Lineberger Comprehensive Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by National Institutes of Health grants to CALGB/SWOG 80405. The study authors' full disclosures can be found at

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