Poorer Outcome With BRAF and KRAS Mutations in Microsatellite-Stable but Not Microsatellite-Unstable Colon Cancer

Key Points

  • Among patients with microsatellite-stable tumors, both KRAS mutation and BRAF V600E mutation were independently prognostic for poorer disease-free and overall survival.
  • Among those with microsatellite-unstable tumors, KRAS mutation was not prognostic for disease-free or overall survival, and BRAF V600E mutation was associated with significantly longer disease-free survival and nonsignificantly longer overall survival.

In an analysis of the PETACC-8 trial reported by Taieb et al in JAMA Oncology, BRAF V600 and KRAS mutations were associated with shorter disease-free and overall survival in patients with microsatellite-stable colon cancer—but not in those with tumors with microsatellite instability—in the setting of adjuvant therapy. The PETACC-8 trial showed that the addition of cetuximab to FOLFOX4 (leucovorin, fluorouracil, and oxaliplatin) did not improve disease-free survival in patients with KRAS exon 2 wild-type disease.

Study Details

The analysis included patients with available tumor blocks from among the total of 2,599 patients in the trial. Microsatellite instability was found in 9.9% (177 of 1,791; microsatellite-stable tumors in 1,614 [90.1%]), KRAS mutation was found in 33.1% (588 of 1,776), and BRAF V600E mutation was found in 9.0% (148 of 1,643) of cases.

Outcome by Mismatch Repair and Mutation Status

In multivariate analysis, no significant prognostic effect for disease-free survival or overall survival was found for microsatellite instability (hazard ratios [HRs] = 1.10, P = .67; 1.02, P = .94) or BRAF V600E mutation (HRs = 1.22, P = .34; 1.13, P = .66); KRAS mutation was significantly associated with shorter disease-free survival (HR = 1.55, P < .001) and overall survival (HR = 1.56, P = .008).

Among patients with microsatellite-stable tumors, both KRAS mutation (HRs = 1.64, P < .001; 1.71, P = .002) and BRAF V600E mutation (HRs = 1.74, P = .01; 1.84, P = .046) were independently prognostic for poorer disease-free and overall survival. Among those with microsatellite-unstable tumors, KRAS mutation was not prognostic for disease-free or overall survival (HRs = 0.94, P = .91; 0.90, P = .88), whereas BRAF V600E mutation was associated with significantly longer disease-free survival (HR = 0.23, P = .04) and nonsignificantly longer overall survival (HR = 0.19, P = .08).

The investigators concluded: “BRAF V600E and KRAS mutations were significantly associated with shorter [disease-free survival] and [overall survival] in patients with microsatellite-stable tumors but not in patients with [microsatellite-unstable] tumors. Future trials in the adjuvant setting will have to take into account mismatch repair, BRAF, and KRAS status for stratification.”

The study was supported by the Ligue Nationale Contre le Cancer, Merck KGaA, and Sanofi.

Julien Taieb, MD, PhD, of the European Georges-Pompidou Hospital and Paris Descartes University, is the corresponding author of the JAMA Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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