A post hoc analysis of the PETACC-8 trial has revealed an interaction between microsatellite instability (MSI) and BRAF and KRAS mutation status when determining the prognosis of patients with resected stage III colon adenocarcinoma.
“Future trials in the adjuvant setting will have to take into account mismatch repair, BRAF, and KRAS status for stratification”, say Julien Taieb, from European Georges Pompidou Hospital in Paris, France, and co-workers in JAMA Oncology.
They explain that the phase III trial failed to find a significant difference in disease-free survival (DFS) between patients with colon cancer who were randomly assigned to receive 6 months of postoperative leucovorin, fluorouracil and oxaliplatin (FOLFOX4) alone or alongside the EGFR inhibitor cetuximab.
Hypothesising that DNA mismatch repair status and the consequential MSI may have impacted this PETACC-8 finding, the team re-examined tumour blocks from 2559 trial participants.
Analysis succeeded in detecting the MSI phenotype in 9.9% of 1791 patients, KRAS exon 2 mutations in 33.1% of 1776 patients, and the BRAF V600E mutation in 9.0% of 1643 patients. Multivariate analyses revealed that the presence of MSI and BRAF V600E did not significantly predict DFS, whereas the KRAS mutation was associated with significantly shorter DFS (hazard ratio [HR]=1.55) and overall survival (OS, HR=1.56).
Analysis of patients with microsatellite stable tumours revealed that the presence of either KRAS or BRAF V600E mutations significantly predicted poorer DFS (HR=1.64 and 1.74, respectively) and OS (HR=1.71 and 1.84, respectively).
However, KRAS mutations did not predict clinical outcomes in patients with MSI tumours while the BRAF V600E mutation was associated with significantly longer DFS (HR=0.23) and a trend towards longer OS, although this was not significant.
Writing in an accompanying comment, Dirk Klingbiel, from Swiss Group for Clinical Cancer Research in Bern, Switzerland, and Sabine Tejpar, from Leuven University Hospital in Belgium, question the decision not to stratify between the treatment arms, noting that there is a known interaction between KRAS status and cetuximab treatment.
They also suggest that it might have been interesting to compare the outcomes of patients positive for BRAF or KRAS mutations with patients who carried the wild-type alleles for both markers rather than those positive for the opposing mutation.
Nevertheless, they “second the conclusion” that future adjuvant chemotherapy trials should stratify patients by MSI, BRAF and KRAS status.
“Any markers that can help guide individualized toxicity and/or efficacy evaluations in this setting are welcome”, the commentators conclude.
“Further stratification of the disease may also help assess more precisely the effect of drugs that failed in the adjuvant setting.”
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