Different prognostic values of KRAS exon 2 submutations and BRAF V600E mutation in microsatellite stable (MSS) and unstable (MSI) stage III colon cancer: an ACCENT/IDEA pooled analysis of seven trials

Abstract

Background

The prognostic value of KRAS and BRAF^V600E mutations in stage III CC remains controversial and has never been clearly analyzed in patients with MSI-H tumors due to sample size limitations. Data are also lacking for KRAS sub-mutations and prognosis.

Methods

We examined clinicopathological variables and prognosis in surgically resected stage III CC patients who participated in 7 clinical trials from the ACCENT/IDEA databases Associations between KRAS exon 2 and BRAF^V600E mutations and time to recurrence (TTR), overall survival (OS), and survival after recurrence (SAR) were assessed by Cox model. The prognostic value of KRAS exon 2 sub-mutations were also analyzed.

Results

Among 8,460 pts of which 11.4% were MSI-H, BRAF^V600E, KRAS exon 2 mutants, or double wild-type were detected in 40.6%, 18.1%, and 41.3% of the MSI-H group and in 7.7%, 38.6%, and 53.8% of the MSS group, respectively. In the MSS group, 5-year TTR rates of 61.8%, 66.3% and 72.9% were observed in pts with BRAF^V600E, KRAS exon 2 mutants versus those that were double wild-type, respectively, (adjHR: 1.58 and 1.31, both p<0.001). In the MSI-H group, 5 yr TTR rates did not differ significantly among the mutated subgroups. Similar results were found for OS. However, survival after relapse (SAR) was significantly shorter in KRAS exon 2 or BRAF^V600E mutated groups in both MSS (adjHR: 2.06 and 1.15; both p<0.05) and MSI-H (adjHR: 1.99 and 1.81; both p<0.05) pts. In MSS patients, KRAS exon 2 mutations were all associated with TTR but only p.G12C, p.G12D, and p.G13D were associated with poor outcome after disease recurrence.

Conclusion

Testing for both RAS and BRAF^V600E mutations in stage III patients should be considered as they can better define individual patient prognosis, and may also enable patient selection for (neo)adjuvant trials dedicated to specific poor prognosis molecular subtypes