553O Prognostic Value of KRAS and BRAF Mutations in Microsatellite Stable (MSS) and Unstable (MSI) Stage III Colon Cancer: an ACCENT/IDEA Pooled Analysis of 7 Trials

Whether KRAS and BRAFV600E mutations are prognostic in stage III CC remains controversial and has never been clearly analyzed in the subgroup of MSI-H patients (pts) due to sample size limitations. The prognostic value of individual KRAS mutations has also not been widely studied. We studied the prognostic impact of individual KRAS exon 2 and BRAFV600E mutations in pts with surgically resected stage III CC who participated in 7 clinical trials from the ACCENT/IDEA databases. Associations between mutations and time to recurrence (TTR), overall survival (OS) and survival after recurrence (SAR) were assessed by Cox model, stratified by study and adjusted for sex, age, performance status, T and N stage, disease grade, and primary tumor location. The prognostic value of individual KRAS exon 2 submutations (G12A, G12C, G12D, G12R, G12S, G12V, G13D and others) was also analyzed. 8286 pts were included, 11.6% were MSI-H (N=967) with 5 yr recurrence rates of 24.1% for MSI-H and 30.3% for MSS subgroups. BRAFV600E, KRAS exon 2 mutants or double wild type represented 40.6%, 18.1% and 41.3% of the MSI-H group and 7.8%, 38.6% and 53.7% of the MSS group, respectively. In the MSS group, 5y TTR rates of 61.7%, 66.4% and 73.2% emerged in pts with BRAFV600E, KRAS exon 2 mutants and in double wild-type pts, respectively, (adjHR: 1.34 and 1.32, both p<0.001), while in the MSI group shorter TTR in mutated subgroups was not seen with 5y TTR rates of 76.1%, 75.8% and 75.6%, respectively (adjHR: 1.01 and 0.98, both p>0.05). Similar results were found for OS. However, SAR was significantly shorter for pts with tumors harboring a KRAS exon 2 or BRAFV600E mutation in both MSS (adjHR: 1.16 and 2.05; both p<0.0001) and MSI (adjHR: 1.76 and 2.00; both p<0.05) pts. No major differences were noted in the prognostic value of KRAS exon 2 submutations. In the largest analysis of the association of KRAS exon 2 and BRAFV600E mutations and disease outcome in resected stage III CC, either mutation was associated with significantly shorter DFS, OS and SAR in MSS tumors, but only with shorter SAR in MSI-H tumors. In addition, all KRAS codon 12 and 13 mutations had similar prognostic value.