Overall, tumors harboring mutations in the KRAS-NRAS-BRAF axis responded poorly to cetuximab-based treatment….tumor A00021 had both AKT1 E17K (27.9%) and BRAF G469A (19.7%) mutations, and tumor A00026 had both BRAF D594G (26.7%) and PIK3CA E542K (15.6%) mutations....tumor A00021 had both AKT1 E17K (27.9%) and BRAF G469A (19.7%) mutations, and tumor A00026 had both BRAF D594G (26.7%) and PIK3CA E542K (15.6%) mutations....tumor A00021 had both AKT1 E17K (27.9%) and BRAF G469A (19.7%) mutations, and tumor A00026 had both BRAF D594G (26.7%) and PIK3CA E542K (15.6%) mutations. Such differences in mutant allele frequencies implies complex intra-tumor heterogeneity, which may also contribute to the lack of response to cetuximab.

All patients but one harboring KRAS, NRAS, or BRAF mutations were non-responders. Mutations in any one of these three genes were associated with a poor response rate (7.1%) and reduced survival (PFS = 8.0 months) compared to wild-type patients (74.4% and 11.6 months).