KRAS and colorectal carcinoma: Studies in CRC and NSCLC patients have shown that KRAS heterogeneity typically arises after therapy, not at baseline.187,188 In a large cohort (8750 pretreated KRAS-mutant tumors), only 3.5% had more than one RAS mutation; in KRASG12C-mutant tumors specifically, secondary RAS mutations appeared in 3% of the samples.189 Cannataro et al. reported no evidence of preexisting resistance mutations in KRAS or its downstream genes prior to KRAS G12C inhibitor therapy.190 Nevertheless, the mechanisms of primary resistance remain poorly understood.