Pathology Research International 3 First line therapy FOLFOX ± bevacizumab or CapeOX ± bevacizumab or FOLFOX ± cetuximab∗ or panitumumab∗ FOLFIRI ± bevacizumab or FOLFIRI ± cetuximab∗ or panitumumab∗ 5-FU/leucovorin ± bevacizumab FOLFOXIRI or or or or or or or Second-line therapy FOLFIRI or irinotecan FOLFIRI + cetuximab∗ or panitumumab∗ Cetuximab∗ + irinotecan FOLFOX or CapeOX Cetuximab∗ or panitumumab∗ or cetuximab∗ + irinotecan FOLFOX or CapeOX FOLFIRI or irinotecan Third-line therapy Cetuximab∗ or panitumumab∗ or cetuximab∗ + irinotecan Clinical trial or best supportive care Cetuximab∗ or panitumumab∗ or cetuximab∗ + irinotecan FOLFOX or CapeOX Irinotecan Cetuximab∗ or panitumumab∗ or cetuximab∗ + irinotecan Figure 2: The current treatment paradigm for patients with metastatic colorectal cancer who are appropriate for intensive therapy [9]. ∗For patients with KRAS WT gene only. CapeOX: capecitabine + oxaliplatin. antibody therapy is not inferior to patients with KRAS WT disease. The evaluation of KRAS mutational status is a mandatory aspect of management of patients at the time of diagnosis of metastatic CRC. 3. Mechanisms of Resistance While KRAS mutations are a major mechanism of primary resistance to antiEGFR monoclonal antibody therapies, resistance mechanisms in KRAS WT patients are also being deﬁned. Forty-sixty percent of patients with KRAS WT tumors fail to respond to treatment with antiEGFR mono- clonal antibodies [51]. Therefore, other possible molecular determinants of response are being identiﬁed in those patients with EGFR monoclonal antibody-resistant WT KRAS disease. The importance and frequency of NRAS (a ras onco- gene variant) mutations in CRC remains under-investigated [52, 53]. Lambrechts et al. found that NRAS, KRAS, and BRAF mutations were all mutually exclusive events, with combined WT status of these genes associated with higher response rates and longer progression-free survival times [54]. Lambrechts et al. also reported that an NRAS mutation was associated with a lack of response to cetuximab. Irahara et al. investigated the relationship between NRAS mutations and clinical outcome in a collection of 225 colorectal cancers from two prospective cohort studies [55]. NRAS mutations were detected in 2.2% of the CRCs. There was no apparent association between the NRAS mutations and any clinical or pathologic features, including patient survival. However, the low frequency of NRAS mutations may obscure a signiﬁcant relation. De Roock et al. conducted a retrospective analysis of over 700 tumor samples from patients treated with cetuximab plus chemotherapy and found a NRAS mutation frequency of 2.6%. Additionally, in KRAS wild types, carriers of NRAS mutations had a signiﬁcantly lower response rate to cetuximab than NRAS wild types (7.7% versus 38.1%, P = .013) [26]. There was, however, no signiﬁcant diﬀerence in median PFS (14 versus 26 weeks, P = .055) and median OS (38 versus 50 weeks, P = .051) between NRAS wild types and mutants [26]. B-type Raf kinase (BRAF) is a component of the RAS- RAF-MEK signaling cascade of the EGFR (see Figure 1) [56]. A speciﬁc mutation in the BRAF gene (V600E) is present in approximately 5–8% of CRCs and is thought to be limited to those tumors without mutations in exon 2 of KRAS [42, 57]. BRAF, which is located directly downstream from RAS, can have activating mutations leading to stimulation of the MEK pathway [56, 58]. BRAF mutations appear to confer a poor prognosis, and it appears that BRAF mutations also predict for a lack of response to antiEGFR monoclonal antibodies [42, 57, 59, 60]. Loupakis et al. analyzed 87 patients with KRAS WT tumors for the BRAF V600E mutation who were receiving irinotecan and cetuximab for refractory metastatic