Treatment with anti-EGFR monoclonal antibodies (cetuximab or panitumumab), either as single-agent or combination therapy, offers improved outcomes in wild-type mCRC. shown promising activity in and mutation status. Future studies will likely focus on improving efficacy of PHA-767491 hydrochloride anti-EGFR-based therapy in mCRC through sustained MAPK pathway inhibition. and are associated with poorer prognosis and have been identified as predictors of resistance to anti-EGFR monoclonal antibodies, cetuximab and panitumumab, in mCRC (14-16). Findings from large, randomized clinical trials have recently confirmed the survival benefits afforded by the addition of anti-EGFR monoclonal antibodies to standard combination chemotherapy in and wild-type metastatic colorectal tumors. Here, we review data from pivotal clinical trials that have redefined our treatment approach in mCRC with respect to and mutation status. RAS mutation status as a biomarker of response to anti-EGFR therapy Oncogenic mutations have historically PHA-767491 hydrochloride been present in approximately 40C50% of CRC cases (17). In a recent pooled analysis, the prevalence of mutations in mCRC has been shown to be as high as 55.9% with mutations in exon 2 being the most common (42.6%) followed by exon 3 (3.8%), exon 4 (6.2%), exon 2 (2.9%), exon3 (4.2%), and exon4 (0.3%) mutations (18). Mutations in codons G12D, G12V, and G12C were most common for exon 2, codons Q61H and Q61R for exon 3, codons A146T and A146V for exon 4, codon G12D for exon2, codons Q61K and Q61R for exon3, and codon A146T for exon4. In the initial RASCAL study, the presence of a mutation was associated with poorer overall survival (OS) and increased risk of relapse in mCRC (19). In addition, an analysis of the N0147 trial has shown an increased relapse rate for mutation in the metastatic disease setting is more controversial, as many non-EGFR containing arms of treatment have failed to show a difference in outcome between mutation status also predicts response to anti-EGFR therapy, in particular cetuximab and panitumumab, in first-line and beyond settings in the treatment of mCRC. Chemotherapy refractory settings Cetuximab first gained Food and Drug Administration (FDA) approval on the basis of the BOND trial. This multicenter, randomized control trial (RCT) CDH5 investigated cetuximab given at initial dose of 400 mg/m2 followed by weekly infusions of 250 mg/m2 alone or in combination with irinotecan in 329 patients with EGFR-expressing mCRC who PHA-767491 hydrochloride progressed on one or more lines of irinotecan-based chemotherapy (24). Cetuximab + irinotecan PHA-767491 hydrochloride demonstrated a significantly improved overall response rate (ORR) and median progression-free survival (PFS) compared to cetuximab alone (mutation status and response to anti-EGFR therapy was not investigated. However, a post hoc analysis of the CO.17 trial involving mutation analysis in 394 tumor specimens collected at the time of diagnosis demonstrated median OS of 4.5 (cetuximab) mutation analysis was limited to codons 12 and 13 of exon 2. mutation status has similarly been shown to predict benefit to the anti-EGFR monoclonal antibody, panitumumab, in chemotherapy-resistant mCRC. The phase III 408 study assigned 463 patients with EGFR-expressing mCRC who progressed on 2 lines of prior chemotherapy to panitumumab [60-minute intravenous (IV) infusion at 6 mg/kg once every 2 weeks] + BSC mutation testing (codons 12 and 13) in 427 available tumors showed improved PFS in and (exon 2) mCRC (31). In chemotherapy refractory settings, cetuximab or panitumumab offers survival advantages in mCRC that are dependent on mutation status. The addition of cetuximab to irinotecan can overcome irinotecan resistance in mCRC previously treated with irinotecan-based chemotherapy. Panitumumab is non-inferior in survival to cetuximab in chemotherapy-resistant wild-type mCRC. The choice of anti-EGFR agent should take into consideration patient factors (e.g., history of infusion reaction) and toxicity profiles of either drug. First-line settings The COIN trial randomized 1,630 patients with chemotherapy-naive mCRC to a control arm [choice of capecitabine 850 mg/m2 orally twice daily for 2 weeks + oxaliplatin 130 mg/m2 2-hour infusion (XELOX) every 3 weeks or 5-FU 400 mg/m2 bolus followed by.