Pathology Research International monoclonal antibodies plus bevacizumab do not improve outcomes and can actually cause increased toxicity irrespec- tive of KRAS mutational status. The PACCE trial evaluated panitumumab combined with oxaliplatin- or irinotecan- based chemotherapy plus bevacizumab. The dual mono- clonal antibody arm was associated with increased toxicity and signiﬁcantly shorter PFS in patients with both KRAS WT and mutant tumors [50]. Similar results were observed with the combination of cetuximab to a regimen containing capecitabine, oxaliplatin, and bevacizumab in the CAIRO2 trial [49]. Novel agents and combinations are being employed in an attempt to overcome antiEGFR monoclonal antibody resistance. Motesanib, an oral inhibitor of VEGF, platelet derived growth factor (PDFG) and Kit receptors is being investigated with or without panitumumab in patients with refractory disease [86]. A number of inhibitors of the mutant BRAF kinase are in clinical development, as discussed above [87]. AMG 102 is an investigational monoclonal antibody against human hepatocyte growth factor (also known as cMET, of which overexpression correlates with cetuximab resistance) is being studied in combination with panitumumab in patients with metastatic CRC [88, 89]. 5. Neoadjuvant and Adjuvant Therapy Given the clinical beneﬁt of antiEGFR monoclonal anti- bodies in patients with metastatic disease, evaluation of these therapies as postoperative (adjuvant) treatment was warranted. In the adjuvant setting, eradication of micrometastatic disease is associated with increased cure rates. N0147 randomized 1760 patients with resected stage III KRAS WT colon cancer to FOLFOX with or without cetuximab [90]. Interim analysis led to premature closure of this trial after it was determined that no group of patients beneﬁted from cetuximab [90]. Initially this trial enrolled patients regardless of KRAS mutational status, and among 658 patients with mutant KRAS, the addition of cetuximab to FOLFOX resulted in impaired disease-free survival (DFS) and a trend toward impaired OS [91]. In patients with rectal cancer, EGFR is a logical tar- get in combination with neoadjuvant radiotherapy (RT). Retrospective analyses have demonstrated lower pathologic complete response (pCR) rates and shorter DFS in patients with rectal cancer expressing EGFR who were treated with neoadjuvant RT, suggesting that radiosensitivity might be increased by targeting the EGFR [92, 93]. Several phase I/II studies have investigated the combinations of cetuximab and chemoradiotherapy in the neoadjuvant setting for patients with rectal cancer. These studies have demonstrated that cetuximab could be safely combined with preoperative chemoradiotherapy but the pCR rates have been low (5– 12%) [94–100]. In two of these studies [96, 99], subsequent analyses were done to correlate KRAS mutation status with response rate. Among patients with KRAS WT tumors, Bengala et al. reported a trend toward a greater rate of tumor regression (36.7% for KRAS WT versus 11% for KRAS mutant), however it did not reach statistical signiﬁcance (P = .12) [101]. Debucquoy et al. also did not ﬁnd 7 a correlation between KRAS WT tumors and pathologic response to therapy [102]. To our knowledge, panitumumab has not been studied in combination with RT in patients with rectal cancer. Given the failure of antiEGFR monoclonal antibodies to demonstrate a beneﬁt in the adjuvant setting for stage III WT KRAS colon cancer, the value of further study of these agents for rectal cancer is doubtful. Preclinically geﬁtinib has demonstrated improved radiosensitization [103]. Valentini et al. investigated the combination of geﬁtinib, continuous infusion 5-ﬂuorouracil (5-FU) and pelvic RT in 41 patients with locally advanced rectal cancer and reported a pCR rate of 30%, however toxicity was an issue and further studies are necessary to establish the safety of this combination [104]. The eﬀect of combined antiEGFR and antiVEGF therapy in combination with preoperative chemoradiotherapy for rectal cancer remains unknown, however given the negative results reported for combined EGFR and VEGF blockade in patients with metastatic CRC in combination with chemotherapy, studies investigating this avenue are unlikely [22, 49, 50]. Blaszkowsky et al. performed a small study investigating the combination of bevacizumab, erlotinib and 5-FU with RT in patients with locally advanced rectal cancer [105]. The regimen was found to be well-tolerated and highly active with a pCR rate of 47% and may deserve further investigation. However, the value of pCR as a surrogate for DFS and OS is uncertain. 6. Conclusion Anti-EGFR monoclonal antibodies are among the standard treatment options for patients with metastatic CRC given their established eﬃcacy. It is now clear that the beneﬁt of antiEGFR monoclonal antibodies is isolated to patients with KRAS WT tumors. It appears that KRAS mutational status is just the beginning of our understanding of the EGFR as an integral component of the biology of CRC. Given that only a subset of patients respond to antiEGFR therapy, there is a need for better predictors to guide patient selection for such therapy. Several important components of the EGFR signaling pathway have been discovered, including BRAF, PTEN, AKT and PI3K, which deserve further study as predictors of response to existing treatments, or as targets of new interventions. The unexpected detrimental outcome associated with combined EGFR and VEGF blockade is a reminder of how much there is still to learn. New combina- tions and novel agents will continue to shed light on how to overcome resistance to inhibitors of the EGFR pathway, and hopefully new targets will be identiﬁed. Further study of how to employ our knowledge of EGFR pathway inhibitors to improve outcomes in the adjuvant and neoadjuvant setting is also warranted. References [1] C. H. Heldin, “Dimerization of cell surface receptors in signal transduction,” Cell, vol. 80, no. 2, pp. 213–223, 1995. [2] G. Carpenter, “Receptors for epidermal growth factor and other polypeptide mitogens,” Annual Review of Biochemistry, vol. 56, pp. 881–914, 1987.