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ECENT RETROSPECTIVE CORrelative analyses of metastatic colorectal cancer trials indicate that patients with KRAS-mutated tumors (NCBI Entrez Gene 3845) do not benefit from the anti-epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab. 1 These retrospective analyses were performed independently, and for each analysis, KRAS wild-type vs mutant were studied grouping codons 12 and 13 mutations together, without subgroup analysis. Health authorities in the United States and Europe have indicated that patients with KRAS codon 12-or KRAS codon 13-mutated tumors should not receive cetuximab or panitumumab. 2-4 However, indications exist that not all KRAS mutations are equal in their biological characteristics. First, the pattern of KRAS mutations is tumor-type spe-Author Affiliations are listed at the end of this article.

Background: KRAS mutation status is a candidate marker for predicting survival in patients with metastatic colorectal cancer (mCRC) treated with cetuximab (CTX). Patients and methods:We studied the KRAS mutation status of 113 patients with irinotecan refractory mCRC treated with CTX in clinical trials. A predictive model for objective response (OR), progression-free survival (PFS) and overall survival (OS) was constructed using logistic and Cox regression.Results: OR was seen in 27 of 66 KRAS wild-type (WT) patients versus 0 of 42 in KRAS mutants. Median OS was significantly better in KRAS WT versus mutants (43.0 versus 27.3 weeks; P = 0.020). Decrease in tumor sizes was significantly larger at all time points in WT patients. KRAS WT patients with an initial relative decrease of tumor size >9.66% at week 6 had a significantly better median OS compared with all other patients (74.9 versus 30.6 weeks; P = 0.0000025). Within KRAS WT patients OS was significantly better in patients with an initial decrease compared with those without [median OS: 74.9 versus 30.6 weeks (P = 0.00000012)].Conclusions: KRAS WT status is associated to survival benefit in CTX treated mCRC. This benefit is even more pronounced in those patients with early radiological response. These characteristics may be exploited for response prediction.Key words: cetuximab, colorectal cancer, EGFR, KRAS, survival introduction A recent advance in oncology is the targeting of the epidermal growth factor receptor (EGFR) in the treatment of many tumor types. Cetuximab (CTX) (ErbituxÒ, Merck KGaA, Darmstadt, Germany) is a chimeric immunoglobulin G1 monoclonal antibody which binds the EGFR with high affinity and competitively inhibits ligand binding [1]. This prevents activation of downstream signalling pathways such as the PI3K/ Akt, RAS/Erk and STAT pathways, resulting in the inhibition of cellular proliferation and in the induction of apoptosis. However, for many tumor types including metastatic colorectal cancer (mCRC), it is not clear what proportion of tumors are dependent on EGFR signalling for their survival, nor how additional molecular alterations present in the tumor may influence primary or secondary resistance to EGFR inhibitors. CTX is approved for irinotecan-resistant mCRC expressing EGFR by immunohistochemistry (IHC). Response rates in this group however only amount to 23% in combination with chemotherapy and about 10% in monotherapy [2,3]. Increased response rates in the combination arm did not translate into increased survival. As yet no clinical or molecular markers are available to identify those patients with a longer overall survival (OS). Predictive markers of response and survival benefit after CTX are urgently required to allow the rational and effective use of these drugs.In a small series, Lièvre et al. [4] have shown objective response (OR) to CTX to be excluded in KRAS-mutated CRC and most importantly, showed an increase in OS for the KRAS wild-type (WT) patients. We retrospectively studied the ability of KRAS mutations and tumo...

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