KRAS Mutation Status Is Predictive of Response to Cetuximab Therapy in Colorectal Cancer

Abstract

The anti-epidermal growth factor receptor (anti-EGFR) cetuximab has been proven to be efficient in metastatic colorectal cancer. The molecular mechanisms underlying the clinical response to this drug remain unknown. Genetic alterations of the intracellular effectors involved in EGFRrelated signaling pathways may have an effect on response to this targeted therapy. In this study, tumors from 30 metastatic colorectal cancer patients treated by cetuximab were screened for KRAS, BRAF, and PIK3CA mutation by direct sequencing and for EGFR copy number by chromogenic in situ hybridization. Eleven of the 30 patients (37%) responded to cetuximab. A KRAS mutation was found in 13 tumors (43%) and was significantly associated with the absence of response to cetuximab (KRAS mutation in 0% of the 11 responder patients versus 68.4% of the 19 nonresponder patients; P = 0.0003). The overall survival of patients without KRAS mutation in their tumor was significantly higher compared with those patients with a mutated tumor (P = 0.016; median, 16.3 versus 6.9 months). An increased EGFR copy number was found in 3 patients (10%) and was significantly associated with an objective tumor response to cetuximab (P = 0.04).In conclusion, in this study, KRAS mutations are a predictor of resistance to cetuximab therapy and are associated with a worse prognosis. The EGFR amplification, which is not as frequent as initially reported, is also associated with response to this treatment. (Cancer Res 2006; 66(8): 3992-5)

KRAS p.G13D mutation and codon 12 mutations are not created equal in predicting clinical outcomes of cetuximab in metastatic colorectal cancer

“…The articles were published between 2005 and 2011. Three studies 6,19,20 were conducted in France, 3 studies 13,18,21 were conducted in Italy, 1 study 14 was conducted in Switzerland, 1 study 17 was conducted in Figure 1. This is a flow chart of study selection for the current analysis.…”

“…Individual data were extracted from 7 studies 6,13,14,[18][19][20][21] that included the available data for ORR but did not perform a comparison between 2 groups of patients.…”

KRAS genotyping in rectal adenocarcinoma specimens with low tumor cellularity after neoadjuvant treatment

“…In 2010, KRAS mutation testing in our institute routinely combined manual dissection and highresolution melting analysis followed by sequencing in case of abnormal profile. 26 This strategy allowed the identification of KRAS mutations in 12/31 pretreatment biopsies (39%, 6 Dworak grade 2 and 6 Dworak grade 3). The identified KRAS mutations (and their frequency) were G12D (3/12), G12V (1/12), G12C (2/12), G12S (2/12), G12R (1/12), G13D (1/12), G13C (1/12), and G13R (1/12).…”

“…[1][2][3][4][5][6][7] Indeed, KRAS mutations result in constitutively active KRAS proteins that lead to continuous activation of the RAS signaling pathway independently of the upstream stimulation by EGFR ligands. As only patients with wild-type KRAS tumors benefit from therapies with anti-EGFR antibodies, accurate determination of the KRAS mutation status is crucial for ethical and economic reasons.…”

Towards novel paradigms for cancer therapy

“…An interesting addition to this concept is that rexinoids exclusively exert their apoptotic action under conditions in which growth factor signaling is impaired (Shankaranarayanan et al, 2009), suggesting that the combination of both anticancer treatments might be an attractive strategy. Although the clinical activity of cetuximab and panitumumab antibodies has been consistently reported, tumors with activated K-RAS present little to no response to therapy, and potentially mutations in B-raf might have the same effect (Lievre et al, 2006;Di Nicolantonio et al, 2008;Karapetis et al, 2008). Other potential markers of response to these compounds include polymorphisms of the cyclooxygenase (Lurje et al, 2008), and the FCGR2A and FCGR2B (Fc g receptors) genes .…”