Determinants of RASistance to anti-epidermal growth factor receptor agents.

There is a general agreement that oncologists are not doing well in selecting patients most likely to benefit from molecularly targeted therapies. The consequences of administering these agents to inappropriately selected patients include unnecessary toxicities for patients who are unlikely to derive benefit, a waste of time, and an inefficient use of increasingly constrained financial resources. Agents directed at epidermal growth factor receptor (EGFR) provide a good example of our need to improve this selection process. On one hand, anti-EGFR agents are approved in the therapy of non–small-cell lung cancer (NSCLC), colon cancer, and head and neck cancer, in which they provide significant clinical benefit. Yet, there is an absence of validated predictive markers of response to anti-EGFR agents with the exception of the rare EGFR mutations/amplifications that occur in NSCLC. It is therefore not surprising that these agents have limited activity; for example, in colon cancer, the anti-EGFR monoclonal antibodies cetuximab and panitumumab have single-agent response rates in the range of only 10%. The lack of validated predictive markers of benefit to antiEGFR agents may be the result of the complex biology of the EGFR system itself that defies the definition of EGFR dependency. This complexity is due to the existence of multiple EGFR ligands, a variety of receptor dimerization partners, and the frequent occurrence of receptor cross-talk with members of other receptor families, among other reasons. Furthermore, it is likely that the biologic consequences of EGFR activation varies as a consequence of other mutations present in the tumor. Taking all of these aspects into consideration, although it has been possible to identify some predictors of clinical benefit, it may be more fruitful to identify negative predictive factors of benefit to anti-EGFR agents. These would be markers that, when present, would render tumors EGFR independent and therefore not sensitive to EGFR inhibition. Emerging data suggest that a hyperactive mutant KRAS is likely to be a powerful negative predictive factor of EGFR response. The RAS proteins are members of a large superfamily of guanosine-5’-triphosphate (GTP)–binding proteins that play a complex role in the normal transduction of growth factor receptor–induced signals. Stimulation of growth factor receptors, such as EGFR, causes activation of multiple regulatory molecules, including the RAS protein. EGFR activates RAS by stimulating its binding to GTP. RAS, in its active, GTP-bound state, binds several key target proteins, which results in the subsequent activation of several downstream pathways, including those mediated by MAP kinase, PI3K, and RAL-GDS. Engagement of these pathways leads to stimulation of cell cycle progression, desensitization of the cell to proapoptotic stimuli, changes in cytoskeletal organization and invasion, and other processes required for cell proliferation. Activating mutations of the KRAS and NRAS genes occurs frequently in human cancer. KRAS mutations are prevalent in pancreatic (60%), colorectal ( 30%), endometrial (15%), biliary tract ( 30%), lung (20%), and cervical cancers (10%). In most cases, the somatic RAS missense mutations found in cancer introduce amino acid substitutions at positions 12, 13, and 61. These mutations disable the endogenous GTPase activity of the RAS protein, and cause cancer-associated RAS to accumulate in the active, GTP-bound conformation. This, in turn, results in activation of PI3K, MAP kinase, and RAL-GDS, which results in malignant transformation. Because RAS is downstream from EGFR, aberrant RAS signaling like the one occurring in cells with mutant KRAS, may lead to dysregulation of RAS-dependent pathways and downstream signaling even if the upstream receptor is silenced by anti-EGFR monoclonal antibodies. Since the introduction of anti-EGFR therapies, there is increasing evidence that this may be the case. Several retrospective analyses have reported lack of benefit from the anti-EGFR monoclonal antibody cetuximab in patients with colorectal cancer (CRC) harboring KRAS mutations. In a recent prospective biomarker driven clinical trial with single-agent cetuximab in patients with CRC with mandatory tumor sampling for the identification of candidate predictive marker, the correlation between KRAS and clinical benefit was also analyzed. In this study, KRAS mutations strongly correlated with lack of clinical benefit; mutations were present in only three (11%) of 27 patients that achieved clinical benefit but were detected in 27 (51%) of 53 nonresponders. In this issue of the Journal of Clinical Oncology, Amado et al assessed the predictive role of KRAS in the recently reported, large, phase III randomized trial comparing the anti-EGFR monoclonal antibody panitumumab, given as monotherapy, to best supportive care (BSC) in patients with chemotherapy-refractory metastatic CRC. KRAS status was assessed in 427 (92%) of 463 patients and KRAS mutations were found in 43%. The treatment effect on progression-free survival in the wild-type (WT) KRAS group (hazard ratio, 0.45) was significantly greater (P .0001) than in the KRAS mutant group, in which panitumumab had no benefit at all. Median progression-free survival in the WT KRAS group was 12.3 weeks for JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 10 APRIL 1 2008