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Originally published as JCO Early Release 10.1200/JCO.2007.15.3700 on March 3 2008 © 2008 American Society of Clinical Oncology.
Determinants of RASistance to Anti–Epidermal Growth Factor Receptor AgentsVall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain
Memorial Sloan-Kettering Cancer Center, New York, NY 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%.1-3 The lack of validated predictive markers of benefit to anti-EGFR 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,4 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.5-7 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.5-8 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%).9 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.10-13 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.4 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 al14 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.3 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)15 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 panitumumab and 7.3 weeks for BSC. Response rates to panitumumab were 17% and 0%, for the WT and mutant groups, respectively. There was also a benefit of panitumumab after cross-over in patients with WT KRAS tumors. In short, benefit to panitumumab was restricted to patients with WT RAS tumors. In those patients with tumors harboring RAS mutations, their clinical outcome when treated with panitumumab was identical to those patients who were treated only with BSC. There was no clinical benefit to panitumumab at all in patients with KRAS mutant tumors and their outcome, in all clinical end points, was identical to those of the patients treated with BSC. This is an ideal negative predictor of response. Based on the results of this study, panitumumab has now been approved for the therapy of colon cancer by the European regulatory authorities (the European Committee for Medicinal Products for Human Use) only for patients with colon cancer harboring WT RAS. This may be the first time that an oncology drug is approved only in the absence of a negative predictive factor, requiring RAS testing to be widely available in the clinic. We applaud this decision and feel that there is no need for additional validation in the studied patient population. Are these findings restricted to colon cancer? Not at all. In NSCLC, the presence of KRAS mutations has been shown to result in lack of clinical benefit from EGFR tyrosine kinase inhibitors in a series of retrospective studies.16-19 In pancreas cancer, where KRAS mutations are the norm, trials with anti-EGFR therapies have been either negative20 or have had limited benefit.21 It is seems therefore that KRAS mutations confer EGFR resistance across tumor types and that strong consideration should be given not to administer anti-EGFR agents in monotherapy in patients with tumors harboring mutant KRAS. The results from this study should also trigger retrospective analyses of KRAS mutations from all available trials in colon, NSCLC, and pancreas cancer in order to extend this work. In advanced colon cancer, an analysis is currently underway in several first- and second-line studies with panitumumab and cetuximab. Analysis of KRAS mutations may be also important in the cetuximab-containing N0147 and PETAC-8 adjuvant studies in colon cancer, although there may be sample size limitations. These studies would enable further establishment of the correlation between KRAS mutation and lack of benefit in different clinical settings. In the meantime, these data strongly suggest that EGFR inhibitors will be ineffective when used as monotherapy to treat CRC and lung cancer with KRAS mutation. This does not mean that they cannot be efficacious when given in combination with other agents. It is possible that EGFR activation will play a role in promoting the survival of tumors in which other signaling pathways have been inhibited or in those undergoing chemotherapy-induced stress. EGFR inhibition has been shown to be ineffective in tumors in which the PTEN tumor suppressor gene is mutated.22 However, combined inhibition of PI3K/AKT signaling and EGFR can induce synergistic apoptosis in these tumor models. Hence, although these findings show that EGFR monotherapy should not be used in CRC and NSCLC with RAS mutation, they should not deter the testing of EGFR in combination with other agents when such trials are based on mechanistic hypotheses supported by preclinical data. The reported findings with RAS may also apply to other mutant oncoproteins present in tumors. In recent years, it has become apparent that drugs that target proteins in mitogenic signaling pathways are quite effective in tumors in which the gene encoding the protein target is mutated. Surprisingly, the drugs tend to also be much less toxic to the host than predicted by their perceived importance in normal physiology. Both of these observations may be due to oncogene addiction—the hypothesis that tumor cells are hypersensitive to the oncoproteins on which they depend. The emerging complementary idea may be that tumors with oncoprotein activation may be insensitive to the inhibition of normal, parallel signaling pathways. Thus, the biology and response to therapy of the individual tumors is very likely to strongly depend on the ensemble of mutations responsible for their development. Many key oncogenic mutations, such as KRAS, NRAS, BRAF, PI3K, LKB, EGFR and others, are quite prevalent. Sequencing these mutations in tumors before therapy will be essential for the proper and most efficient clinical evaluation of novel agents. Advances in the technology of DNA sequencing will in the very near future will make this feasible. In summary, Amado et al should be congratulated for this very important study that has changed the way we select patients with CRC for treatment with anti-EGFR monoclonal antibodies. It points to the importance of good clinical trial design, to the availability of tumor tissues to conduct appropriate biomarker studies, and of having an appropriate control arm. The findings from this study should also provide a strong drive to develop agents that interfere with RAS function. An important consideration of this work is that by enriching our therapy population by excluding those patients with tumors bearing KRAS mutations, we are likely to improve the ability to identify the efficacy of cetuximab- or panitumumab-containing combinations in early stages colon cancer with WT RAS. This brings us to one final suggestion. Be nice to your pathologist, because from now on before you recommend an anti-EGFR therapy to a patient with colon cancer you may want to know the RAS mutational status of the tumor. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: José Baselga, exelixis (U) Stock Ownership: None Honoraria: José Baselga, Merck KGaA Research Funding: None Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: José Baselga, Neal Rosen Data analysis and interpretation: José Baselga Manuscript writing: José Baselga, Neal Rosen Final approval of manuscript: José Baselga, Neal Rosen REFERENCES 1. Mendelsohn J, Baselga J: Epidermal growth factor receptor targeting in cancer. Semin Oncol 33:369-385, 2006[CrossRef][Medline] 2. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004 3. Van Cutsem E, Peeters M, Siena S, et al: Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25:1658-1664, 2007 4. Khambata-Ford S, Garrett CR, Meropol NJ, et al: Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 25:3230-3237, 2007 5. Downward J: Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 3:11-22, 2003[CrossRef][Medline] 6. Schubbert S, Shannon K, Bollag G: Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 7:295-308, 2007[CrossRef][Medline] 7. Malumbres M, Barbacid M: RAS oncogenes: The first 30 years. Nat Rev Cancer 3:459-465, 2003[CrossRef][Medline] 8. Izumi Y, Hirata M, Hasuwa H, et al: A metalloprotease-disintegrin, MDC9/meltrin- gamma/ADAM 9 and PKC delta are involved in TPA-induced ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor. EMBO J 17:7260-7272, 1998[CrossRef][Medline] 9. Forbes S, Clements J, Dawson E, et al: Cosmic 2005. Br J Cancer 94:318-322, 2006[CrossRef][Medline] 10. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, et al: Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res 67:2643-2648, 2007 11. Di Fiore F, Blanchard F, Charbonnier F, et al: Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br J Cancer 96:1166-1169, 2007[CrossRef][Medline] 12. Lievre A, Bachet JB, Le Corre D, et al: KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66:3992-3995, 2006 13. De Roock W, Piessevaux H, De Schutter J, et al: KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol [epub ahead of print on November 12, 2007] 14. Amado RG, Wolf M, Peeters M, et al: Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer: Results from a phase III trial of panitumumab compared to best supportive care. J Clin Oncol 26:1626-1634, 2008 15. Bowtell DD: Options available -from start to finish- for obtaining expression data by microarray. Nature 21:25-32, 1999 (suppl) 16. Pao W, Wang TY, Riely GJ, et al: KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2:e17, 2005[CrossRef][Medline] 17. Massarelli E, Varella-Garcia M, Tang X, et al: KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. Clin Cancer Res 13:2890-2896, 2007 18. Miller VA, Zakowski M, Riely GJ, et al: EGFR mutation and copy number, EGFR protein expression and KRAS mutation as predictors of outcome with erlotinib in bronchioloalveolar cell carcinoma (BAC): Results of a prospective phase II trial. J Clin Oncol 24:364s, 2006 (abstr 7003) 19. Eberhard DA, Johnson BE, Amler LC, et al: Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non- small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 23:5900, 2005 20. Philip PA, Benedetti J, Fenoglio-Preiser C, et al: Phase III study of gemcitabine [G] plus cetuximab [C] versus gemcitabine in patients [pts] with locally advanced or metastatic pancreatic adenocarcinoma [PC]: SWOG S0205 study. J Clin Oncol 25:199s, 2007 (abstr LBA4509) 21. Moore MJ, Goldstein D, Hamm J, et al: Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960-1966, 2007 22. Mellinghoff IK, Wang MY, Vivanco I, et al: Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353:2012-2024, 2005
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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