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Originally published as JCO Early Release 10.1200/JCO.2005.10.951 on January 27 2005 © 2005 American Society of Clinical Oncology.
Epidermal Growth Factor Receptor Inhibitors in Colorectal Cancer: It's Time to Get Back on TargetFox Chase Cancer Center, Philadelphia, PA A key signature of targeted cancer therapy is selectivity. This selectivity depends on identification of a target that is tightly associated with the malignant phenotype. Inhibition of the target must alter this phenotype and must not adversely affect normal tissues. An ability to measure the presence of the target is a requirement for clinical development, such that individuals with tumors that do not express the target are spared exposure to ineffective treatment. Inhibitors of the epidermal growth factor receptor (EGFR) illustrate some of the triumphs and pitfalls associated with the development of targeted cancer therapy. Murine epidermal growth factor was identified more than 40 years ago, and its human homolog and receptor were isolated 15 years later.1-5 Subsequently, the receptor was shown to have intrinsic kinase activity.5 During the 1980s and 1990s, several significant observations established EGFR as a potential therapeutic target.6,7 First, studies demonstrated homology between EGFR and the proto-oncogene v-erbB.8 Second, frequent expression of EGFR was found in a variety of epithelial malignancies, with expression conferring poor prognosis. Finally, inhibitory antibodies and small molecules were shown to block receptor phosphorylation, cellular proliferation, and xenograft growth.9-12 Given the frequent expression of EGFR in colorectal cancer (approximately 70% to 75% by immunohistochemistry [IHC]),13 this malignancy was identified as appropriate for the clinical development of EGFR inhibitors. Clinical activity has been demonstrated for the anti-EGFR monoclonal antibodies cetuximab14-16 (a human-mouse chimera) and panitumumab17 (a fully human antibody) in patients with metastatic colorectal cancer. Cetuximab is approved by the US Food and Drug Administration for use in patients with EGFR-expressing metastatic colorectal cancer.18 Based on xenograft models that indicated potentiation of anti-EGFR monoclonal activity with cytotoxic chemotherapy,11 the initial phase II trial of cetuximab in patients with metastatic colorectal cancer was a combination study of irinotecan plus cetuximab.14 Subsequent clinical trials confirmed the hypothesis that irinotecan plus cetuximab in combination is superior to cetuximab monotherapy, with response rates of approximately 20% v 10%, respectively, in patients who previously showed resistance to irinotecan.15,16 The most common toxicity associated with cetuximab is skin rash, and the presence and severity of rash have been consistently predictive of response and survival in patients with colorectal cancer.14,16 This clinical observation has led to the exploration of skin as a surrogate pharmacodynamic marker of EGFR inhibition, and numerous studies have demonstrated the predicted downstream perturbations of EGFR signaling, such as phosphorylated EGFR, phosphorylated AKT, Ki67, and p27 in the skin of patients treated with antibody and small-molecule EGFR inhibitors.19-21 Unfortunately, a clear association between signaling inhibition in skin and antitumor response has not been found. Although cetuximab initially seemed to exemplify the principles of targeted therapy, emerging clinical information has clouded this picture. In this issue, Chung et al22 report a single-institution retrospective case series in which 16 patients with irinotecan-resistant colorectal cancer whose tumors were EGFR negative by IHC were treated with cetuximab. Four objective responses were observed (confirmed at > 6 weeks) on treatment with irinotecan plus cetuximab. Previous clinical trials had required EGFR positivity by IHC as an entry criterion, based on the conventional wisdom that a target should be present before administering a targeted therapy. However, it should be noted that these prior studies with either cetuximab or panitumumab found no association between extent of tumor EGFR staining and likelihood of response.15-17 Chung et al22 thus hypothesized that even EGFR-negative tumors might be responsive to cetuximab. Although this study is a small and retrospective review, it provides provocative support for the contention that at least some colon cancers lacking EGFR expression by IHC may still be sensitive to cetuximab. This study highlights limitations associated with the use of IHC for patient selection. The authors point out that testing of archived material is likely associated with protein degradation and loss of sensitivity.23 In this series, the median interval between tissue acquisition and testing was 24 months, and only two samples were tested within 1 year of fixation. It is uncertain how long the tissues were fixed in formalin before embedding in paraffin and how long it was before the slides were stained and prepared, which are two factors that may affect IHC results. Detailed information regarding immunostaining methodology that could affect assay sensitivity was not provided. Of the 16 cases, only three included testing of metastases; it is also plausible that the predictive value of EGFR IHC may be improved with testing of metastatic tissue. Although IHC interpretation is generally subject to interobserver variability, this potential is minimized for EGFR testing in which a binary distinction between complete absence compared with any membrane staining is required; there was also excellent concordance when the cases reported by Chung et al22 were reviewed by a second pathologist (although not blinded to the previous report). Furthermore, the contribution of laboratory reagent selection to study findings was minimized because the investigators were able to test 13 of the 16 tumor samples with two different EGFR antibodies (Ventana Medical Systems clone 31G7; Zymed Laboratories Inc, South San Francisco, CA; and DakoCytomation clone 2-18C9; Dako, Carpinteria, CA). The authors report that 30% of patients receiving nonprotocol cetuximab during the study period had EGFR-negative tumors. It would also be important to know how many colorectal cancer specimens overall were tested for EGFR expression during the study period and the results of this testing to establish concordance with expected positivity rates. The data presented by Chung et al22 suggest that, as currently used, IHC for EGFR expression is a poor screening method for identifying patients with colorectal cancer who will not respond to cetuximab therapy. Larger, multicenter, prospective series are required to delineate the true response rate with cetuximab in combination with chemotherapy or as monotherapy in tumors that do not demonstrate EGFR by IHC. The current data do not tell us whether IHC testing of metastases, IHC testing of archived primary material, testing of fresh tumor, or the use of other EGFR antibodies will be more predictive of response to cetuximab. Have we lost our target for this targeted approach to colorectal cancer? I think not. Rather, efforts initially focused on target identification must now be expanded to determine which subset of tumors is driven by and dependent on this target and its associated downstream signaling pathways. Unlike the case with trastuzumab therapy of HER2/neu-expressing breast cancers, EGFR gene amplification is not a predictive marker for potential inhibitor activity in colorectal cancer.24 In a large proportion of gastrointestinal stromal tumors and a small minority of lung cancers, specific somatic mutations give rise to constitutive activation of a receptor tyrosine kinase upon which the cells are dependent, rendering exquisite sensitivity to perturbation of that receptor.25-27 Such driving mutations in the tyrosine kinase domain have not been identified in colorectal cancers, perhaps suggesting a more complex molecular context. A number of potential influences on response to EGFR inhibitors in colorectal cancer are listed in Table 1, none of which have yet been validated clinically. Although IHC is not predictive of response, there is likely a threshold (below the sensitivity of IHC) below which response would not be expected. The EGFR gene is polymorphic, and protein expression is modulated by promoter CA repeat sequence length.28 Additional somatic receptor mutations and posttranslational modifications may be identified that affect ligand binding and phosphatase activity.29,30 It is also plausible that specific receptor sequences in antibody-binding extracellular domains will be identified that impact response to anti-EGFR antibodies, which is analogous to recent findings of intracellular tyrosine kinase domain mutations predictive of gefitinib response in lung cancer.26,27 EGFR can heterodimerize with other members of the HER family of receptor tyrosine kinases, and the clinical impact of this dimerization on signaling and pathway dependence is unknown.31 EGFR can also interact with other cell-surface receptors, such as the insulin-like growth factor receptor, which may also be involved in the pathogenesis of some colorectal cancers.32-34 Furthermore, phosphatase activity of the EGFR initiates a variety of downstream pathways, including AKT, MAPK, and STAT, and these pathways interact with one another as well as with signals from other intracellular systems.30,32,33 Finally, autocrine stimulation of the EGFR can be impacted by ligand expression.
Drug development that began with a simple focus on the receptor as target has expanded to a focus on understanding which tumors have EGFR pathway dependence. The clinical development of EGFR inhibitors against colorectal cancer should leave us neither discouraged nor complacent. The challenge for clinical investigators is to design the next generation of studies that will explore the target as system, so that patient selection and combination treatment strategies may be optimized. Author's Disclosures of Potential Conflicts of Interest The following author or his immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Neal J. Meropol, Bristol-Myers Squibb. Research Funding: Neal J. Meropol, Amgen, Bristol-Myers Squibb. For a detailed description of these 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 of Information for Contributors found in the front of every issue.
Acknowledgment I wish to thank Roger Cohen, MD, Harry Cooper, MD, and Louis Weiner, MD, for their helpful discussions and review of this Editorial. REFERENCES 1. Cohen S: Nobel lecture: Epidermal growth factor. Biosci Rep 6:1017-1028, 1986[CrossRef][Medline]
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19. Albanell J, Rojo F, Averbuch S, et al: Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: Histopathologic and molecular consequences of receptor inhibition. J Clin Oncol 20:110-124, 2002
20. Baselga J, Rischin D, Ranson M, et al: Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol 20:4292-4302, 2002
21. Vanhoefer U, Tewes M, Rojo F, et al: Phase I study of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with advanced solid tumors that express the epidermal growth factor receptor. J Clin Oncol 22:175-184, 2004
22. Chung KY, Shia J, Kemeny NE, et al: Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 23:1803-1810, 2005
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29. Moriai T, Kobrin MS, Hope C, et al: A variant epidermal growth factor receptor exhibits altered type alpha transforming growth factor binding and transmembrane signaling. Proc Natl Acad Sci U S A 91:10217-10221, 1994
30. Sordella R, Bell DW, Haber DA, et al: Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 305:1163-1167, 2004 31. Earp HS, Dawson TL, Li X, et al: Heterodimerization and functional interaction between EGF receptor family members: A new signaling paradigm with implications for breast cancer research. Breast Cancer Res Treat 35:115-132, 1995[CrossRef][Medline]
32. Chakravarti A, Loeffler JS, Dyson NJ: Insulin-like growth factor receptor I mediates resistance to anti-epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling. Cancer Res 62:200-207, 2002
33. Lu D, Zhang H, Ludwig D, et al: Simultaneous blockade of both the epidermal growth factor receptor and the insulin-like growth factor receptor signaling pathways in cancer cells with a fully human recombinant bispecific antibody. J Biol Chem 279:2856-2865, 2004
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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