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Journal of Clinical Oncology, Vol 23, No 36 (December 20), 2005: pp. 9265-9274 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.03.0536 Randomized Phase II Trial of the Clinical and Biological Effects of Two Dose Levels of Gefitinib in Patients With Recurrent Colorectal AdenocarcinomaFrom the Vanderbilt-Ingram Cancer Center, Nashville, TN; Dana-Farber Cancer Center, Boston, MA; University of Wisconsin Cancer Center, Madison, WI; University of Pittsburgh Cancer Center, Pittsburgh, PA; Northwestern University Lurie Cancer Center, Chicago, IL. Address reprint requests to Mace L. Rothenberg, MD, Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, 777 Preston Research Building, Nashville, TN 37232-6307; e-mail: mace.rothenberg{at}vanderbilt.edu
PURPOSE: The clinical objective of this trial was to evaluate gefitinib in patients with metastatic colorectal cancer that had progressed despite prior treatment. Serial tumor biopsies were performed when possible and analyzed for activation of the epidermal growth factor receptor (EGFR) signaling pathway. Serial serum samples were measured for amphiregulin and transforming growth factor–alpha (TGF  ). PATIENTS AND METHODS: One hundred fifteen patients were randomly assigned to receive gefitinib 250 or 500 mg orally once a day. One hundred ten patients were assessable for clinical efficacy. Biologic evaluation was performed on paired tumor samples from 28 patients and correlated with clinical outcome. RESULTS: Median progression-free survival was 1.9 months (95% CI, 1.8 to 2.1 months) and 4-month progression-free survival rate was 13% ± 5%. One patient achieved a radiographic partial response (RR = 1%; 95% CI, 0.01% to 5%). Median survival was 6.3 months (95% CI, 5.1 to 8.2 months). The most common adverse events were skin rash, diarrhea, and fatigue. In the biopsy cohort, expression of total or activated EGFR, activated Akt, activated MAP-kinase, or Ki67 did not decrease following 1 week of gefitinib. However, a trend toward decreased post-treatment levels of activated Akt and Ki67 was observed in patients with a PFS higher than the median, although these did not reach the .05 level of significance. CONCLUSION: Gefitinib is inactive as a single agent in patients with previously treated colorectal cancer. In tumor samples, gefitinib did not inhibit activation of its proximal target, EGFR. Trends were observed for inhibition of downstream regulators of cellular survival and proliferation in patients achieving longer progression-free survival.
Epidermal growth factor (EGF) is a growth-regulating molecule that modulates cell proliferation and differentiation through its interaction with the EGF receptor (EGFR).1 In addition to EGF, a group of related ligands bind to and activate the EGFR. This group includes transforming growth factor–alpha (TGF ) and amphiregulin, which are frequently upregulated in colorectal cancer.2 Ligand engagement of the EGFR leads to receptor homo- and heterodimerization and activation via tyrosine autophosphorylation. This activates key mediators of signal transduction, such as MAP kinase and Akt, and culminates in the transmission of signals to the nucleus that stimulate cellular survival, proliferation, angiogenesis, and metastasis.3 The EGFR signaling pathway has been implicated in the etiology of a variety of malignancies in general, and in colorectal cancer, in particular. Approximately 40% to 70% of human colorectal cancers express EGFR.1 Higher levels of EGFR expression have been found in colorectal adenocarcinomas compared with surrounding normal colonic epithelium.4 In addition, injection of cells with high levels of EGFR expression into nude mice results in a higher incidence of liver metastases than injection of cells with lower levels of EGFR expression.5 Two clinical strategies have emerged to block the EGFR signaling pathway: monoclonal antibodies directed against the extracellular domain of the receptor that prevent ligand engagement, and small molecule tyrosine kinase inhibitors that bind to the adenosine triphosphate (ATP) -binding site and prevent receptor autophosphorylation and activation. Gefitinib (ZD1839; Iressa; AstraZeneca, Wilmington, DE) is a low molecular weight–competitive inhibitor of ATP binding to the tyrosine kinase site on EGFR.6 Preclinical studies demonstrated that gefitinib could inhibit EGF-stimulated receptor autophosphorylation and tumor growth at nanomolar concentrations in vitro.6 In a murine model of four human colorectal cancer xenografts, oral administration of gefitinib inhibited tumor growth by 43% to 96%.6 During the phase I development of gefitinib, prolonged stable disease was observed in four of 28 patients with previously treated metastatic colorectal cancer.7,8 In those trials, skin biopsies obtained pre- and post-treatment initiation demonstrated that gefitinib significantly inhibited phosphorylation of EGFR and MAP kinase and resulted in a decrease in Ki67. The maximum-tolerated dose in those trials was 600 mg/d, but plasma concentrations of gefitinib sufficient to inhibit the EGFR signaling pathway in vitro were observed at doses of 225 mg/d and above.
This multicenter phase II trial was designed to evaluate the effect of gefitinib in patients with metastatic colorectal cancer who had progressed despite previous treatment with irinotecan, fluorouracil, and leucovorin. Patients were randomly assigned to one of two dose levels of gefitinib: a "minimum biologically effective dose" of 250 mg/d, and a higher dose of 500 mg/d that more closely approximated the maximum-tolerated dose. In the subset of patients with disease that could be easily biopsied, and who granted consent, pre- and 1-week post-treatment initiation biopsies were obtained for biologic correlative studies. Serum levels of TGF
Eligibility Criteria Patients eligible for this study had histologically or cytologically confirmed adenocarcinoma arising in the colon or rectum and radiographic evidence of metastatic progressive disease during or within 6 months of completing systemic chemotherapy. Patients had to have previously received fluorouracil and/or its analogs, with or without leucovorin or levamisole, and irinotecan in any order or combination as systemic chemotherapy for locally advanced or metastatic disease. No other systemic therapies for colorectal cancer were allowed. Other inclusion criteria included the ability to take and retain oral medications, metastatic tumor sites potentially accessible for repeat biopsy, Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, age  18 years old, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST), completion of prior chemotherapy at least 4 weeks before enrollment and resolution of any treatment-related toxicities, absolute neutrophil count 1.5 x 109/L, platelet count 100 x 109/L, serum creatinine  1.5x the institution upper limit of normal (IULN) or creatinine clearance 60 mL/min, total bilirubin 1.5x IULN, and AST and ALT 2.5x IULN (or 5x IULN if liver metastases are present). All patients had to sign a consent form approved by the institutional review board or Institutional Ethics Committee in adherence with provisions set forth in the Helsinki Agreement.
Treatment Treatment was held for nausea or vomiting that reached grade 2 or any other toxicity that reached grade 3 in intensity. On resolution of grade 2 or worse nausea or vomiting, prophylactic antiemetics were administered before restarting full-dose gefitinib. If grade 2 or worse nausea or vomiting recurred despite this measure, the gefitinib dose was reduced by 50% (ie, patients receiving 500 mg/d were reduced to 250 mg/d; patients on 250 mg/d were reduced to 250 mg every-other-day). On resolution of all other grade 3 or worse toxicities, the dose of gefitinib was reduced by 50%.
Evaluation Biologic materials for correlative studies were collected only from those patients who consented to the use of their samples for these purposes. Thin-needle biopsies were performed under ultrasound or computed tomography guidance at baseline and one week after treatment initiation. Serum samples were obtained at baseline and at the end of 1 and 2 weeks of treatment and once every 2 months after that.
Assessment Criteria and Statistical Analysis
In the subset of patients who underwent pre- and 1-week post-treatment initiation tumor biopsies, the tissue was formalin fixed and paraffin embedded. Sections cut from these blocks were subjected to immunohistochemical staining using the antibodies, methods, and conditions summarized in Table 1. The scoring systems chosen for EGFR,
Baseline Characteristics One hundred fifteen patients were registered onto this study from 11 ECOG institutions over an 8-month period. Three patients were ineligible (randomly assigned before baseline measurements [1], baseline ANC obtained > 14 days before randomization [1], or target lesion below RECIST criteria[1]). Two patients withdrew consent before the initiation of treatment. Baseline characteristics on the 110 assessable patients are listed in Table 2. Approximately two thirds of the patients were male, more than half had an impaired performance status of 1 or 2, and nearly three quarters had more than one organ involved by tumor metastases. The most common sites of metastases were liver (75%) and lung/pleura (45%). Overall, baseline factors were evenly distributed between the two arms of the study.
Treatment The median number of treatment cycles administered (1 cycle = 28 days) was two (range, one to 14 cycles) for those patients treated at the 250 mg/d dose level, and three (range, one to 9) for those treated at the 500 mg/d dose level. The most common reasons for treatment discontinuation from the 250-mg treatment arm and the 500-mg treatment arm were disease progression (80% and 85%, respectively) and treatment-related toxicity (4% and 5%, respectively).
Clinical Efficacy
Toxicity The toxicities observed in this trial were typical of those associated with tyrosine kinase inhibitors of EGFR, and are listed in Table 4. The most common toxicities were dermatologic (including skin rash, dry skin, and pruritis), gastrointestinal (including nausea, vomiting, and anorexia), constitutional (primarily fatigue), and anemia. Most of these toxicities were grade 1 to 2 in intensity and resolved with dose reduction or discontinuation. The frequency and severity of skin rash and diarrhea appeared to be dose related. The overall incidence of grade 3 toxicity was twice as high in the group treated at 500 mg/d (31%) as it was in the group treated at 250 mg/d (16%). There were only two episodes of grade 4 toxicity. One patient treated with gefitinib 250 mg/d experienced grade 4 abdominal pain and one patient treated with gefitinib 500 mg/d experienced grade 4 neutropenia. There was a weak positive correlation (0.13) identified between skin rash and 4-month PFS in all eligible patients, but this did not reach statistical significance (P = .19).
Tumor Biopsies When this study was designed, NCI guidelines specified that tumor biopsies could not be required unless the proposed biologic assays used validated techniques and constituted the primary objective of the study. Because neither was the case for this study, tumor biopsies were an optional component of this study. Of the 110 assessable patients enrolled onto this trial, 80 (73%) consented to participate in the tumor biopsy portion of this trial. This reflects the willingness of patients to contribute to the better understanding of cancer and cancer treatment even if that information is of no direct benefit to them. At least one biopsy was obtained in 50 patients (45%). Paired tumor biopsies—one obtained just before treatment initiation and one obtained 1 week after treatment initiation—containing viable tumor were obtained in 28 patients (25%). Reasons for not obtaining analyzable biologic data on 22 patients included necrotic tissue on one or both biopsies (11 patients), patient refusal (five patients), inappropriate material collection (eg, fine-needle aspiration rather than core biopsy; four patients), and early progression of disease before scheduled second biopsy (one patient). When compared with the entire group of 110 patients, there were no marked differences in baseline clinical characteristics in the 28 patients in whom biologic data were available (data not shown). No serious adverse events resulted from the tumor biopsies.
Biologic Correlative Studies
Because it was possible that the low level of clinical activity could have obscured certain biologic changes in a subset of patients with potentially gefitinib-responsive tumors, we then analyzed patients based on progression-free survival greater than or the mean PFS of 1.8 months (Table 6). Although the number of patients in each subset was small, two interesting trends were observed. A decrease in phosphorylated Akt, a key element in the survival pathway of a cell that is influenced by EGFR, was observed in one (11%) of nine patients with progression-free survival 1.8 months, whereas a decrease in this marker was observed in six (40%) of 15 patients with progression-free survival greater than the mean (P = .20). Similarly, Ki67, a marker of cellular proliferation, demonstrated no change or a slight upward trend in those patients with PFS 1.8 months, and a downward trend in those patients with PFS greater than 1.8 months (P = .11). Although neither of these changes reached statistical significance of .05, both of these variables moved in the direction that would be expected following inhibition of the EGFR-signaling pathway.
Another question addressed in this study was whether there was any difference in the biologic effect observed in tumors obtained from patients treated at the 250 mg/d dose or 500 mg/d dose. Table 7 summarizes these data. Again, no statistically significant differences were identified, but two notable trends emerged. Five (45%) of 11 patients treated with gefitinib 500 mg/d had a decrease in tumor-phosphorylated Akt following treatment initiation compared with only two (14%) of 14 patients treated with gefitinib 250 mg/d (P = .18). In contrast, a decrease in phosphorylated EGFR was observed in tumors from three (30%) of 10 patients treated with gefitinib 250 mg/d, but none of nine patients treated with gefitinib 500 mg/d (P = .21). Overall, no consistent trends were observed between dose of gefitinib and inhibition of the EGFR-signaling pathway.
When analysis of the biologic outcomes was restricted to only the subset of patients in whom a change could be seen, ie, who had detectable levels of the biomarker at baseline, the results of all biologic correlative studies performed on tumor biopsies remained the same—no significant association was detected.
Paired serum samples (baseline and 1 to 2 weeks post-treatment initiation) were obtained from 28 patients. Six (38%) of 16 patients receiving gefitinib 500 mg/d had an increase of at least 1 pg/mL in TGF
The epidermal growth factor receptor and its signaling pathway have been the focus of intense study over the past decade, not only to gain insight into tumor biology but also as potentially exploitable therapeutic targets. The two pathways believed to be the most important in conveying the biologic information from an activated EGFR include the PI3 kinase  Akt cell survival pathway and the Ras/Raf MEK/ERK MAP kinase cell proliferation pathway. In preclinical models, inhibition of EGFR activation, either by blocking ligand engagement via a monoclonal antibody or by blocking receptor phosphorylation via an ATP-mimetic tyrosine kinase inhibitor, effectively inhibits signaling through each of these pathways and cause significant inhibition of cell growth, proliferation, invasion, angiogenesis, and metastasis. Over the last 4 years, EGFR has been confirmed as a clinically valid target in several cancers. In pooled data from three phase II trials of single-agent gefitinib, 10% of patients with advanced non–small-cell lung cancer that progressed despite prior chemotherapy achieved an objective response.12,13 More recently, erlotinib improved survival when used as a single agent for second- or third-line treatment of non–small-cell lung cancer and also improved survival when combined with gemcitabine as first-line therapy for advanced pancreatic cancer.14,15 Phase II trials of the monoclonal antibody cetuximab in patients with advanced colorectal cancer produced a 10% response rate when used as a single agent, and a 23% response rate when used in combination with irinotecan in patients whose tumors had progressed despite prior treatment with irinotecan.16,17 As a result of these studies, gefitinib was approved by the US Food and Drug Administration (FDA) in May 2003, cetuximab was approved by the FDA in February 2004, and erlotinib was granted FDA approval in November 2004. Our study was undertaken to evaluate the clinical activity of single-agent gefitinib in patients with progressive colorectal cancer, and to determine its biologic activity in tumor samples obtained just before and just after the initiation of therapy. Gefitinib proved ineffective in this setting. Only one of 110 assessable patients achieved a partial response and that response lasted only 2.3 months. The median progression-free survival was 1.9 months (95% CI, 1.8 to 2.1 months) and the 4-month progression-free survival rate was 13% ± 5%. The null hypothesis of a median PFS of 2.5 months and a 4-month PFS rate of 28% could not be rejected (P = .99). These clinical results are consistent with those reported by others who have evaluated EGFR tyrosine kinase inhibitors in patients with progressive colorectal adenocarcinoma.18,19 It is unlikely that these results were due to underdosing of gefitinib because a similar lack of activity was observed in a phase II trial reported by Mackenzie et al19 that utilized a 750 mg/d dose. Gefitinib was specifically designed to inhibit phosphorylation of EGFR at low, clinically achievable concentrations. Preclinical studies demonstrated that it potently inhibited EGFR tyrosine kinase in vitro with an IC50 = 0.02 µmol/L, and inhibited the growth of EGF-stimulated KB oral carcinoma cells in culture with an IC50 = 0.08 µmol/L.1 Similar effects were seen in other tumor types including the HT-29 colorectal cancer cell line.1 Phase I trials of gefitinib demonstrated that plasma concentrations greater than or equal to the in vitro IC90 were consistently achieved at doses above 225 mg/d.7,8 In addition, these studies demonstrated marked inhibition of phosphorylation of EGFR and MAPK and decreased levels of Ki67 in skin biopsies obtained following the initiation of gefitinib treatment, confirming that a biologic effect could be obtained at clinically tolerable doses.7,8 However, tumor biopsies were not included as a part of those phase I trials.
Our results suggest that phosphorylation of EGFR and critical components in its signaling pathway, such as MAP kinase and Akt, are not effectively inhibited in colorectal cancer tissue by gefitinib. This lack of biologic effect is consistent with gefitinib's lack of clinical effect in patients with recurrent colorectal cancer. Although there are several possible explanations for this, this correlation must be interpreted cautiously. First of all, 7 days following the initiation of treatment with gefitinib may have been too short a period for the full inhibition of EGFR to be observed in biologic specimens. Prior experience, however, suggests that biologic changes could be observed in this time frame with effective therapy, as was observed in a patient with Ménétrier's disease treated with cetuximab.20 A second factor to consider is that the results of the biologic studies could have been spuriously affected by the method in which tissue was processed and by limitations in currently available reagents. Phosphorylated Akt may be dephosphorylated if the tissue is not processed rapidly.21 A third factor is that EGFR has five autophosphorylation sites in its tyrosine kinase catalytic domain. The monoclonal antibody used to detect
Daneshmand et al22 performed a similar analysis of 11 paired tumor samples obtained from patients treated with gefitinib 750 mg/d. They reported a significant decrease in post-treatment proliferative index as measured by Ki67 (eight of 10 patients), and isolated cases in which post-treatment biopsies demonstrated a decrease in
It is apparent that overexpression of EGFR is one of only several ways in which the EGFR-signaling pathway may be engaged and activated. Only after this study was completed did data emerge regarding the association between activating mutations in the catalytic domain of EGFR and clinical response to EGFR-directed tyrosine kinase inhibitors.23,24 Although EGFR-activating mutations are observed in In conclusion, the results from this study suggest that single-agent gefitinib is clinically and biologically inactive in patients with relapsed or refractory colorectal cancer. Paired tumor biopsies containing viable tumor were obtained from 28 patients or 24% of patients overall. New clinical trials that include biologic correlative studies have been initiated to explore the effect of blocking the EGFR-signaling pathway at multiple levels and the effect of blocking pathways that may interact with the EGFR-signaling pathway.
The authors indicated no potential conflicts of interest.
This trial represents a collaboration between the Vanderbilt Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancer (NCI P50 CA95103) and the Eastern Cooperative Oncology Group (NCI U10 CA21115). We acknowledge the significant contributions of the patients, clinical study personnel, and research scientists who contributed to this effort.
Supported by PHS Grants No. CA23318, CA66636, CA21115, CA49957, CA21076, CA17145, and CA39229 (to Eastern Cooperative Oncology Group institutions), P50 CA95103 (Vanderbilt Specialized Program Of Research Excellence [SPORE] in Gastrointestinal Cancer grant), CA46413 (to R.J.C.), and K24 CA82301 (to M.L.R.). This study was conducted as a collaboration between the Eastern Cooperative Oncology Group (PI: Robert L. Comis, MD) and the Vanderbilt SPORE in Gastrointestinal Cancer (PI: R.J.C.). Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004, and at the 12th SPORE Investigators' Workshop, Baltimore, MD, July 10-13, 2004. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Woodburn JR: The epidermal growth factor receptor and its inhibition in cancer therapy. Pharmacol Ther 82:241-250, 1999[CrossRef][Medline] 2. Halter SA, Dempsey P, Matsui Y, et al: Distinctive patterns of hyperplasia in transgenic mice with mouse mammary tumor virus transforming growth factor-alpha: Characterization of mammary gland and skin proliferations. Am J Pathol 140:1131-1146, 1992[Abstract] 3. Mendelsohn J, Baselga J: Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 21:2787-2799, 2003 4. Messa C, Russo F, Caruso MG, et al: EGF, TGF-alpha, and EGF-R in human colorectal adenocarcinoma. Acta Oncol 37:285-289, 1998[CrossRef][Medline] 5. Radinsky R, Risin S, Fan D, et al: Level and function of epidermal growth factor receptor predict the metastatic potential of human colon carcinoma cells. Clin Cancer Res 1:19-31, 1995 6. Wakeling AE, Guy SP, Woodburn JR, et al: ZD1839 (Iressa): An orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res 62:5749-5754, 2002 7. Herbst RS, Maddox AM, Rothenberg ML, et al: Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: Results of a phase I trial. J Clin Oncol 20:3815-3825, 2002 8. 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 9. Rothenberg ML, Cox JV, DeVore RF, et al: A multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated colorectal carcinoma. Cancer 85:786-795, 1999[CrossRef][Medline] 10. Rothenberg ML, Oza AM, Bigelow RH, et al: Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: Interim results of a phase III trial. J Clin Oncol 21:2059-2069, 2003 11. Merchant N, Rogers C, Trivedi B, et al: Ligand-dependent activation of the epidermal growth factor receptor by secondary bile acids in polarizing colon cancer cells. Surgery 138:415-421, 2005[CrossRef][Medline] 12. Kris MG, Natale RB, Herbst RS, et al: Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: A randomized trial. JAMA 290:2149-2158, 2003 13. Cohen MH, Williams GA, Sridhara R, et al: FDA drug approval summary: Gefitinib (ZD1839) (Iressa) tablets. Oncologist 8:303-306, 2003 14. Shepherd FA, Rodrigues-Pereira J, Ciuleanu T, et al: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123-132, 2005 15. Moore MJ, Goldstein D, Hamm J, et al: Erlotinib plus gemcitabine compared to gemcitabine alone in patients with advanced pancreatic cancer: A phase III trial of the National Cancer Institute Clinical Trials Group. J Clin Oncol 23:1s, 2005 (suppl; abstr 1) 16. Saltz LB, Meropol NJ, Loehrer PJ Sr, et al: Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 22:1201-1208, 2004 17. 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 18. Oza AM, Townsley CA, Siu LL, et al: Phase II study of erlotinib (OSI-774) in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 22:196, 2003 (abstr 785) 19. Mackenzie MJ, Hirte HW, Glenwood G, et al: A phase II trial of ZD1839 (Iressa) 750 mg per day, an oral epidermal growth factor receptor-tyrosine kinase inhibitor, in patients with metastatic colorectal cancer. Invest New Drugs 23:165-170, 2005[CrossRef][Medline] 20. Burdick JS, Chung E, Tanner G, et al: Treatment of Menetrier's disease with a monoclonal antibody against the epidermal growth factor receptor. N Engl J Med 343:1697-1701, 2000 21. Baker AF, Dragovich T, Ihle NT, et al: Stability of phosphoprotein as a biological marker of tumor signaling. Clin Cancer Res 11:4338-4340, 2005 22. Daneshmand M, Parolin DA, Hirte HW, et al: A pharmacodynamic study of the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in metastatic colorectal cancer patients. Clin Cancer Res 9:2457-2464, 2003 23. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004 24. Paez JG, Janne PA, Lee JC, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304:1497-1500, 2004 25. Barber TD, Vogelstein B, Kinzler KW, et al: Somatic mutations of EGFR in colorectal cancers and glioblastomas. N Engl J Med 351:2883, 2004 26. Shia J, Klimstra DS, Li AR, et al: Epidermal growth factor receptor expression and gene amplification in colorectal carcinoma: An immunohistochemical and chromogenic in situ hybridization study. Mod Pathol 18:1350-1356, 2005[CrossRef][Medline] 27. Cappuzzo F, Hirsch FR, Rossi E, et al: Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 97:643-655, 2005 28. Shao J, Evers BM, Sheng H: Prostaglandin E2 synergistically enhances receptor tyrosine kinase-dependent signaling system in colon cancer cells. J Biol Chem 279:14287-14293, 2004 29. Kwon J, Lee SR, Yang KS, et al: Reversible oxidation and inactivation of the tumor suppressor PTEN in cells stimulated with peptide growth factors. Proc Natl Acad Sci U S A 101:16419-16424, 2004 30. Lockhart C, Berlin JD: The epidermal growth factor receptor as a target for colorectal cancer therapy. Semin Oncol 32:52-60, 2005[CrossRef][Medline] Submitted June 10, 2005; accepted September 26, 2005.
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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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ABSTRACT
INTRODUCTION
EGFR, and 
10% of non–small-cell lung cancers, these mutations appear to occur with a much lower frequency in human colorectal cancers, with an estimated incidence of 0.3%.
