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Lung Cancer

Understanding the New Genetics of Responsiveness to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

Department of Hematology-Oncology, Istituto Clinico Humanitas, Rozzano, Italy

Key Words. Epidermal growth factor receptor • Tyrosine kinase inhibitors • Gefitinib • Erlotinib • Non-small cell lung cancer

Correspondence: Federico Cappuzzo, M.D., Istituto Clinico Humanitas IRCCS, via Manzoni 56, 20086 Rozzano, Italy. Telephone: +39 (0)2 82248224; Fax: +39-02-82244590; e-mail: federico.cappuzzo{at}humanitas.it

Received September 28, 2006; accepted for publication October 29, 2006.

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction EGFR Tyrosine Kinase Inhibitors EGFR Protein Expression EGFR Gene Mutations EGFR Gene Copy Number Other Biological Markers Conclusion Disclosure of Potential... References

 
After completing this course, the reader will be able to:

1. Select a patient candidate for a tyrosine kinase inhibitor therapy.
   
2. Describe the mechanism of action of gefitinib and erlotinib.
   
3. Discuss the role of clinical and biological factors as determinants for sensitivity or resistance to tyrosine kinase inhibitors in lung cancer.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction EGFR Tyrosine Kinase Inhibitors EGFR Protein Expression EGFR Gene Mutations EGFR Gene Copy Number Other Biological Markers Conclusion Disclosure of Potential... References

 
The epidermal growth factor receptor (EGFR) is implicated in cancer progression and development and, being overexpressed in a variety of human malignancies, is an attractive target for selective anticancer therapy. EGFR tyrosine kinase inhibitors (TKIs) have been demonstrated to produce dramatic and durable responses in a fraction of non-small cell lung cancer patients. During the last few years, clinical and biological predictors for TKI sensitivity have been identified. Among clinical features, never-smoking history seemed the most critical factor, probably because of the different spectrum of molecular abnormalities associated with cigarette-smoking exposure. Among biological predictors, several studies indicate that EGFR mutations and increased EGFR gene copy number are implicated in response to TKI therapy, with conflicting results in survival. Mutations in the EGFR gene as well as in K-ras and HER2 genes seemed to impair TKI effects, leading to TKI resistance. Because most available data come from retrospective studies, there is an urgent need to validate these results in prospective trials. Several studies have been recently completed, and these data could indicate how to properly select patients who are candidates for TKI therapy.

	INTRODUCTION

Top Learning Objectives Abstract Introduction EGFR Tyrosine Kinase Inhibitors EGFR Protein Expression EGFR Gene Mutations EGFR Gene Copy Number Other Biological Markers Conclusion Disclosure of Potential... References

 
Recent advances in cancer biology have led to the identification of several potential molecular targets that play a key role in cancer development and progression. Selective targeting of cancer cells on the basis of their molecular phenotype can provide effective anticancer activity, avoiding the commonly experienced side effects induced by chemotherapy. Among these targets, the epidermal growth factor receptor (EGFR) has become widely investigated in different human malignancies due to its critical role in cancer proliferation and survival.

The EGFR superfamily includes four distinct, closely related transmembrane receptors: EGFR/erbB-1, HER2/ erbB-2, HER3/erbB-3, and HER4/erbB-4 [1]. EGFR is normally found on the surface of epithelial cells and has been found to be commonly overexpressed in a variety of human malignancies [2–4]. Different ligands can lead to EGFR activation and subsequent signal transduction, including the epidermal growth factor, the transforming growth factor , and neuregulins. After ligand binding to the extracellular receptor domain, EGFR undergoes homo- or heterodimerization and autophosphorylation of its intracellular tyrosine kinase domain. These autophosphorylation events trigger a cascade of downstream signals that ultimately result in an increase of cellular motility, proliferation and invasion, and a block of apoptosis, contributing to cancer development and progression. Strategies aimed at inhibiting the EGFR pathway include different classes of compounds, with tyrosine kinase inhibitors (TKIs) and monoclonal antibodies being the most widely investigated agents. This review focuses on molecular predictors for sensitivity and resistance to EGFR TKIs and possible clinical implications.

	EGFR TYROSINE KINASE INHIBITORS

Top Learning Objectives Abstract Introduction EGFR Tyrosine Kinase Inhibitors EGFR Protein Expression EGFR Gene Mutations EGFR Gene Copy Number Other Biological Markers Conclusion Disclosure of Potential... References

 
Gefitinib (ZD 1839, Iressa; AstraZeneca, London) and erlotinib (OSI 774, Tarceva; Genentech, South San Francisco, CA) are the first EGFR TKIs to have reached clinical trial testing, but several other agents, including lapatinib, EKB-569, CI-1033, PKI-166, and AEE-788, are currently under investigation. Both gefitinib and erlotinib are orally active, selective EGFR TKIs that demonstrated antitumor activity in a variety of human cancer cell lines overexpressing EGFR [5, 6]. Phase I studies were conducted in patients affected with different solid tumors, including non-small cell lung cancer (NSCLC) and ovarian, breast, colorectal, and head and neck cancers [7–14]. Gefitinib showed promising antitumor activity at doses of at least 150 mg/day, with dose-limiting toxicity observed at 800 mg/day or 1,000 mg/ day. Main side effects, which occurred in approximately 70%–80% of the patients, and especially above 600 mg/ day, were diarrhea and skin rash, both dose-dependent and reversible. On the basis of these studies, 250 mg/day and 500 mg/day were the fixed doses chosen for phase II studies. Erlotinib showed a similar activity and toxicity pattern, with 150 mg/day emerging as the optimal dose for phase II trial testing [13].

In the Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL)-1 and -2 studies, a total of 426 NSCLC patients progressing after one or more chemotherapy regimens were randomized to receive 250 mg/day of gefitinib versus 500 mg/day [15, 16]. These trials showed response rates of 10%–19%, with a clear symptom improvement in approximately 40% of the patients, leading to U.S. Food and Drug Administration (FDA) gefitinib approval for use in NSCLC. Subgroup analyses indicated that response to gefitinib was associated with Asian ethnicity, adenocarcinoma histology (especially in the presence of bronchioloalveolar features), female sex, and never-smoking history [15, 16].

Similar results were observed with erlotinib. In a phase II study, the drug produced a 12.3% response rate, with no grade 4 toxicity and minimal grade 3 side effects [17]. As for gefitinib, high response rate was observed in nonsmokers and adenocarcinomas with bronchioloalveolar features (37% and 30%, respectively).

The promising EGFR TKI single-agent activity observed in these studies has not been confirmed in subsequent phase III combination trials. Four large prospective studies, including more than 4,000 patients with advanced NSCLC (Iressa NSCLC Trail Assessing Combination Treatment [INTACT]-1 and -2, Tarceva Responses in Conjunction with Paclitaxel and Carboplatin [TRIBUTE], Tarceva Responses in Conjunction with Cisplatin and Gemcitabine [TALENT]), randomly assigned untreated patients to standard chemotherapy plus a TKI, or the same chemotherapy regimen plus placebo [18 –21]. All trials failed to demonstrate any survival advantage for patients receiving the TKI, probably because of the lack of patient selection. Unplanned subgroup analyses showed that never-smokers receiving the TKI had a significant survival improvement compared with never-smokers treated with placebo, supporting the relevant role of smoking history for TKI sensitivity [21]. Recently, two large randomized phase III studies assessed gefitinib and single-agent erlotinib in advanced NSCLC patients who experienced treatment failure with at least one chemotherapy regimen [22, 23]. The Iressa Survival Evaluation in Lung cancer (ISEL) trial included 1,692 patients who were randomized to 250 mg/day of gefitinib or placebo [22]. Despite higher response rate and longer time to progression in the gefitinib arm, the study concluded that the drug produced no survival advantage over best supportive care in advanced NSCLC (5.6 months vs. 5.1 months; p = .09). Conversely, the BR21 trial, in which 731 previously treated advanced NSCLC patients were randomized to receive 150 mg/day of erlotinib or placebo, succeeded in meeting its primary endpoint, with patients in the experimental arm experiencing a statistically significant improvement in overall survival with a hazard ratio of 0.70 [23]. Results from these large randomized trials led to erlotinib approval by the FDA and to restrictions for gefitinib use, limiting drug administration to patients currently receiving gefitinib and benefiting from the agent or patients who have previously received and benefited from gefitinib. Although the ISEL and the BR21 trials produced different results, both studies showed that never-smokers treated with a TKI had a significantly longer survival compared with never-smokers who received placebo, with no survival difference in smokers irrespective of the treatment [22, 23].

The relevance of smoking history in TKI sensitivity has been confirmed in a recently published phase II trial of gefitinib as first-line treatment in Korean never-smokers with lung adenocarcinoma [24]. In this study, authors observed a 69% response rate, with an estimated 1-year survival of 73%. These results are remarkable, supporting further studies comparing a TKI with standard chemotherapy in selected cohorts of NSCLC.

In summary, erlotinib is the only TKI that has been demonstrated to significantly improve survival versus best supportive care in pretreated NSCLC patients, with no survival benefit in combination with chemotherapy in untreated NSCLC. Among clinical features, smoking history is probably the most relevant predictor for TKI sensitivity, and both gefitinib and erlotinib have been demonstrated to significantly prolong survival in never-smokers in large phase III trials.

	EGFR PROTEIN EXPRESSION

Top Learning Objectives Abstract Introduction EGFR Tyrosine Kinase Inhibitors EGFR Protein Expression EGFR Gene Mutations EGFR Gene Copy Number Other Biological Markers Conclusion Disclosure of Potential... References

 
Although clinical characteristics could be useful for identifying patients more likely to have a benefit, selection of patients who are candidates for TKI therapy should be performed on the basis of biological characteristics (Tables 1, 2). That is because clinical features associated with TKI efficacy are not important per se but are relevant only because they reflect particular biological aspects of the disease.

These conflicting results suggest that IHC is probably not an optimal method for patient selection. Nevertheless, the relevant data from the BR21 study indicated that TKI therapy should not be denied to EGFR IHC-positive individuals.

	EGFR GENE MUTATIONS

Top Learning Objectives Abstract Introduction EGFR Tyrosine Kinase Inhibitors EGFR Protein Expression EGFR Gene Mutations EGFR Gene Copy Number Other Biological Markers Conclusion Disclosure of Potential... References

 
In 2004, three groups showed that mutations in the TK domain of EGFR were associated with response of NSCLC to gefitinib [31–33] or erlotinib [33]. These mutations were somatic and more frequently observed in patients with clinical features known to be associated with TKI sensitivity, such as female sex, adenocarcinoma histology, Asian ethnicity, and never-smoking history. Pham et al. [34] recently observed that the likelihood of harboring EGFR mutations in lung adenocarcinomas decreases as the exposure to tobacco smoke increases. The most common EGFR-sensitizing mutations, accounting for ~85% of all EGFR mutations in NSCLC, include deletions in exon 19 and L858 substitutions in exon 21. Such EGFR mutations increase sensitivity to TKIs, most likely through induction of critical structural modifications of the ATP-binding site in the tyrosine kinase domain [31, 32]. Several other EGFR gene mutations have been described, but their role is not clear, and it is not possible to exclude that some of them are artifacts [35]. The threonine-to-methionine substitution at amino acid position 790 (T790M) in exon 20 of the EGFR gene has been reported in progressing lesions after gefitinib or erlotinib therapy [36, 37]. In vitro experiments confirmed that the presence of the T790M substitution confers resistance to EGFR mutant cell lines usually sensitive to either gefitinib or erlotinib, probably modifying the structure of the EGFR tyrosine kinase domain [36–38]. Interestingly, this mutation might be present in a small fraction of tumor cells before drug treatment and might have germline transmission, resulting in inherited lung cancer susceptibility and intrinsic TKI resistance [39–41].

Most studies showed a significant association of EGFR mutations, particularly exon 19 deletion, and response to TKIs [42–51]. Recent prospective studies confirmed that responders to gefitinib or erlotinib harbored an EGFR gene mutation [52–57]. In a phase II study conducted by the Spanish Lung Cancer Group, 297 chemotherapy-naïve, advanced NSCLC patients were screened for exon 19, 20, and 21 mutations [52]. Overall, the incidence of mutated EGFR was 12.5%, with 25 exon 19 deletions, 11 L858R substitutions, and no exon 20 mutation. Among the 21 patients evaluable, response rate was 90%. In a similarly designed trial with gefitinib in a chemotherapy-naïve Japanese population, Inoue et al. [53] observed a 33% incidence of EGFR mutations in the 75 tumors screened. Sixteen EGFR-mutated patients received 250 mg/day of gefitinib, with an overall response rate of 75%. Although available data indicate that patients with EGFR mutations respond to TKIs, the impact on survival is unclear because of the possible prognostic rather than predictive value of such mutations (Table 3) and the possible different role of exon 19 rather than exon 21 mutation in TKI sensitivity.

	EGFR GENE COPY NUMBER

Top Learning Objectives Abstract Introduction EGFR Tyrosine Kinase Inhibitors EGFR Protein Expression EGFR Gene Mutations EGFR Gene Copy Number Other Biological Markers Conclusion Disclosure of Potential... References

 
Available data indicate that a significant fraction of patients with EGFR mutations (12%–84%) do not respond to TKIs [29, 30, 42]. Retrospective analyses of large phase III trials [29, 58] did not show any significant improvement in response rate for patients with EGFR mutations treated with a TKI. Moreover, in the BR21 study, response to TKI was not confined to patients with mutations, and some individuals with wild-type EGFR experienced dramatic response [29]. These findings suggest that other mechanisms are involved in TKI sensitivity, and recent findings indicate that increased copy number of the EGFR gene is relevant for TKI sensitivity. Several studies evaluated EGFR gene copy number by fluorescent in situ hybridization (FISH) [29, 30, 65, 66]. In the Cappuzzo et al. study [30], individuals with EGFR high polysomy or gene amplification (defined as EGFR FISH-positive) had a significantly higher response rate and a significantly longer time to progression and survival than did patients with no EGFR gene gain (defined as EGFR FISH-negative). Importantly, EGFR FISH-positive status was significantly associated with certain clinical and biological characteristics predictive for TKI sensitivity, such as female sex, never-smoking history, and the presence of EGFR mutations. Tsao et al. [29] successfully performed EGFR FISH analysis in 125 patients who participated in the BR21 trial. Increased gene copy number was detected in 45% of the patients and was not associated with the presence of EGFR mutations. This large study showed that EGFR FISH-positive patients treated with erlotinib had a higher response rate and longer survival than did EGFR FISH-positive patients treated with placebo (HR, 0.44; p = .008), whereas there was no advantage determined by the drug in EGFR FISH-negative patients. Hirsch et al. [65] performed EGFR FISH analysis in patients enrolled in the ISEL trial. This study confirmed the better outcome in terms of response rate and survival for EGFR FISH-positive patients treated with gefitinib than for EGFR FISH-positive patients treated with placebo, with no survival difference in EGFR FISH-negative patients irrespective of the treatment. In the Southwest Oncology Group S0126 trial, where patients with BAC were treated with 500 mg/day of gefitinib, Hirsch et al. [66] observed longer survival for EGFR FISH-positive patients over those who had no gene gain (HR, 2.02; p = .042).

Other methods have been used for EGFR gene copy number assessment. In the study performed by Miller et al. [27] in patients with bronchioloalveolar carcinoma, individuals with increased EGFR gene copy number detected by chromogenic in situ hybridization had a significantly better response rate (38% vs. 14%; p = .03) and time to progression (8.8 months vs. 2.3 months) and a trend toward longer survival than did EGFR-negative individuals.

EGFR gene copy number was evaluated by quantitative polymerase chain reaction (PCR) in 90 patients from the IDEAL trials and 453 tumors of the INTACT trials [58]. Amplification of the EGFR gene was detected in 8% and 7% of the cases, respectively, and was associated with female sex (p = .02). However, no association with adenocarcinoma histology or with never-smoking status was observed. In the IDEAL trials, patients with more than a four-fold amplification had a response rate to gefitinib not significantly higher than did those with no gene gain (29% vs. 15%; p = .39). When considering patients with EGFR gene amplification in the INTACT trials, no advantage in terms of response to chemotherapy plus gefitinib was observed over those with no gene gain (56% vs. 53%). A trend toward improved time to progression (7.3 months vs. 4.6 months) and survival (>20 months vs. 10.2 months) irrespective of gefitinib addition was observed for patients with EGFR amplification, raising questions about a possible prognostic role for EGFR gene gain in chemotherapy-treated NSCLC patients.

In the study performed by Takano et al. [44], EGFR gene copy number was assessed by quantitative real-time PCR in 66 gefitinib-treated Asian patients. EGFR gene gain (3.0 genes per cell) was found in 29 patients (44%), and it was associated with the presence of EGFR-sensitizing mutations (p = .014). In particular, high EGFR gene copy number (6.0 genes per cell) was observed only in patients with a high proportion (60%) of mutant alleles. In this study, increased EGFR gene copy number was significantly associated with a higher response rate and longer time to progression.

In a recently published trial, Dziadziuszko et al. [67] evaluated EGFR mRNA expression and EGFR gene dosage by quantitative PCR in a cohort of NSCLC patients who received gefitinib for advanced disease. Responding patients had a significantly higher median relative EGFR mRNA expression compared with nonresponders (p = .012), whereas no difference in terms of gene dosage was observed. Moreover, patients with high EGFR mRNA expression, but not those with high gene dosage, had significantly longer progression-free survival compared with individuals with low EGFR mRNA expression (p = .028), with no advantage in survival. Of note, EGFR mRNA expression but not EGFR gene dosage significantly correlated with FISH status, suggesting that EGFR mRNA expression might be interchangeably used with FISH to select patients who might benefit from treatment with TKIs.

In summary, although prospective studies are needed, available data suggest that EGFR FISH analysis is an accurate predictor for gefitinib sensitivity and that this method should be used for selection of patients candidate for TKI therapy. Moreover, FISH technology is well established and has a short turnaround in clinical cytogenetics and molecular pathology laboratories, and an EGFR FISH probe is already commercially available. Other methods for EGFR gene copy number assessment produced conflicting results and are not recommended outside clinical trials.

	OTHER BIOLOGICAL MARKERS

Top Learning Objectives Abstract Introduction EGFR Tyrosine Kinase Inhibitors EGFR Protein Expression EGFR Gene Mutations EGFR Gene Copy Number Other Biological Markers Conclusion Disclosure of Potential... References

 
HER2
Several biological markers that play a key role in the EGFR downstream pathway have been investigated in the last few years as potential predictors for TKI sensitivity. HER2 is the major partner of EGFR because activated heterodimers containing HER2 are more stable than complexes containing other members of the EGFR family [68]. Overexpression of HER2 in various cancer cell lines or xenografts increases antitumor effects of gefitinib [69–72]. Recently, Hirata et al. [73] demonstrated that the effects of gefitinib are independent of EGFR levels but are influenced by HER2 expression in one NSCLC cell line transfected with the HER2 gene. As for EGFR, the method for HER2 assessment is of great relevance. In a small study, the HER2 protein was evaluated by IHC in 43 NSCLC patients treated with gefitinib [26]. This study did not demonstrate any association of HER2 protein expression and gefitinib sensitivity in terms of response rate, time to progression, and survival. Nevertheless, only eight patients showed strong HER2 positivity (3+), and FISH analysis was performed in a limited number of cases. To further investigate the role of HER2 in patients exposed to TKIs, we evaluated HER2 gene copy number by FISH in 101 NSCLC patients treated with gefitinib [74]. Using the same score system adopted for EGFR [30], and considering HER2 FISH-positive patients with gene amplification as well as patients with high polysomy, we observed that HER2 FISH-positive individuals had significantly higher response rate (34.8% vs. 6.4%; p = .001) and time to progression (9.1 months vs. 2.7 months; p = .02), with a trend toward longer survival (20.8 months vs. 8.4 months; p = .056), compared with HER2 FISH-negative individuals. Interestingly, HER2 FISH-positive patients were frequently EGFR FISH-positive and EGFR mutation-positive, a phenomenon not previously reported and probably relevant for tumor cell survival. Independent of the method for EGFR assessment, EGFR-positive patients who also had increased HER2 gene copy number had a better outcome in terms of response and survival, suggesting that HER2 gene gain increases sensitivity to gefitinib only in presence of EGFR. In fact, EGFR-negative patients with HER2 FISH-positive status had the same outcome as did patients negative for both markers.

Mutation of the HER2 gene was reported in lung adenocarcinoma, offering the potential for additional therapy targeted at the altered protein [75]. HER2 mutations, which mainly consist of exon 20 insertions/duplications, target the same corresponding region as do EGFR mutations [75, 76]. These mutations were more frequently observed in never-smokers and in adenocarcinomas [75, 76], and recent findings indicated that NSCLC presenting these mutations remains sensitive to HER2-targeted therapies but insensitive to EGFR TKIs [77, 78]. Han et al. [79] observed no response to gefitinib in four NSCLC patients harboring an HER2 mutation, suggesting that detection of such mutation could help in patient selection.

Overall, available data suggest that HER2 gene assessment might be a complementary tool to EGFR assay in selecting patients who are candidates for TKI treatment, providing the rationale for exploring anti-HER2 strategies, alone or in combination with EGFR inhibitors, in selected NSCLC populations.

K-Ras
K-ras is a critical downstream effector of the EGFR pathway that has been found to be mutated in about 15%–30% of lung adenocarcinomas [80, 81]. Activating mutations of k-ras usually occur in codons 12 and 13 in exon 2 [82, 83] and have been reported to be associated with unfavorable outcome [84–87]. Mutations in k-ras are commonly associated with history of tobacco smoke exposure and are hardly found in never-smokers [75, 84]. Several studies showed that EGFR-sensitizing mutations and k-ras mutations are mutually exclusive [39, 59, 61, 63, 81, 88–91]. NSCLC patients harboring k-ras mutations are insensitive to TKI therapy [90]. Pao et al. [90] investigated the possible role of k-ras mutations in 60 patients with lung adenocarcinomas who have shown to be sensitive or refractory to either gefitinib or erlotinib; k-ras mutations were identified in 9 (24%) of 38 patients refractory to either drug, whereas no mutations were found in the 21 sensitive patients (p = .02). Conversely, 17 (77%) of 22 responding patients carried EGFR mutations, whereas none were found in the 38 refractory tumors. All 17 tumors harboring EGFR mutations responded to TKIs, whereas none of the nine tumors with k-ras mutations showed drug sensitivity. In the BR21 study, patients with k-ras mutation had lower response rate and significantly shorter survival (HR, 1.63; p = .03) compared with those with wild-type k-ras [92]. Those data indicated that k-ras mutations are associated with intrinsic TKI resistance, and k-ras gene sequencing could be useful for selecting candidates for TKI therapy. This concept is reinforced by the provocative results of the TRIBUTE trial. In that study, patients with k-ras mutations had significantly shorter survival when treated with chemotherapy plus erlotinib, suggesting a possible detrimental effect of TKIs in patients harboring such mutations [59]. As for the previously presented biomarkers, prospective studies for k-ras are warranted to better define the relevance of such mutations for patient selection.

	CONCLUSION

Top Learning Objectives Abstract Introduction EGFR Tyrosine Kinase Inhibitors EGFR Protein Expression EGFR Gene Mutations EGFR Gene Copy Number Other Biological Markers Conclusion Disclosure of Potential... References

 
Novel targeted therapies directed against the EGFR signaling pathway offer new hope to cancer patients. EGFR TKIs have emerged as particularly effective drugs in subsets of NSCLCs, with never-smoking history, EGFR mutations, and increased EGFR gene copy number as the major predictors for sensitivity to these agents. However, most available data derive from retrospective analyses; thus, prospective validation is needed. Several prospective phase II and III trials are currently ongoing and will allow us to define the optimal paradigm for patient selection.

	DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

Top Learning Objectives Abstract Introduction EGFR Tyrosine Kinase Inhibitors EGFR Protein Expression EGFR Gene Mutations EGFR Gene Copy Number Other Biological Markers Conclusion Disclosure of Potential... References

 
The authors indicate no potential conflicts of interest.

	REFERENCES

Top Learning Objectives Abstract Introduction EGFR Tyrosine Kinase Inhibitors EGFR Protein Expression EGFR Gene Mutations EGFR Gene Copy Number Other Biological Markers Conclusion Disclosure of Potential... References

 

1. Salomon DS, Brandt R, Ciardiello F et al. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995;19:183–232.[Medline]
2. Arteaga C. Overview of epidermal growth factor receptor biology and its role as a therapeutic target in human neoplasia. Semin Oncol 2002;29:3–9.[Medline]
3. Woodburn JR. The epidermal growth factor receptor and its inhibition in cancer therapy. Pharmacol Ther 1999;82:241–250.[CrossRef][Medline]
4. Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene 2000;19:6550–6565.[CrossRef][Medline]
5. Bunn PA Jr, Franklin W. Epidermal growth factor receptor expression, signal pathway, and inhibitors in non-small cell lung cancer. Semin Oncol 2002;29(suppl 14):38–44.[Medline]
6. Natale RB. Biologically targeted treatment of non-small-cell lung cancer: Focus on epidermal growth factor receptor. Clin Lung Cancer 2003;5(suppl 1):S11–S17.
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 2002;20:3815–3825.[Abstract/Free Full Text]
8. Ranson M, Hammond LA, Ferry D et al. ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: Results of a phase I trial. J Clin Oncol 2002;20:2240–2250.[Abstract/Free Full Text]
9. Nakagawa K, Tamura T, Negoro S et al. Phase I pharmacokinetic trial of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor gefitinib (‘Iressa’ ZD1839) in Japanese patients with solid malignant tumors. Ann Oncol 2003;14:922–930.[Abstract/Free Full Text]
10. Baselga J, Rischin D, Ranson M et al. Phase I safety, pharmacokinetics, and pharmacodynamic trial of ZD 1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol 2002;20:4292–4302.[Abstract/Free Full Text]
11. Goss G, Hirte H, Miller WH Jr et al. A phase I study of oral ZD1839 given daily in solid tumors: IND.122, a study of the Investigational New Drug Program of the National Cancer Institute of Canada Clinical Trials Group. Invest New Drugs 2005;23:147–155.[CrossRef][Medline]
12. Knight LA, Di Nicolantonio F, Whitehouse P et al. The in vitro effect of gefitinib (Iressa) alone and in combination with cytotoxic chemotherapy on human solid tumours. BMC Cancer 2004;4:1–8.[CrossRef][Medline]
13. Hidalgo M, Siu LL, Nemunaitis J et al. Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 2001;19:3267–3279.[Abstract/Free Full Text]
14. Giaccone G. Her1/EGFR-targeted agents: Predicting the future for patients with unpredictable outcomes to therapy. Ann Oncol 2005;16:538–548.[Abstract/Free Full Text]
15. Fukuoka M, Yano S, Giaccone G et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) [published correction appears in J Clin Oncol 22:4811]. J Clin Oncol 2003;21:2237–2246.[Abstract/Free Full Text]
16. 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 2003; 290:2149–2158.[Abstract/Free Full Text]
17. Perez-Soler R, Chachoua A, Huberman M et al. Final results of a phase II study of erlotinib (Tarceva) monotherapy in patients with advanced non-small cell lung cancer following failure of platinum based chemotherapy. Lung Cancer 2003;41(suppl 2):S246.
18. Giaccone G, Herbst RS, Manegold C et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: A phase III trial—INTACT 1. J Clin Oncol 2004;22:777–784.[Abstract/Free Full Text]
19. Herbst RS, Giaccone G, Schiller JH et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: A phase III trial—INTACT 2. J Clin Oncol 2004;22:785–794.[Abstract/Free Full Text]
20. Gatzemeier U, Pluzanska A, Szczesna A et al. Results of a phase III trial of erlotinib (OSI-774) combined with cisplatin and gemcitabine (GC) chemotherapy in advanced non-small cell lung cancer (NSCLC). J Clin Oncol 2004;22(suppl):617s:7010a.
21. Herbst RS, Prager D, Hermann R et al. TRIBUTE—A phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2005; 23:5892–5899.[Abstract/Free Full Text]
22. Thatcher N, Chang A, Parikh P et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: Results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet 2005;366:1527–1537.[CrossRef][Medline]
23. Shepherd FA, Pereira J, Ciuleanu TE et al. Erlotinib in previously treated non-small cell lung cancer. N Engl J Med 2005;353:123–132.[Abstract/Free Full Text]
24. Lee DH, Han JY, Lee HG et al. Gefitinib as a first-line therapy of advanced or metastatic adenocarcinoma of the lung in never-smokers. Clin Cancer Res 2005;11:3032–3037.[Abstract/Free Full Text]
25. Bailey LR, Kris M, Wolf M et al. Tumor EGFR membrane staining is not clinically relevant for predicting response in patients receiving gefitinib (‘Iressa’, ZD1839) monotherapy for pretreated advanced non-small-cell lung cancer: IDEAL 1 and 2. Proc Am Assoc Cancer Res 2003;44:1362 LB-170a.
26. Cappuzzo F, Gregorc V, Rossi E et al. Gefitinib in pretreated non-small-cell lung cancer (NSCLC): Analysis of efficacy and correlation with HER2 and epidermal growth factor receptor expression in locally advanced or meta-static NSCLC. J Clin Oncol 2003;21:2658–2663.[Abstract/Free Full Text]
27. 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: Results of a prospective phase II trial. Proc Am Soc Clin Oncol 2006;24:324s:7003a.
28. Villaflor VM, Buckingham L, Gale M et al. EGFR mutations (muts), IHC and FISH status, and chromosome 7 gene copy number combined with pAkt expression as potential predictors of survival in non-small cell lung cancer (NSCLC) patients (pts) treated with gefitinib (GEF). J Clin Oncol 2006;24(suppl):18s:7182a.
29. Tsao MS, Sakurada A, Cutz JC et al. Erlotinib in lung cancer—molecular and clinical predictors of outcome. N Engl J Med 2005;353:133–144.[Abstract/Free Full Text]
30. 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 2005;97:643–655.[Abstract/Free Full Text]
31. 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 2004;350:2129–2139.[Abstract/Free Full Text]
32. Paez JG, Janne PA, Lee JC et al. EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 2004;304:1497–1500.[Abstract/Free Full Text]
33. Pao W, Miller V, Zakowski M et al. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 2004; 101:13306–13311.[Abstract/Free Full Text]
34. Pham D, Kris MG, Riely GJ et al. Use of cigarette-smoking history to estimate the likelihood of mutations in epidermal growth factor receptor gene exons 19 and 21 in lung adenocarcinomas. J Clin Oncol 2006;24:1700–1704.[Abstract/Free Full Text]
35. Marchetti A, Felicioni L, Buttitta F. Assessing EGFR mutations. N Engl J Med 2006;354:526–528.[Free Full Text]
36. Pao W, Miller VA, Politi KA et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005;2:1–11.
37. Kobayashi S, Boggon TJ, Dayaram T et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005;352:786–792.[Abstract/Free Full Text]
38. Greulich H, Chen TH, Feng W et al. Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants. PLoS Med 2005;2:e313.[CrossRef][Medline]
39. Kosaka T, Yatabe Y, Endoh H et al. Mutations of the epidermal growth factor receptor gene in lung cancer: Biological and clinical implications. Cancer Res 2004;64:8919–8923.[Abstract/Free Full Text]
40. Bell DW, Gore I, Okimoto RA et al. Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR. Nat Genet 2005;37:1315–1316.[CrossRef][Medline]
41. Shigematsu H, Gazdar AF. Somatic mutations of epidermal growth factor receptor signaling pathway in lung cancers. Int J Cancer 2006;15:118:257–262.
42. Han SW, Kim TY, Hwang PG et al. Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol 2005;23:2493–2501.[Abstract/Free Full Text]
43. Kim KS, Jeong JY, Kim YC et al. Predictors of the response to gefitinib in refractory non-small cell lung cancer. Clin Cancer Res 2005;11:2244–2251.[Abstract/Free Full Text]
44. Takano T, Ohe Y, Sakamoto H et al. Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer. J Clin Oncol 2005;23: 6829–6837.[Abstract/Free Full Text]
45. Cortes-Funes H, Gomez C, Rosell R et al. Epidermal growth factor receptor activating mutations in Spanish gefitinib-treated non-small cell lung cancer patients. Ann Oncol 2005;16:1081–1086.[Abstract/Free Full Text]
46. Villaflor VM, Buckingham L, Gale M et al. EGFR mutations and pAKT expression as potential predictors of gefitinib efficacy in non-small cell lung cancer (NSCLC) patients (pts). J Clin Oncol 2005;23(suppl):639s: 7077a.
47. Chou TY, Chiu CH, Li LH et al. Mutation in the tyrosine kinase domain of epidermal growth factor receptor is a predictive and prognostic factor for gefitinib treatment in patients with non-small cell lung cancer. Clin Cancer Res 2005;11:3750–3757.[Abstract/Free Full Text]
48. Taron M, Ichinose Y, Rosell R et al. Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor are associated with improved survival in gefitinib-treated chemorefractory lung adenocarcinomas. Clin Cancer Res 2005;11:5878–5885.[Abstract/Free Full Text]
49. Mu XL, Li LY, Zhang XT et al. Gefitinib-sensitive mutations of the epidermal growth factor receptor tyrosine kinase domain in Chinese patients with non-small cell lung cancer. Clin Cancer Res 2005;11:4289–4294.[Abstract/Free Full Text]
50. Zhang XT, Li LY, Mu XL et al. The EGFR mutation and its correlation with response of gefitinib in previously treated Chinese patients with advanced non-small-cell lung cancer. Ann Oncol 2005;16:1334–1342.[Abstract/Free Full Text]
51. Mitsudomi T, Kosaka T, Endoh H et al. Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in-patients with non-small-cell lung cancer with postoperative recurrence. J Clin Oncol 2005;23:2513–2520.[Abstract/Free Full Text]
52. Paz-Ares L, Sanchez JM, García-Velasco A et al. A prospective phase II trial of erlotinib in advanced non-small cell lung cancer (NSCLC) patients (p) with mutations in the tyrosine kinase (TK) domain of the epidermal growth factor receptor (EGFR). J Clin Oncol 2006;24(suppl):18s:7020a.
53. Inoue A, Suzuki T, Fukuhara T et al. Prospective phase II study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations. J Clin Oncol 2006; 24:3340–3346.[Abstract/Free Full Text]
54. Okamoto I, Kashii T, Urata Y et al. EGFR mutation-based phase II multi-center trial of gefitinib in advanced non-small cell lung cancer (NSCLC) patients (pts): Results of West Japan Thoracic Oncology Group trial (WJ-TOG0403). J Clin Oncol 2006;24(suppl):382s:7073.
55. Sutani A, Nagai Y, Udagawa K et al. Phase II study of gefitinib for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) gene mutations detected by PNA-LNA PCR clamp. J Clin Oncol 2006;24(suppl):383s:7076a.
56. Sunaga N, Yanagitani N, Kaira K et al. Phase II study of the efficacy of gefitinib in patients with non-small cell lung cancer with the EGFR mutations. J Clin Oncol 2006;24(suppl):18s:7183a.
57. Asahina H, Yamazaki K, Kinoshita I et al. Phase II study of gefitinib as a first-line therapy for advanced non-small cell lung cancers with epidermal growth factor receptor (EGFR) gene mutations. J Clin Oncol 2006; 24(suppl):18s:13014a.
58. Bell DW, Lynch TJ, Haserlat SM et al. Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: Molecular analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol 2005;23: 8081–8092.[Abstract/Free Full Text]
59. 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 2005;23:5900–5909.[Abstract/Free Full Text]
60. Gatzemeier U, Heller A, Foernzler D et al. Exploratory analyses EGFR, kRAS mutations and other molecular markers in tumors of NSCLC patients (pts) treated with chemotherapy +/– erlotinib (TALENT) J Clin Oncol 2005;23(suppl):16s:7028a.
61. Shigematsu H, Lin L, Takahashi T et al. Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 2005;97:339–346.[Abstract/Free Full Text]
62. Riely GJ, Pao W, Pham D et al. Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. Clin Cancer Res 2006;12:839–844.[Abstract/Free Full Text]
63. Jackman DM, Yeap BY, Sequist LV et al. Exon 19 deletion mutations of epidermal growth factor receptor are associated with prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib. Clin Cancer Res 2006;12:3908–3914.[Abstract/Free Full Text]
64. Hirsch FR, Franklin WA, McCoy J et al. Predicting clinical benefit from EGFR TKIs: Not all EGFR mutations are equal. J Clin Oncol 2006; 24(suppl):18s:7072a.
65. Hirsch FR, Varella-Garcia M, Bunn PA et al. Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small cell lung cancer. J Clin Oncol 2006;24:5034–5042.[Abstract/Free Full Text]
66. Hirsch FR, Varella-Garcia M, McCoy J et al. Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: A Southwest Oncology Group Study. J Clin Oncol 2005;23:6838–6845.[Abstract/Free Full Text]
67. Dziadziuszko R, Witta SE, Cappuzzo F et al. Epidermal growth factor receptor messenger RNA expression, gene dosage, and gefitinib sensitivity in non-small cell lung cancer. Clin Cancer Res 2006;12:3078–3084.[Abstract/Free Full Text]
68. Lenferink AE, Pinkas-Kramarski R, van de Poll ML et al. Differential endocytic routing of homo- and hetero-dimeric ErbB tyrosine kinases confers signaling superiority to receptor heterodimers. EMBO J 1998;17:3385–3397.[CrossRef][Medline]
69. Moasser MM, Basso A, Averbuch SD et al. The tyrosine kinase inhibitor ZD1839 ("Iressa") inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells. Cancer Res 2001;61:7184–7188.[Abstract/Free Full Text]
70. Moulder SL, Yakes FM, Muthuswamy SK et al. Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/ neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo. Cancer Res 2001;61:8887–8895.[Abstract/Free Full Text]
71. Normanno N, Campiglio M, De LA et al. Cooperative inhibitory effect of ZD1839 (Iressa) in combination with trastuzumab (Herceptin) on human breast cancer cell growth. Ann Oncol 2002;13:65–72.[Abstract/Free Full Text]
72. Anido J, Matar P, Albanell J et al. ZD1839, a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, induces the formation of inactive EGFR/HER2 and EGFR/HER3 heterodimers and prevents heregulin signaling in HER2-overexpressing breast cancer cells. Clin Cancer Res 2003;9:1274–1283.[Abstract/Free Full Text]
73. Hirata A, Hosoi F, Miyagawa M et al. HER2 overexpression increases sensitivity to gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, through inhibition of HER2/HER3 heterodimer formation in lung cancer cells. Cancer Res 2005;65:4253–4260.[Abstract/Free Full Text]
74. Cappuzzo F, Varella-Garcia M, Shigematsu H et al. Increased HER2 gene copy number is associated with response to gefitinib therapy in epidermal growth factor receptor-positive non-small-cell lung cancer patients. J Clin Oncol 2005;23:5007–5018.[Abstract/Free Full Text]
75. Shigematsu H, Takahashi T, Nomura M et al. Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res 2005;65:1642–1646.[Abstract/Free Full Text]
76. Stephens P, Hunter C, Bignell G et al. Lung cancer: Intragenic ERBB2 kinase mutations in tumours. Nature 2004;431:525–526.[Medline]
77. Cappuzzo F, Bemis L, Varella-Garcia M. HER2 mutation and response to trastuzumab therapy in non-small-cell lung cancer. N Engl J Med 2006; 354:2619–2621.[Free Full Text]
78. Wang SE, Narasanna A, Perez-Torres M et al. HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors. Cancer Cell 2006; 10:25–38.[CrossRef][Medline]
79. Han SW, Kim TY, Jeon YK et al. Optimization of patient selection for gefitinib in non-small cell lung cancer by combined analysis of epidermal growth factor receptor mutation, K-ras mutation, and Akt phosphorylation. Clin Cancer Res 2006;15:12:2538–2544.
80. Ahrendt SA, Decker PA, Alawi EA et al. Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung. Cancer 2001;92:1525–1530.[CrossRef][Medline]
81. Marchetti A, Martella C, Felicioni L et al. EGFR mutations in non-small-cell lung cancer: Analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment. J Clin Oncol 2005;23:857–865.[Abstract/Free Full Text]
82. Rodenhuis S, Slebos RJ, Boot AJ et al. Incidence and possible clinical significance of K-ras oncogene activation in adenocarcinoma of the human lung. Cancer Res 1988;48:5738–5741.[Abstract/Free Full Text]
83. Suzuki Y, Orita M, Shiraishi M et al. Detection of ras gene mutations in human lung cancers by single-strand conformation polymorphism analysis of polymerase chain reaction products. Oncogene 1990;5:1037–1043.[Medline]
84. Nelson HH, Christiani DC, Mark EJ et al. Implications and prognostic value of K-ras mutation for early-stage lung cancer in women. J Natl Cancer Inst 1999;91:2032–2038.[Abstract/Free Full Text]
85. Broermann P, Junker K, Brandt BH et al. Trimodality treatment in Stage III nonsmall cell lung carcinoma: Prognostic impact of K-ras mutations after neoadjuvant therapy. Cancer 2002;94:2055–2062.[CrossRef][Medline]
86. Grossi F, Loprevite M, Chiaramondia M et al. Prognostic significance of K-ras, p53, bcl-2, PCNA, CD34 in radically resected non-small cell lung cancers. Eur J Cancer 2003;39:1242–1250.[CrossRef][Medline]
87. Huncharek M, Muscat J, Geschwind JF. K-ras oncogene mutation as a prognostic marker in non-small cell lung cancer: A combined analysis of 881 cases. Carcinogenesis 1999;20:1507–1510.[Abstract/Free Full Text]
88. Yokoyama T, Kondo M, Goto Y et al. EGFR point mutation in non-small cell lung cancer is occasionally accompanied by a second mutation or amplification. Cancer Sci 2006;97:753–759.[CrossRef][Medline]
89. Suzuki M, Shigematsu H, Iizasa T et al. Exclusive mutation in epidermal growth factor receptor gene, HER-2, and KRAS, and synchronous methylation of nonsmall cell lung cancer. Cancer 2006;106:2200–2207.[CrossRef][Medline]
90. Pao W, Wang TY, Riely GJ et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2005;2:e17.[CrossRef][Medline]
91. Conde E, Angulo B, Tang M et al. Molecular context of the EGFR mutations: Evidence for the activation of mTOR/S6K signaling. Clin Cancer Res 2006;12:710–717.[Abstract/Free Full Text]
92. Tsao M, Zhu C, Sakurada A et al. An analysis of the prognostic and predictive importance of K-ras mutation status in the National Cancer Institute of Canada Clinical Trials Group BR.21 study of erlotinib versus placebo in the treatment of non-small cell lung cancer. J Clin Oncol. 2006;24(suppl): 18s:7005a.

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