Clinical Cancer Research AACR Conference on Cancer Prevention Infection and Cancer: Biology, Therapeutics, and Prevention
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bunn, P. A.
Right arrow Articles by Hirsch, F. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bunn, P. A., Jr.
Right arrow Articles by Hirsch, F. R.
Clinical Cancer Research Vol. 12, 3652-3656, June 15, 2006
© 2006 American Association for Cancer Research

CCR Practice of Translational Oncology

Biological Markers for Non–Small Cell Lung Cancer Patient Selection for Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy

Paul A. Bunn, Jr.1, Rafal Dziadziuszko1,3, Marileila Varella-Garcia1, Wilbur A. Franklin2, Samir E. Witta1, Karen Kelly1 and Fred R. Hirsch1,2

Authors' Affiliations: Departments of 1 Medicine and 2 Pathology, University of Colorado Cancer Center and University of Colorado Health Sciences Center, Aurora, Colorado; and 3 Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland

Requests for reprints: Paul A. Bunn, Jr., University of Colorado Cancer Center, Mail Stop 8111, P.O. Box 6511, Aurora, CO 80045. Phone: 303-315-3007; Fax: 303-315-3304; E-mail: paul.bunn{at}uchsc.edu.

The selection of patients for tumor-specific therapies using molecular/biological properties of the patient's tumor has been a long tradition in breast cancer (e.g., estrogen receptor, progesterone receptor, and HER-2/neu) but has not been widely accepted in lung cancer therapy selection (1, 2). The epidermal growth factor receptor (EGFR) is an excellent target for lung cancer therapy, and it should be possible to select patients based on their expression of the EGFR gene, EGFR protein, or related genes and proteins (3). This article summarizes the results of studies using clinical or biological features to predict benefit from EGFR tyrosine kinase inhibitors (TKI).

Clinical features. Many studies have documented a relationship between female gender, adenocarcinoma histology, Asian ethnicity, and never smoking status with higher response rates to EGFR TKIs (4–9). About survival, subset analyses of randomized trials comparing EGFR TKIs to placebo showed some survival advantage in all clinical subsets, including smokers, nonadenocarcinoma histology, males, and non-Asians (10, 11). Some prospective studies that select patients based on clinical features have been conducted, but the results are not yet available. These features are thus not yet ready for routine use in patient selection.

Molecular features: EGFR mutations. The exciting discovery that certain mutations in the tyrosine-binding domain of the EGFR receptor were associated with objective response to EGFR TKIs brought renewed interest in molecular selection of patients (12, 13). Subsequent studies showed that EGFR mutations were significantly associated with never smoking status, Asian ethnicity, adenocarcinoma histology, and female gender (14–18). Because of the association with favorable prognostic features, it was not surprising that EGFR mutations were shown to be associated with a good prognosis irrespective of the type of therapy. For example, a randomized trial comparing chemotherapy alone to chemotherapy with erlotinib, EGFR-mutated patients had a superior outcome regardless of the therapy (19). Similarly, in the randomized BR21 trial comparing erlotinib to placebo, EGFR-mutated patients had superior survival even when treated with placebo (hazard ratio (HR) = 0.7; 20). This prognostic feature of EGFR mutations makes it difficult to assess the meaning of improved survival after TKI therapy in phase II trials (21–24). Some large phase II trials in Caucasian patients failed to show a significant association between EGFR mutations and survival (25, 26). Figure 1 illustrates the importance of distinguishing between a biomarker of prognosis versus a predictor of therapeutic benefit. In this example, a favorable prognostic biomarker will also associate with a favorable outcome with chemotherapy treatment, placebo-treated or EGFR-specific therapy. The hazard rate advantage in randomized trials will show no difference in benefit between EGFR-specific therapy and placebo as observed in a large randomized trial comparing erlotinib to placebo (BR21; refs. 10, 20).


Figure 1
View larger version (65K):
[in this window]
[in a new window]
  		Fig. 1. Typical figures from a test that showed a prognostic but not a predictive survival effect. A, hypothetical survival results from a test showing a favorable prognosis. Patients with early-stage lung cancer and with a positive EGFR test have a superior survival compared with patients with a negative test. B, hypothetical survival results from an EGFR test showing a favorable prognosis in stage IV NSCLC treated with systemic chemotherapy. C, hypothetical survival results from an EGFR test showing a favorable prognosis in stage IV NSCLC patients treated with placebo in a randomized trial comparing the EGFR TKI to placebo. D, hypothetical survival results from an EGFR test showing a favorable prognosis in stage IV NSCLC patients treated with the EGFR TKI in a randomized trial comparing the EGFR TKI to placebo. These survival curves are similar to those results reported for EGFR mutations in two large randomized trials (24, 25).

 
The predictive value of EGFR mutations could depend on the type of EGFR mutation and/or the genetic background of patients. For example, both Colorado and Memorial Sloan-Kettering Cancer Center groups found that patients with deletions in exon 19 had a favorable outcome after gefitinib therapy, whereas those with exon 21 point mutations had no favorable benefit (27).4 Larger and prospective studies will be necessary to validate whether some mutations are better able to predict survival benefit from EGFR TKIs and whether predictive biomarkers will differ by ethnic background.

What then is the clinical value of obtaining EGFR mutations? In Caucasian patients, a small minority will harbor such mutations. Many patients without these mutations will benefit from EGFR TKI therapy. Thus, the clinical value of the test is limited at present, and prospective trials are needed.

EGFR gene copy number: fluorescence in situ hybridization testing. High EGFR copy numbers determined by fluorescence in situ hybridization (FISH) were associated with a slightly worse prognosis (28) or no difference in survival compared with those with lower gene copy numbers (29). In these studies, FISH positivity was defined as true gene amplification or high polysomy with more than four EGFR gene copies in >40% of cells (25, 26, 30). The randomized BR21 and in situ end-labeling studies also showed that FISH-positive patients randomized to placebo had a slightly inferior survival compared with FISH-negative patients randomized to placebo (20, 30). A single study evaluating the prognostic implications of FISH positivity in non–small cell lung cancer (NSCLC) patients treated with chemotherapy found no significant survival differences based on FISH results (29). Thus, as shown in Fig. 2 , the lack of a prognostic effect is unlikely to confound the potential predictive value of the FISH test.


Figure 2
View larger version (65K):
[in this window]
[in a new window]
  		Fig. 2. Typical figures from a test that showed a predictive but not a prognostic survival effect. A, hypothetical survival results from an EGFR test showing no significant effect on survival in early-stage NSCLC patients after surgery. B, hypothetical survival results from an EGFR test showing no significant relationship between the test result and survival in stage IV NSCLC patients treated with chemotherapy. C, hypothetical survival results from an EGFR test showing no relationship between the test result and survival in stage IV NSCLC patients treated with placebo in a randomized trial comparing an EGFR TKI with placebo. D, hypothetical survival results from an EGFR test showing a significant association between positive test results and an improved survival in stage IV NSCLC patients treated with an EGFR TKI in a randomized trial comparing the EGFR TKI to placebo. These survival curves are similar to results published for high EGFR copy number by FISH in large randomized and nonrandomized trials (20, 25, 26, 28).

 
Phase II studies of EGFR TKIs showed that FISH positivity was associated with higher response rates and longer time to progression and survival (25, 26). In the randomized BR21 trial, FISH-positive patients (~40%) randomized to erlotinib had a significantly superior survival compared with FISH-positive patients randomized to placebo (HR = 0.44; P = 0.01; ref. 20). In the FISH-negative patients, there were no significant differences in survival (HR = 0.93). In the Iressa Survival Evaluation in Lung Cancer (ISEL) study, FISH-positive patients (~30%) receiving gefitinib also had a superior survival compared with FISH-positive patients receiving placebo (HR = 0.61; P = 0.06; ref. 30). In FISH-negative patients, there was no survival benefit from gefitinib (HR = 1.16; P = 0.42). In this study, FISH-positive patients treated with gefitinib had a superior outcome irrespective of gender, histology, or smoking status. These data strongly suggest the predictive clinical value of FISH testing for EGFR similar to FISH testing for HER-2/neu in breast cancer patients as shown in Fig. 2. It is likely that high EGFR copy number by FISH may predict for benefit of EGFR inhibitors in other tumor types as well. For example, Moroni et al. recently reported a strong association between EGFR gene copy number by FISH and response of colorectal cancer patients to therapy with cetuximab and panitumumab (31).

EGFR gene copy number: FISH versus quantitative PCR. There are fewer studies evaluating EGFR gene copy number by quantitative PCR (qPCR) as a predictive biomarker. None of these reports are randomized trials (14, 24).5 Furthermore, Dziadziuszko et al. found no correlation between qPCR and FISH for gene copy number in 82 NSCLC samples,5 suggesting that results obtained by the different two methods cannot be considered comparable. This is born out in clinical studies, in which, in contrast to FISH, qPCR measurements of gene copy number are not associated with improved response rate, progression-free, or overall survival of gefitinib-treated patients. Bell et al. have reported that EGFR amplification detected by qPCR was present in 8% of patients in the IDEAL gefitinib trials and 7% of the INTACT gefitinib trials (14). In this study, there was no predictive value of gefitinib benefit in a subset of patients with EGFR amplification by qPCR. Takano et al. reported that amplified EGFR detected by qPCR correlated with the presence of EGFR mutations and predicted time to progression but not survival (24). Thus, no study has established a strong predictive correlation between EGFR gene copy number by qPCR and survival after EGFR TKI therapy.

EGFR protein expression. There are conflicting data about the prognostic importance of EGFR protein levels in NSCLC. A meta-analysis of these studies failed to show a significant correlation between EGFR levels and survival (32). Retrospective evaluations of the relationship between EGFR positivity by immunohistochemistry and response reported that EGFR immunohistochemistry results were not predictive of response in the original trials of gefitinib (33).

Hirsch et al. developed a different immunohistochemistry scoring system that considered both the staining intensity scored from 0 to 4 and the percentage of positive cells from 0% to 100% and used a different antibody (Zymed Laboratories, San Francisco, CA; refs. 25, 28). Thus, the score ranged from 0 to 400. Cappuzzo et al. (25) and Hirsch et al. (34) explored the predictive nature of the EGFR immunohistochemistry score on response and survival after gefitinib therapy using this system. Both studies found immunohistochemistry positivity in ~60% of patients, and both reported that immunohistochemistry-positive patients had significantly higher response and disease control rates and significantly longer time to progression and survival than patients with lower scores. In the randomized phase III BR21 trial comparing erlotinib to placebo, immunohistochemistry-positive patients (57% using DAKO antibody) treated with erlotinib had a significantly superior survival compared with placebo-treated patients (HR = 0.68; 95% confidence interval, 0.49-0.95; P = 0.02; ref. 20). In the ISEL randomized trial, gefitinib produced a reduction in the HR for survival in immunohistochemistry-positive patients (HR = 0.77), but this was not significant (P = 0.13) compared with placebo in immunohistochemistry-positive patients (30).

An important issue is whether the combined use of two tests would provide superior data compared with the use of a single test. Hirsch et al. combined the results from two cohorts and reported that smoking status, performance status, FISH results, and immunohistochemistry results provided independent prediction of survival in multivariate analysis. The combination of FISH and immunohistochemistry results allowed patients to be grouped into three groups: (a) FISH positive/immunohistochemistry positive (n = 42; 23%), (b) FISH positive/immunohistochemistry negative or FISH negative/immunohistochemistry positive (n = 84; 46%), and (c) FISH negative/immunohistochemistry negative (n = 55; 30%). The objective response rates in the three groups were 41%, 10%, and 2%, respectively. The median survival times were 21, 11, and 6 months in the three groups, respectively (34). Thus, double-negative patients had no clinical benefit, whereas double-positive patients had a significant survival benefit, and one test-positive patients had an intermediate benefit. The long survival in patients with both tests positive seems to be superior to the survival produced by triple agent chemotherapy with carboplatin/paclitaxel/bevacizumab (35). Prospective trials to confirm this observation are indicated. The survival of patients with a single positive test is similar to that achieved with triple agent chemotherapy, and prospective trials are also indicated. Double-negative patients need not be offered EGFR TKI therapy.

Other molecular markers: phosphorylated AKT and Kras. AKT is a protein downstream of EGFR in the signal transduction cascade, and baseline levels of activated AKT (phosphorylated AKT) might indicate an "addiction" to the EGFR pathway (3). Cappuzzo et al. reported that phosphorylated AKT levels assessed by immunohistochemistry were associated with response after gefitinib (36). Subsequent studies confirmed a significant association between phosphorylated AKT expression by immunohistochemistry and response to EGFR TKIs but failed to show an association between phosphorylated AKT expression and survival (25). The results from the randomized ISEL trial also failed to confirm an association between phosphorylated AKT expression and survival (30).

Kras mutations are known to occur in a minority of NSCLC patients, usually with adenocarcinoma histology. The vast majority of these mutations are also known to occur in smokers compared with never smokers. Many series have shown that EGFR and Kras mutations rarely occur in the same tumor. Patients with Kras mutations have lower response rates to EGFR TKI therapy compared with those without such mutations. The two trials that reported survival data showed no association between Kras mutations and survival in gefitinib-treated patients (19).4

Epithelial to mesenchymal transition markers. E-cadherin (an epithelial marker) and vimentin (a mesenchymal marker) were reported to be directly and inversely related to responsiveness to gefitinib, respectively (37–39). The expression of E-cadherin is transcriptionally repressed by transcription factors of the Slug/Snail family, such as Zeb1 (38). A negative correlation between response rates to EGFR TKIs and Zeb1 expression was also reported in NSCLC cell lines. An analysis of the randomized trial comparing chemotherapy to chemotherapy plus erlotinib suggested that patients with high E-cadherin levels benefited from the addition of erlotinib, whereas others did not (39). Additional clinical data are needed.

HER-2 and HER-3. HER-2 is a member of EGFR/HER family of receptors and an important partner for EGFR heterodimerization (3). Cappuzzo et al. reported that high HER-2 gene copy number, present in 22% of gefitinib-treated patients, was associated with significantly better response rate, time to progression, and a trend for improved survival (40). In this study, a correlation between increased HER-2 and EGFR copy number was shown. Patients with both abnormalities have the highest response rates and the longest survival.

HER-3, another member of the EGFR/HER family of receptors, was reported to be positively associated with response to EGFR TKI therapy in both patient samples and NSCLC cell lines (41, 42). In the study of Cappuzzo et al., gefitinib-treated patients with high HER-3 gene copy number had significantly higher response rate (36% versus 10%), time to progression (7.7 versus 2.7 months), but not overall survival (10 versus 11 months; ref. 41).

Primary resistance to EGFR TKIs. The expression of both E-cadherin and HER-3 is transcriptionally repressed by Zeb1, and a strong negative correlation between Zeb1 versus E-cadherin and HER-3 was reported in NSCLC cell lines (38). The Zeb1 family of transcription factors requires histone deacetylation for activation. Witta et al. showed that histone deacetylase inhibitors could decrease Zeb1 expression and increase E-cadherin expression and sensitivity to EGFR TKIs (38). Clinical trials testing the combinations of HDAC inhibitors and EGFR TKIs are planned.

Acquired resistance to EGFR TKIs. Acquired mutations in exon 20 of the EGFR gene would change conformation of the receptor and block binding of gefitinib and erlotinib to the active site creating resistance to these EGFR TKIs (43, 44). Irreversibly binding EGFR TKIs were shown to maintain activity in tumors with these exon 20 mutations and are being tested in clinical trials (45).


   Conclusions
Top
 Conclusions
References
 
The EGFR is an excellent target for novel therapeutics for lung cancer and other epithelial malignancies. The original trials in NSCLC did not select patients based on tumor expression of the EGFR gene or protein and evaluated combinations of chemotherapeutic agents combined with EGFR inhibitors without regard to EGFR expression or drug scheduling. These trials showed that erlotinib improved survival in the second or third line settings (HR = 0.73), whereas gefitinib failed to provide a significant survival advantage (HR = 0.89). Neither agent improved survival when combined with chemotherapy. A major issue is whether the outcome could be improved by selecting patients for EGFR gene or protein expression, especially in the first line and adjuvant settings. In phase II trials, EGFR mutations, EGFR gene copy number and EGFR protein levels were shown to correlate with response and survival following gefitinib or erlotinib in many but not all trials. The mutation analyses were complicated by the finding of improved survival of advanced NSCLC patients with EGFR mutation irrespective of therapy. In two large randomized trials comparing erlotinib and gefitinib to placebo, increased EGFR copy number by FISH was associated with significantly improved response, time to progression, and survival. EGFR mutations were associated with improved survival after both placebo or EGFR TKI therapy. Thus, retrospective studies provide compelling data that EGFR gene copy number by FISH is an excellent predictive biomarker for selection of NSCLC patients for EGFR TKI therapy. Now, prospective trials with FISH-selected patients in both advanced disease and adjuvant settings are needed. Prospective studies evaluating the anti-EGFR antibodies are also needed. EGFR mutations are clearly prognostic for favorable survival in advanced NSCLC patients irrespective of the type of therapy. Whether the presence of any mutation or specific mutations is predictive for survival benefit from EGFR TKIs requires further study. High EGFR protein expression by immunohistochemistry was positively associated with outcome in the two large randomized trials comparing EGFR TKIs to placebo. Prospective selection studies are also indicated.


   Footnotes
 
Grant support: National Cancer Institute grants CA046934 and CA058187. National Cancer Institute-International Union Against Cancer Translational Cancer Research Fellowship, funded by National Cancer Institute (R. Dziadziuszko).

4 Hirsch FR, Varella-Garcia M, Cappuzzo F, et al. Increased EGFR gene copy number by FISH and EGFR protein expression by immunohistochemistry can be used to select advanced non–small cell lung cancer patients to EGFR TKI therapy, submitted for publication. Back

5 Dziadziuszko R, Witta SE, Cappuzzo F, et al. EGFR mRNA expression, gene dosage, and gefitinib sensitivity in non–small cell lung cancer. Clin Cancer Res accepted for publication. Back

Received 2/ 6/06; revised 4/26/06; accepted 4/28/06.


   References
Top
 Conclusions
 References
 

  1. Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004;350:1081–92.[Abstract/Free Full Text]
  2. Hortobagyi GN. Trastuzumab in the treatment of breast cancer. N Engl J Med 2005;353:1734–6.[Free Full Text]
  3. Baselga J, Arteaga CL. Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol 2005;23:2445–59.[Abstract/Free Full Text]
  4. Perez-Soler R. Phase II clinical trial data with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib (OSI-774) in non-small-cell lung cancer. Clin Lung Cancer 2004;6 Suppl 1:S20–3.
  5. 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). J Clin Oncol 2003;21:2237–46.[Abstract/Free Full Text]
  6. 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;290:2149–58.[Abstract/Free Full Text]
  7. Ho C, Murray N, Laskin J, et al. Asian ethnicity and adenocarcinoma histology continues to predict response to gefitinib in patients treated for advanced non-small cell carcinoma of the lung in North America. Lung Cancer 2005;49:225–31.[CrossRef][Medline]
  8. Miller VA, Kris MG, Shah N, et al. Bronchioloalveolar pathologic subtype and smoking history predict sensitivity to gefitinib in advanced non-small-cell lung cancer. J Clin Oncol 2004;22:1103–9.[Abstract/Free Full Text]
  9. Batevik R, Grong K, Segadal L, Stangeland L. The female gender has a positive effect on survival independent of background life expectancy following surgical resection of primary non-small cell lung cancer: a study of absolute and relative survival over 15 years. Lung Cancer 2005;47:173–81.[CrossRef][Medline]
  10. Shepherd FA, Rodrigues PJ, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123–32.[Abstract/Free Full Text]
  11. 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;366:1527–37.[CrossRef][Medline]
  12. 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;350:2129–39.[Abstract/Free Full Text]
  13. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497–500.[Abstract/Free Full Text]
  14. 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;23:8081–92.[Abstract/Free Full Text]
  15. 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;101:13306–11.[Abstract/Free Full Text]
  16. 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;97:339–46.[Abstract/Free Full Text]
  17. 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;11:5878–85.[Abstract/Free Full Text]
  18. Tokumo M, Toyooka S, Kiura K, et al. The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers. Clin Cancer Res 2005;11:1167–73.[Abstract/Free Full Text]
  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 2005;23:5900–9.[Abstract/Free Full Text]
  20. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer—molecular and clinical predictors of outcome. N Engl J Med 2005;353:133–44.[Abstract/Free Full Text]
  21. 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;16:1081–6.[Abstract/Free Full Text]
  22. 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;23:2493–501.[Abstract/Free Full Text]
  23. 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;23:2513–20.[Abstract/Free Full Text]
  24. 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;23:6829–37.[Abstract/Free Full Text]
  25. 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;97:643–55.[Abstract/Free Full Text]
  26. 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;23:6838–45.[Abstract/Free Full Text]
  27. 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;12:839–44.[Abstract/Free Full Text]
  28. Hirsch FR, Varella-Garcia M, Bunn PA, Jr., et al. Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 2003;21:3798–807.[Abstract/Free Full Text]
  29. Dziadziuszko R, Holm B, Skov BG, et al. Prognostic significance of EGFR FISH and EGFR IHC in non-small cell lung cancer patients treated with chemotherapy alone. Proc Am Soc Clin Oncol. In press 2006.
  30. Hirsch FR, Varella-Garcia M, Bunn PA, et al. Molecular analysis of EGFR gene copy number, EGFR expression, and Akt activation status in advanced non-small cell lung cancer (aNSCLC) treated with gefitinib or placebo (ISEL trial). Clin Cancer Res 2005;24:9031s.
  31. Moroni M, Veronese S, Benvenuti S, et al. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to anti EGFR treatment in colorectal cancer: a cohort study. Lancet Oncol 2005;6:279–86.[CrossRef][Medline]
  32. Meert AP, Martin B, Delmotte P, et al. The role of EGF-R expression on patient survival in lung cancer: a systematic review with meta-analysis. Eur Respir J 2002;20:975–81.[Abstract/Free Full Text]
  33. 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;44:1362–1.
  34. Hirsch FR, McCoy J, Cappuzzo F, et al. FISH and immunohistochemistry can be used to select NSCLC patients, who will not benefit from gefitinib treatment. Lung Cancer 2005;49:S38.
  35. Sandler AB, Gray R, Brahmer J, et al. Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC #704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): an Eastern Cooperative Oncology Group (ECOG) Trial E4599. Abstract LBA4. Proc Am Soc Clin Oncol 2005;23:250.
  36. Cappuzzo F, Magrini E, Ceresoli GL, et al. Akt phosphorylation and gefitinib efficacy in patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 2004;96:1133–41.[Abstract/Free Full Text]
  37. Thomson S, Buck E, Petti F, et al. Epithelial to mesenchymal transition is a determinant of sensitivity of non-small-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibition. Cancer Res 2005;65:9455–62.[Abstract/Free Full Text]
  38. Witta SE, Gemmill RM, Hirsch FR, et al. Restoring e-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines. Cancer Res 2006;66:944–50.[Abstract/Free Full Text]
  39. Yauch RL, Januario T, Eberhard DA, et al. Epithelial versus mesenchymal phenotype determines in vitro sensitivity and predicts clinical activity of erlotinib in lung cancer patients. Clin Cancer Res 2005;1511:8686–98.
  40. 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;23:5007–18.[Abstract/Free Full Text]
  41. Cappuzzo F, Toschi L, Domenichini I, et al. HER3 genomic gain and sensitivity to gefitinib in advanced non-small-cell lung cancer patients. Br J Cancer 2005;93:1334–40.[CrossRef][Medline]
  42. Engelman JA, Janne PA, Mermel C, et al. ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines. Proc Natl Acad Sci U S A 2005;102:3788–93.[Abstract/Free Full Text]
  43. 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;352:786–92.[Abstract/Free Full Text]
  44. 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:e73.[CrossRef][Medline]
  45. Kwak EL, Sordella R, Bell DW, et al. Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci U S A 2005;102:7665–70.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Clin. Cancer Res.Home page
F. R. Hirsch, M. Varella-Garcia, R. Dziadziuszko, Y. Xiao, S. Gajapathy, M. Skokan, M. Lin, V. O'Neill, and P. A. Bunn Jr.
Fluorescence In situ Hybridization Subgroup Analysis of TRIBUTE, a Phase III Trial of Erlotinib Plus Carboplatin and Paclitaxel in Non-Small Cell Lung Cancer
Clin. Cancer Res., October 1, 2008; 14(19): 6317 - 6323.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Prevention ResearchHome page
X. Tang, M. Varella-Garcia, A. C. Xavier, E. Massarelli, N. Ozburn, C. Moran, and I. I. Wistuba
Epidermal Growth Factor Receptor Abnormalities in the Pathogenesis and Progression of Lung Adenocarcinomas
Cancer Prevention Research, August 1, 2008; 1(3): 192 - 200.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
F. R. Hirsch, R. S. Herbst, C. Olsen, K. Chansky, J. Crowley, K. Kelly, W. A. Franklin, P. A. Bunn Jr, M. Varella-Garcia, and D. R. Gandara
Increased EGFR Gene Copy Number Detected by Fluorescent In Situ Hybridization Predicts Outcome in Non-Small-Cell Lung Cancer Patients Treated With Cetuximab and Chemotherapy
J. Clin. Oncol., July 10, 2008; 26(20): 3351 - 3357.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
V. A. Miller, G. J. Riely, M. F. Zakowski, A. R. Li, J. D. Patel, R. T. Heelan, M. G. Kris, A. B. Sandler, D. P. Carbone, A. Tsao, et al.
Molecular Characteristics of Bronchioloalveolar Carcinoma and Adenocarcinoma, Bronchioloalveolar Carcinoma Subtype, Predict Response to Erlotinib
J. Clin. Oncol., March 20, 2008; 26(9): 1472 - 1478.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
R. Lilenbaum, R. Axelrod, S. Thomas, A. Dowlati, L. Seigel, D. Albert, K. Witt, and D. Botkin
Randomized Phase II Trial of Erlotinib or Standard Chemotherapy in Patients With Advanced Non-Small-Cell Lung Cancer and a Performance Status of 2
J. Clin. Oncol., February 20, 2008; 26(6): 863 - 869.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
M. Loprevite, M. Tiseo, M. Chiaramondia, M. Capelletti, C. Bozzetti, B. Bortesi, N. Naldi, R. Nizzoli, P. Dadati, A. Kunkl, et al.
Buccal Mucosa Cells as In vivo Model to Evaluate Gefitinib Activity in Patients with Advanced Non Small Cell Lung Cancer
Clin. Cancer Res., November 1, 2007; 13(21): 6518 - 6526.
[Abstract] [Full Text] [PDF]

Home page
 JNCI J Natl Cancer InstHome page
M.-S. Tsao, G. Liu, and F. A. Shepherd
Serum Proteomic Classifier for Predicting Response to Epidermal Growth Factor Receptor Inhibitor Therapy: Have We Built a Better Mousetrap?
J Natl Cancer Inst, June 6, 2007; 99(11): 826 - 827.
[Full Text] [PDF]

This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bunn, P. A.
Right arrow Articles by Hirsch, F. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bunn, P. A., Jr.
Right arrow Articles by Hirsch, F. R.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online