Journal of Thoracic Oncology:
Consensus for EGFR Mutation Testing in Non-small Cell Lung Cancer: Results from a European Workshop
Pirker, Robert MD*; Herth, Felix J. F. MD, PhD, FCCP†; Kerr, Keith M. MD, FRCPath‡; Filipits, Martin PhD*; Taron, Miquel PhD§∥; Gandara, David MD¶; Hirsch, Fred R. MD#; Grunenwald, Dominique MD**; Popper, Helmut MD††; Smit, Egbert MD, PhD‡‡; Dietel, Manfred MD§§; Marchetti, Antonio MD, PhD∥∥; Manegold, Christian MD¶¶; Schirmacher, Peter MD##; Thomas, Michael MD, PhD†; Rosell, Rafael MD, PhD§∥; Cappuzzo, Federico MD***; Stahel, Rolf MD†††; on Behalf of the European EGFR Workshop Group
*Medical University of Vienna, Vienna, Austria; †Thoraxklinik University of Heidelberg, Heidelberg, Germany; ‡Aberdeen Royal Infirmary, Aberdeen, United Kingdom; §Catalan Institute of Oncology, Badalona, Spain; ∥Pangaea Biotech, USP Institut Universitari Dexeus, Barcelona, Spain; ¶University of California Davis Cancer Center, Sacramento, California; #University of Colorado Health Sciences Center, Aurora, Colorado; **Hopital Tenon, University of Paris VI, Paris, France; ††Medical University of Graz, Graz, Austria; ‡‡Vrije Universiteit Medical Centre, Amsterdam, The Netherlands; §§Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany; ∥∥Clinical Research Center, Center of Excellence on Aging, University-Foundation, Chiety, Italy; ¶¶Medical Center Mannheim, Heidelberg University, Mannheim, Germany; ##Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany; ***Livorno Hospital, Livorno, Italy; and †††University Hospital Zurich, Zurich, Switzerland.
Disclosure: Robert Pirker, MD, has received speaker's fees and honorari for consulting from AstraZeneca, Boehringer Ingelheim, Merck Serono, and Roche. Keith M. Kerr, MD, FRCPath, has received consulting fees and honoraria from AstraZeneca and Roche. Martin Filipitis, PhD, has received speaker's feed and honoraria for advisory boards from AstraZeneca. Miquel Taron, PhD, has received honoraria for advisory boards and speaker's fees from AstraZeneca. David Gandara, MD, has received consulting fees from Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, BMS/Imclone, GlaxoSmithKline, Genentech, Merck, Novartis, and Sanofi-Aventis, as well as research grants from Abbott, BMS/Imclone, Genentech, Eli Lilly, Merck, Novartis, and Pfizer. Fred R. Hirsch, MD, has received honoraria for advisory boards from AstraZeneca, OSI, Roche, Genentech, and Boehringer Ingelheim; research grants from AstraZeneca, OSI, and Genentehc; and is an inventor of a University of Colorado-owned patent (EGFR FISH predictive marker for EGFR inhibitors). Helmut Popper, MD, has received honoraria for advisory boards from AstraZeneca and Roche. Manfred Dietel, MD, has received honoraria for scientific advisory boards from AstraZeneca. Peter Schirmacher, MD, had received honoraria fror advisory boards from AstraZeneca and Roche, as well as research grants from AstraZeneca. Rolf Stahel, MD, has received honoraria for scientific advisory boards from AstraZeneca and merck Serono. The other authors declare no conflicts of interest.
Address correspondence to: Robert Pirker, Medical University of Vienna, Waehringer Guertel 18–20, 1090 Vienna, Austria. E-mail: email@example.com
Introduction: Activating somatic mutations of the tyrosine kinase domain of epidermal growth factor receptor (EGFR) have recently been characterized in a subset of patients with advanced non-small cell lung cancer (NSCLC). Patients harboring these mutations in their tumors show excellent response to EGFR tyrosine kinase inhibitors (EGFR-TKIs). The EGFR-TKI gefitinib has been approved in Europe for the treatment of adult patients with locally advanced or metastatic NSCLC with activating mutations of the EGFR TK. Because EGFR mutation testing is not yet well established across Europe, biomarker-directed therapy only slowly emerges for the subset of NSCLC patients most likely to benefit: those with EGFR mutations.
Methods: The “EGFR testing in NSCLC: from biology to clinical practice” International Association for the Study of Lung Cancer-European Thoracic Oncology Platform multidisciplinary workshop aimed at facilitating the implementation of EGFR mutation testing. Recommendations for high-quality EGFR mutation testing were formulated based on the opinion of the workshop expert group.
Results: Co-operation and communication flow between the various disciplines was considered to be of most importance. Participants agreed that the decision to request EGFR mutation testing should be made by the treating physician, and results should be available within 7 working days. There was agreement on the importance of appropriate sampling techniques and the necessity for the standardization of tumor specimen handling including fixation. Although there was no consensus on which laboratory test should be preferred for clinical decision making, all stressed the importance of standardization and validation of these tests.
Conclusion: The recommendations of the workshop will help implement EGFR mutation testing in Europe and, thereby, optimize the use of EGFR-TKIs in clinical practice.
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib and erlotinib have demonstrated efficacy in the treatment of advanced non-small cell lung cancer (NSCLC), particularly in females, never-smokers, and those with adenocarcinoma histology.1–3 In 2004, specific mutations in the EGFR TK domain were identified, which confer sensitivity to EGFR TKIs.4–6 These activating somatic mutations of the EGFR gene were more prevalent in patients who derived greater clinical benefit from EGFR-TKIs.4–9 The most common EGFR sensitizing mutations are exon 19 microdeletions, which remove a leucine-arginine-glutamic acid-alanine motif, and the exon 21 L858R point mutation, which produces a leucine-to-arginine substitution (Figure 1). Together, these two types of mutations comprise up to approximately 85 to 90% of known EGFR activating mutations in NSCLC.8–11 Some mutations, particularly in exon 20, are associated with resistance to EGFR TKIs.10,12
The Phase III IRESSA Pan-ASia Study compared gefitinib with carboplatin/paclitaxel in previously untreated, never-smokers/light ex-smokers with advanced pulmonary adenocarcinoma in East Asia and confirmed the predictive value of EGFR mutations. Patients with EGFR mutation-positive tumors (n = 261) had significantly longer progression-free survival (PFS) with gefitinib (hazard ratio [HR, gefitinib:carboplatin/paclitaxel] 0.48; 95% confidence interval [CI] 0.36–0.64; p < 0.001), whereas those in the mutation-negative subgroup (n = 176) had significantly shorter PFS with gefitinib (HR 2.85; 95% CI 2.05–3.98; p < 0.001).13 Patients with EGFR mutation-positive tumors also had higher objective response rates with gefitinib versus carboplatin/paclitaxel (71.2% versus 47.3%; p < 0.001), whereas those with EGFR mutation-negative tumors had lower objective response rates with gefitinib compared with carboplatin/paclitaxel (1.1% versus 23.5%; p = 0.001).
Results similar to the Phase III IRESSA Pan-ASia Study have also been seen in several other studies including other prospective studies of first-line gefitinib,14–21 and three further randomized phase III studies that compared first-line gefitinib with doublet chemotherapy.22–24 In one of these phase III studies (NEJ002; n = 198), gefitinib compared with carboplatin/paclitaxel resulted in a higher response rate (74.5% versus 29.0%) and longer PFS (HR 0.357; 95% CI 0.252–0.507; p < 0.001) in patients with EGFR mutation-positive tumors.24
Activating EGFR mutations also seem to be associated with response to erlotinib. A large-scale screening study identified EGFR mutations in patients with NSCLC, who were then considered for first- or second-line therapy with erlotinib.25 From 2105 screened patients, EGFR mutations were detected in 350 patients, and of these, 217 patients received erlotinib. In those patients with EGFR mutation-positive tumors, erlotinib resulted in an objective response rate of 70.6%. The exon 19 deletion mutation was associated with a higher probability of response (odds ratio 3.08; 95% CI 1.63–5.81; p = 0.001). This study also demonstrated that large-scale screening of patients for EGFR mutations is feasible and results in improved clinical outcome.
Gefitinib has received European approval for the treatment of adult patients with locally advanced or metastatic NSCLC with activating mutations of the EGFR-TK. Although American Society of Clinical Oncology guidelines recommend EGFR mutation testing in patients with NSCLC,26 this procedure has yet to be broadly established in Europe as it has been for KRAS mutation testing in colorectal cancer.27–29
The “EGFR testing in NSCLC: from biology to clinical practice” workshop was held on 27–28 November 2009, Vienna, Austria, under the auspices of the International Association for the Study of Lung Cancer and the European Thoracic Oncology Platform. This European multidisciplinary workshop, which was attended by clinical and scientific experts involved in the management of advanced NSCLC, aimed to develop recommendations to facilitate the implementation of EGFR mutation testing in clinical practice. The 122 participants included molecular biologists, pathologists, surgeons, chest physicians, and medical oncologists. Breakout groups addressed the identification and preparation of suitable biopsy/sample material and optimal methods for high-quality EGFR mutation testing. The key conclusions of the breakouts were reviewed and discussed in plenary sessions among the entire workshop group. Here, we summarize consensus recommendations for biopsy methods and EGFR mutation testing and provide a flowchart of the overall process (Figure 2).
GENERAL CONSIDERATIONS FOR EGFR MUTATION TESTING
A key conclusion was that close collaboration, communication flow, and coordination between the departments involved in the management of lung cancer is essential to implement EGFR mutation testing in routine practice. This process involves clinicians, pathologists, molecular biologists, and radiologists. Awareness of the need for tumor material for routine EGFR mutation testing has to be raised. This is a key step in allowing all patients with EGFR sensitizing mutations to benefit from treatment with an EGFR TKI.
Which Patients Should Be Tested?
The decision to test for EGFR mutations should be made by the treating physician at the time of diagnosis. This decision may depend on the availability of sufficient tissue; therefore, it is vital that biopsy methods are optimized, and that tissue is conserved at initial diagnosis and whenever possible thereafter. Although all patients with NSCLC may eventually be tested, the primary focus could be on patients with adenocarcinoma and/or patients with a negative smoking history because the frequencies of mutations are particularly high in these patients.
Potential prescreening strategies were discussed. These included the issue of whether focus should be on specific patient populations such as never-smokers and/or patients with adenocarcinoma. Molecular prescreening techniques such as high-resolution melting analysis were of some interest for prescreening.30–32 Immunohistochemistry could be a useful prescreening test because it detects the most common and relevant mutations at the protein level (e.g., exon 19 deletions), but does not detect all mutations.33,34 Circulating tumor cell DNA testing could also provide an initial screen. However, circulating tumor cells are limited by numbers and difficult to extract. Some participants suggested KRAS mutation testing as a prescreen method but currently, its use is not standard for excluding EGFR mutations in clinical practice. Although some of these assays may prove useful as prescreening methods in the future, there was no consensus agreement on current prescreening algorithms.
Are There Minimum Requirements for a Laboratory to Undertake EGFR Mutation Testing?
EGFR mutation testing should only be done in a quality-assured setting. There should be accreditation for EGFR mutation testing in Europe, at a national or even European level. The establishment of reference laboratories in Europe may also be helpful: such laboratories exist for KRAS mutation testing in colorectal cancer.27–29
What Are Acceptable Timelines for the Different Stages in the Process?
Timelines are a key consideration in the management of patients with advanced NSCLC. Results from mutation testing should become available to the treating physician as soon as possible. After tumor biopsy and its transport to the pathologist within 24 hours, the pathology report (except immunohistochemistry) should be completed within 1 to 2 working days. The EGFR mutation testing should then be completed within another 5 to 7 working days. The overall process from sampling (or ordering of the test) to availability of the mutation results should not take more than 10 working days (Figure 2).
BIOPSY AND TISSUE SAMPLING METHODS
When Should Tissue Collection Occur?
Tissue collection specifically for EGFR mutation testing is unlikely to occur. Therefore, samples used for tumor diagnosis will also be used for mutation analysis. Rebiopsy, specifically for EGFR mutation testing could be considered at the time of recurrence or disease progression, or even during initial patient work-up, if diagnostic samples are inadequate for mutation analysis. The benefits of obtaining as much tumor tissue as possible during any biopsy procedure and storage of this tissue after initial pathologic diagnosis were emphasized.
It might be good to also obtain a plasma or blood sample that can be tested if the tumor analysis fails, but this approach is currently considered experimental.
From Which Tumor Site Should the Biopsy Be Taken?
The biopsy site should be selected by the clinician who will perform the biopsy. In general, the biopsy should be taken from the most easily accessible tumor. Although pathologists had no preference with regard to the disease site, e.g., primary tumor, lymph node, or distant metastases, all participants agreed that further research into the potential mutation discordance between the primary and different metastatic sites is clearly indicated.35
Which Biopsy Techniques Should Be Used to Ensure High-Quality Tissue Samples and What Volume of Sample Is Needed?
Several well-established biopsy techniques can be used to obtain high-quality tissue samples: needle core biopsy, transbronchial biopsy, endobronchial biopsy, computed tomography-guided needle biopsy, mediastinoscopy, video-assisted thoracic surgery, and thoracotomy. Number of biopsies and cells obtained by the various techniques are summarized in Table 1.
How Can Complications Be Prevented and Minimized?
Every precaution should be taken to prevent and minimize complications. Additional biopsies have little adverse effect on the complication rate.
What Tumor Content Should the Biopsy Material Have for Successful EGFR Mutation Analysis?
Before molecular analysis, the tumor cell content of the tissue sample should be determined to assess the reliability of subsequent test results. There was agreement that the ratio of malignant to normal cells within the sample is crucial for the detection of tumor-specific mutations. In this regard, determination of the relative proportion of tumor (cellularity) in the sample being tested, as a percentage of all cells, is recommended. Tumor cell enrichment by manual dissection may be required to improve accuracy of the test results in case of sequencing. Laser capture microdissection can also be used but is not required.
The minimum number of tumor cells required for adequate mutation testing is ill-defined, although the clear consensus was that as much material as possible should be obtained. Ideally, a sample should contain at least 200 to 400 tumor cells, but this is rarely achieved in routine. For DNA sequencing, the percentage of tumor cells should ideally be at least 50% although with good technical procedures reliable results can be obtained with tumor percentage as low as 10 to 20%. Several methods with higher detection sensitivity can detect mutations present at very low levels (1–5% of EGFR gene copies mutated), allowing the possibility of mutation detection when tumor cell proportion is less than 10% of the test sample.
How Should the Biopsy Material Be Prepared for Subsequent Pathology and EGFR Mutation Testing?
Handling of tumor specimens has yet to be standardized. There was agreement that 10% neutral-buffered formalin is the optimum fixative, whereas Bouin's fluid should not be used and other fixatives have yet to be validated against formalin. The fixation time should be as short as possible, yet sufficient to permit diagnosis. For example, it has been shown that fixation times of 6 to 12 hours for small biopsy samples and 8 to 18 hours for larger surgical specimens generally give best results. For other techniques, such as DNA extraction and polymerase chain reaction (PCR), the optimal fixation times have yet to be established. Because tissue samples are only fixed once, immediately after the biopsy procedure, variations in fixation time according to analytical technique are not practical, and techniques are best adapted to these standard fixation times. Sections cut from the formalin-fixed paraffin-embedded tissue block are the standard resource used for DNA extraction. Between 1 and 6 sections of 5- to 10-μm thickness should be used. Laboratories that use laser capture microdissection will require thinner sections. Tissue fixation and processing have the potential to denature DNA, especially when using automated processes.
Can Cytology Samples Be Used?
Cytology samples may be suitable for analysis but further research is needed to fully understand the clinical reliability of mutational data obtained from these samples. Until then, clinicians should be encouraged to provide tissue biopsy samples whenever possible.
STANDARD METHODS FOR EGFR MUTATION TESTING
What Are the Best DNA Extraction Methods?
A range of extraction methods may be used. There was no consensus on which was the best method. Simple column-free methods, e.g., Gentra Puregene Blood kit (QIAGEN GmbH, Germany), were recommended in cases in which sample material is limited, whereas other methods, e.g., QIAGEN FFPET kit (Formalin-Fixed Paraffin-Embedded Tissue kit; QIAGEN GmbH, Germany) can be used when material is more abundant. Alternative, simple purification steps may be appropriate for all samples. Further research to define the optimal DNA extraction method is needed.
There was general agreement that the quality of amplifiable DNA is more important than its quantity. Mutation testing should only proceed when the PCR-amplified DNA has been judged to be sufficient. To improve results, quality assurance (QA) procedures have been recommended, based on defined criteria for the quality of the sample. The QA results should also be reported to the clinician. If a sample that does not meet these QA criteria is EGFR mutation positive, and a standard EGFR mutation test has been carried out, the result can be reported as it is rare to have false positives. However, if a sample that does not meet these QA criteria is EGFR mutation negative, it should be reported that a mutation was not found but that the presence of a mutation cannot be excluded due to the poor quality of the sample.
What Are the Best EGFR Mutation Testing Techniques?
A variety of methods are used to detect EGFR mutations. These methods include direct sequencing, the Amplification Refractory Mutation System (ARMS), length analysis, and denaturing high-performance liquid chromatography. These methods have different advantages and disadvantages (Table 2), and there was no consensus agreement on which was the best method. Some tests only detect the most common activating mutations, whereas other tests can detect all mutations. DNA sequencing is widely used. It can detect all mutations, but is usually more time-consuming. However, with sequencing there is no need for batching of samples and it provides better contamination control as the exact, specific mutation in the sample can be determined. ARMS is more sensitive than sequencing, but detects fewer mutations. In cases in which available DNA template is limited, the most common sensitizing mutations found within exons 19 and 21 should be assessed as a priority.
Under What Circumstances Should the EGFR Mutation Test Be Repeated?
Several criteria for the test to be repeated have been recommended. The test should be repeated if a new (unreported) mutation is found because of the possibility of a false positive result.36 The test should also be repeated in case of poor sequence data (with primary PCR and sequencing), if the cycle threshold is close to the defined cut-off limit (with the ARMS-based kits) or if other quality assessment criteria are not met.
In case of failed tests, the following options exist: repeat PCR; fragment analysis for exon 19, which is very sensitive; TaqMan for exon 20 and 21; DNA extraction from new tissue sections; repeating the test using different samples, if available; and discussing other options with the pathology team. Networking for second opinions with different methodologies might also be useful. In all cases, it is best to start again from tissue if available and to discuss difficult samples with the individual clinician or team managing the patient.
How Should the Results Be Reported?
The report on the mutation status should be submitted by the pathologist or the molecular biologist in close collaboration with the pathologist. The report should contain the following information: details of the tissue block tested, sample source, biopsy method used, sample size and quality, tumor content of the sample extracted for DNA, methodology used, exons tested, and mutation present/absent. Details of the specific mutation found and their relevance with regard to response to EGFR-directed TKIs should be documented, e.g., whether they are sensitizing mutations to TKIs, TKI-resistant mutations (T790M) or mutations with unknown relevance with regard to response to EGFR-directed TKIs. New mutations should be checked against the Greek mutations database37 regarding their clinical implication and a recommendation should be made accordingly, noting that it is a new or minority mutation. Other relevant comments should be recorded to assist interpretation of the test, such as the analytical sensitivity of the test (in the context of the percentage of tumor cells in the extracted sample). Quantitative data on mutations may also be valuable.
Further evaluation of the significance of some EGFR mutations is needed, including assessment of the functional importance (clinical and/or predictive significance) of the less-common activating mutations. The results of the Greek mutations database have been published.37 A continuously up-dated international database of mutation variants and patients' response to treatment is required. In some patients, the T790M mutation in exon 20 has been associated with acquired resistance to gefitinib.10,38 However, the clinical implications of the T790M mutation also needs further investigation; this mutation has also been found additionally in patients who have an activating EGFR mutation.17 Other areas requiring further investigation include the reasons for nonresponse to TKIs in some patients with EGFR activating mutations, the heterogeneity in mutation expression within the primary tumor and mutation discordance between the primary tumor and metastases, and the significant association that has been observed between tumor histologic phenotype and EGFR mutations.39 The relationship between new imaging technologies and EGFR mutation testing should also be investigated, as imaging may provide a way of assessing changes in tissue during treatment.40
Additional mutation testing techniques are being developed, such as the peptide nucleic acid-locked nucleic acid PCR clamp assay,11,41–43 and may be useful in the future. However, it should be noted that any methodology that has not been used in the main clinical trials require validation and accreditation to ensure that they provide comparable results. With this in mind, simple standardized techniques as validated in trials may be optimal. Advanced techniques with increased sensitivity are being developed, but with these, comes the increased risk of false-positive results. These must be avoided, so that patients do not receive treatment from which they are unlikely to benefit.
Clinical characteristics and histology have previously been documented as predictive factors for response to EGFR-TKIs in NSCLC, e.g., female gender, never-smokers, and adenocarcinoma histology. However, recent findings suggest that tumor molecular profiling may soon supersede these selection factors in individualizing NSCLC treatment.44 The most striking biomarker results have been the identification of activating EGFR mutations within NSCLC tumors, which have conferred superior patient outcomes with gefitinib compared with chemotherapy.13 In this dawning era of personalized care in advanced NSCLC, EGFR mutations have emerged as a key predictive biomarker for EGFR-TKI treatment and should be the primary standard for selection of patients for first-line treatment with an EGFR-TKI. These recommendations from a multidisciplinary International Association for the Study of Lung Cancer-European Thoracic Oncology Platform workshop will help to optimize routine EGFR mutation testing in NSCLC for the use of EGFR-TKIs in Europe (Table 3). These early recommendations will help to facilitate the implementation of EGFR mutation testing, but further research to identify the best techniques is required, both within clinical studies and as the guidelines are validated in clinical practice.
The “EGFR Testing in NSCLC: from biology to clinical practice” workshop that was held on November 27–28, 2009 in Vienna, Austria, was made possible by unrestricted educational grants from AstraZeneca (principal sponsor) and Merck Serono (secondary sponsor).
The authors thank all the participants. A list of participants is included in the Appendix.
APPENDIX: PARTICIPANTS OF THE “EGFR TESTING IN NSCLC” WORKSHOP
Robert Pirker, Martin Filipits, Helmut Popper (Austria); Dominique Grunenwald (France); Felix Herth (Germany); Federico Cappuzzo (Italy); Egbert Smit (The Netherlands); Rafael Rosell (Spain); Rolf Stahel (Switzerland); Keith Kerr (UK).
Breakout Session Chairs and Cochairs
Biopsy and sampling session: Felix Herth (Germany); Dominique Grunenwald (France); Robert Pirker (Austria).
Pathology session: Keith Kerr (UK); Egbert Smit (The Netherlands); Peter Schirrmacher (Germany).
EGFR mutation testing session: Martin Filipits (Austria); Miquel Taron (Spain); Antonio Marchetti (Italy).
Other methodologies session: Fred Hirsch (USA); Christian Manegold (Germany).
Full List of Workshop Participants
Austria: Madeleine Arns-Dietl, Walter Berger, Martin Filipits, Michaela Hack, Balàzs Hegedús, Wolfgang Hilbe, Maximilian Hochmair, Mir Alireza Hoda, Florian Huemer, Wolfgang Hulla, Klaus Kirchbacher, Hubert Koller, Sören Kreuzer, Elham Pedram, Robert Pirker, Helmut Popper, Petra Prüfert-Holzinger, Michael Reiter, Richard Wasicky, Christoph Zielinski, Sabine Zöchbauer-Müller.
Belgium: Nadia Badri, Brigitte Gutendorf, Christian Hansen, Chrisitof Koelsch, Christof Kölsch, Adrien Lebrun, Marleen Praet, Ilian Tchakov, Erik Teugels, Els Van De Walle, Peter Vandenberghe.
Czech Republic: Jan Ledecky, Lubos Petruzelka, Ales Ryska, Petr Zatloukal.
Denmark: Karin de Stricker, Morten Grauslund, Birgit Guldhammer-Skov, Henrik Hager.
France: Marie Melanie Dauplat, Dominique Grunenwald.
Finland: Jenni Järvi, Aija Knuttila, Kaisa Salmenkivi.
Germany: Yuan Chen, Tiantian Cui, Barbara De Bals, Manfred Dietel, Wilfried Eberhardt, Isabella Eder, Beatrix Hein, Felix Herth, Liu Hongyu, Rudolf M. Huber, Katrin Kruetzfeldt, Christian Manegold, Roland Penzel, Peter Schirmacher, Michael Thomas, Linlin Yang.
Ireland: Kathy Gately.
Greece: Ioannis Boukovinas, Alexandros Moulis, Samuel Murray, Angelica Saetta, Antonios Vassias.
Italy: Letizia Bazzola, Fiamma Buttitta, Maria Dono, Marcello Gambacorta, Antonio Marchetti, Ettore Mari, Nicola Normanno, Antonio Rossi, Giancarlo Troncone, Silvio Veronese, Simonetta Zupo.
Portugal: Margarida Almeida, Teresina Amara, Lina Carvalho, Ana Rita Lima.
Spain: Susanna Benlloch, Jesus Garica Foncillas, Carmen Gonzalez Arenas, Mangeles Lopez Garcia, Fernando Lopez-Rios, Julian Sanz, Miquel Taron, Sandra Zazo Hernandez.
Sweden: Johan Botling, Daniel Brattström, Simon Ekman, Göran Elmberger, Leif Johansson, Hirsch Koyi, Jeanette Spinnars, Karin Sundqvist.
Switzerland: Mico Frattini, Sonja Jehle, Rolf Stahel.
The Netherlands: Anne-Marie Dingemans, Manfred Marang, Petra Nederlof, Egbert Smit, Erik Thunnissen.
Turkey: Havva Didem Akpir Soydan, Adnan Aydiner, E Dilek Yilmazbayhen.
United Kingdom: Rachel Butler, Caroline Clark, Ian Cook, Ian Cree, David Gonzalez De Castro, Alison Horsfield, Keith Kerr, Gael McWalter, Philippe Taniere, Jane Theaker, Graham Walker.
USA: David Gandara, Fred Hirsch.
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Epidermal growth factor receptor; EGFR mutation; EGFR testing recommendations; Gefitinib; Erlotinib; Non-small cell lung cancer; Tyrosine kinase inhibitors
© 2010International Association for the Study of Lung Cancer
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