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Counterpoint: Should Epidermal Growth Factor Receptor Mutations Be Routinely Tested for in Patients With Lung Cancer? NoNo Test for EGFR Mutations? No FREE TO VIEW

David C. L. Lam, MBBS (HK), PhD (HK), FCCP
Author and Funding Information

From the Department of Medicine, University of Hong Kong.

Correspondence to: David C. L. Lam, MBBS (HK), PhD (HK), FCCP, Department of Medicine, University of Hong Kong, Queen Mary Hospital, 102 Pokfulam Rd, Hong Kong, SAR, China; e-mail: dcllam@hku.hk


Financial/nonfinancial disclosures: The author has reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2013;143(3):600-602. doi:10.1378/chest.12-2548
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The square one question is why we need to do the epidermal growth factor receptor (EGFR) mutation tests. The answer is that there is corresponding targeted therapy, namely EGFR-tyrosine kinase inhibitor (TKI), for subjects with tumors that bear EGFR mutations at exons 18 to 21. This is in line with the strategy of personalizing therapy for lung cancer with the ultimate goals of making biomarker-based therapeutic decisions to receive EGFR-TKI and to improve treatment outcome in patients with advanced-stage non-small cell lung cancer (NSCLC).1

Is current evidence in support of testing for EGFR mutations in every subject with lung cancer? EGFR mutations have been found in a variable proportion of lung adenocarcinomas, from 20% to 40% in Caucasians to 40% to 50% in Asians.2,3EGFR mutations were found to be more common in lung adenocarcinomas from female nonsmokers of Asian origin.4 Higher prevalence of EGFR mutations of up to 70% has been reported in an enriched cohort of subjects with lung cancer.5 Testing for EGFR mutation could identify a specific population of patients with lung adenocarcinomas who could benefit from EGFR-TKI therapy.4 Based on the Iressa Pan-Asia Study (IPASS), subjects with lung adenocarcinomas bearing EGFR mutations showed superior progression-free survival and a trend toward better overall survival than those patients who had EGFR mutations but received platinum-based chemotherapy.5EGFR mutation testing could potentially benefit those groups of subjects with lung adenocarcinomas who would consider EGFR-TKI as first-line therapy.6 Pulmonary adenocarcinomas displayed heterogeneity in histology, and the prevalence of EGFR mutations ranged from 3% to 40% in different histologic subtypes of adenocarcinomas.7 Thus, routine testing for EGFR mutations in pulmonary adenocarcinomas could not be fully justified. Physicians should exercise clinical judgement as to whether EGFR mutation tests should be considered on an individual basis rather than routine testing to the extent of screening. For subjects who refuse treatment, testing would not offer any benefit to patients. Additional caution needs to be taken in subjects with lung cancer who have concomitant interstitial lung disease. The risk of interstitial pneumonitis has been reported in >5% in the Japanese population and <5% in other ethnic populations.8 There is not sufficient evidence for EGFR mutation tests to be routinely performed in subjects with pulmonary adenocarcinomas.

Bearing in mind the potentially different spectrum of driver mutations between Caucasians and Asians, one may have to adopt slightly different approaches in testing for therapeutic targets in subjects of different ethnic origin.2,3 The relatively higher prevalence of EGFR mutations in Asian patients with lung cancer may provide more support for wider, but not yet routine, testing for EGFR mutations so that subjects with EGFR mutations could consider EGFR-TKI if appropriate and subjects who are EGFR wild type could proceed with chemotherapy or further testing for other therapeutic targets. On the other hand, as EGFR mutation is not the predominant type of driver mutations in the Caucasian population with lung cancer, rapid screening for multiple targets instead of stepwise target testing could be more cost effective,9 especially when we are witnessing a pipeline of newer targeted agents going through different phases of clinical trials, a few of which have obtained health authority approval for clinical use, such as crizotinib for tumors with EML4-ALK gene rearrangement.

How available are the tests and how reliable are they? Various methods of testing for EGFR mutations have been adopted. The gold standard is still direct sequencing of the relevant polymerase chain reaction amplicons of exons 18 to 21 of EGFR. There are increasing trends of adopting alternative methods, such as real-time polymerase chain reaction or similar multiplexing strategy for simultaneous detection of multiple therapeutic targets.9,10 Different methods of testing performed at different sensitivity and specificity.11 The morphologic or histopathologic features of lung tumors in biopsy or cytologic specimens are also highly variable, from tumor specimens with low to high tumor-to-stromal ratios and from nonnecrotic to highly necrotic tumor.12 These could again affect the performance of different types of tests used for EGFR mutation detection. Mutation detection methods have to be standardized and validated before being put into routine or regular clinical services.13 Clinicians should know the methods available at their local hospitals or collaborating laboratories before considering whether the tests should be recommended.

From a scientific point of view, it would be irresponsible to state that if resources are unlimited, all available tests for therapeutic targets, including EGFR mutation tests, should be done. Routine testing for EGFR mutations in subjects with lung cancer have shown a small degree of cost-effectiveness, but this has to be stated in the presence of the ever-increasing cost of laboratory testing.14 If subjects have already decided for best supportive care because of suboptimal performance status or financial reasons that subsequent EGFR-TKI would not be affordable, testing for EGFR mutations or other therapeutic targets would only be of academic interest in further understanding the biology of a particular tumor.

EGFR mutations have been reported rarely in squamous cell carcinoma15 and small cell carcinoma.16 Although the presence of EGFR mutation in histologic subtypes other than adenocarcinomas may support wider testing in squamous cell carcinoma and small cell carcinoma, systemic chemoirradiation remains the choice of therapy for these tumors in the advanced stage, and routine testing for EGFR mutation with such low prevalence of such mutations in these types of tumors is not cost effective unless there is no better treatment alternative (eg, in patients who have run out of first-line or second-line systemic chemotherapy options).

The optimal testing for EGFR mutation requires biopsy or cytologic samples of sufficient quality,17 which is not always possible in advanced-stage lung cancer. Patients who present late with advanced-stage lung cancer may not allow invasive procedures to obtain adequate amount of tumor tissues for testing. Patients with prior irradiation or chemotherapy may have necrotic tumors that preclude optimal tumor biopsy. Pulmonologist should be engaged in explaining to subjects the necessity of adequate sampling of tumor to allow for molecular testing unless this is impossible because of a patient’s performance status.

EGFR mutations at different exons exhibit differential sensitivity to EGFR-TKI.4 The most common mutations of L858R at exon 21 and 15 base-pair deletion at exon 19 are the most sensitive ones to EGFR-TKI, albeit with a best clinical response rate of 70% even in a mutation-enriched cohort, and there has been no adequate explanation for the clinical unresponsiveness of the remaining 30% of EGFR-mutated tumors.11 Tumors with EGFR mutations at exon 18 have reduced sensitivity to EGFR-TKI, and mutations at exon 20 are generally believed to confer resistance to EGFR-TKI.18 Besides the known T790M mutation at exon 20, which confers resistance to EGFR-TKI, there are increasing reports of combinations of different types of EGFR mutations in the same tumor, and the clinical response of these tumors to EGFR-TKI is generally undefined.18 The detection of these rare EGFR mutations would add difficulties in clinical therapeutic decisions as to a short period of therapeutic trial with available EGFR-TKI or to switch the decision to systemic chemotherapy in appropriate patients.

Another unanswered question is whether resected early-stage NSCLC should be tested for EGFR mutations,19 given the possibility of subclinical micrometastasis and that a significant proportion of subjects had tumor resected at an early stage with later relapse.20 There are generally two ways of thinking on this issue. Some clinicians believe that testing for EGFR mutations in resected tumor specimens would provide a reference for therapeutic decision when the tumor later relapses.21 However, critics are saying that relapsing tumors may not be holding the same clonal origin as the original resected tumor; thus, rebiopsy is always advocated if possible for relapsed tumors.21 Patients should be informed of the benefit of rebiopsy whenever possible to formulate the best therapeutic strategy.

In summary, EGFR mutation tests provide important and pivotal information for making relevant therapeutic decisions, especially in patients with advanced-stage NSCLC. However, the prevalence of EGFR mutations appeared to vary between patients with NSCLC of different ethnic origin and tumors of different histologic subtypes. The availability of EGFR mutation tests also varies in different countries or locations. The applicability and validity of testing for EGFR mutation in early-stage resected tumors are also controversial. Our conclusion is that EGFR mutation tests should be considered routinely but not performed in every patient with NSCLC without selection.

References

Tanner NT, Pastis NJ, Sherman C, Simon GR, Lewin D, Silvestri GA. The role of molecular analyses in the era of personalized therapy for advanced NSCLC. Lung Cancer. 2012;76(2):131-137. [CrossRef] [PubMed]
 
Li C, Fang R, Sun Y, et al. Spectrum of oncogenic driver mutations in lung adenocarcinomas from East Asian never smokers. PLoS ONE. 2011;6(11):e28204. [CrossRef] [PubMed]
 
Pao W, Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncol. 2011;12(2):175-180. [CrossRef] [PubMed]
 
da Cunha Santos G, Shepherd FA, Tsao MS. EGFR mutations and lung cancer. Annu Rev Pathol. 2011;6:49-69. [CrossRef] [PubMed]
 
Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-957. [CrossRef] [PubMed]
 
Keedy VL, Temin S, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: epidermal growth factor receptor (EGFR) mutation testing for patients with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy. J Clin Oncol. 2011;29(15):2121-2127. [CrossRef] [PubMed]
 
Travis WD, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011;6(2):244-285. [CrossRef] [PubMed]
 
Togashi Y, Masago K, Fujita S, et al. Differences in adverse events between 250 mg daily gefitinib and 150 mg daily erlotinib in Japanese patients with non-small cell lung cancer. Lung Cancer. 2011;74(1):98-102. [CrossRef] [PubMed]
 
Sequist LV, Heist RS, Shaw AT, et al. Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice. Ann Oncol. 2011;22(12):2616-2624. [CrossRef] [PubMed]
 
Su Z, Dias-Santagata D, Duke M, et al. A platform for rapid detection of multiple oncogenic mutations with relevance to targeted therapy in non-small-cell lung cancer. J Mol Diagn. 2011;13(1):74-84. [CrossRef] [PubMed]
 
Gately K, O’Flaherty J, Cappuzzo F, Pirker R, Kerr K, O’Byrne K. The role of the molecular footprint of EGFR in tailoring treatment decisions in NSCLC. J Clin Pathol. 2012;65(1):1-7. [CrossRef] [PubMed]
 
Travis WD. Pathology of lung cancer. Clin Chest Med. 2011;32(4):669-692. [CrossRef] [PubMed]
 
Dacic S. Molecular diagnostics of lung carcinomas. Arch Pathol Lab Med. 2011;135(5):622-629. [PubMed]
 
de Lima Lopes G Jr, Segel JE, Tan DS, Do YK, Mok T, Finkelstein EA. Cost-effectiveness of epidermal growth factor receptor mutation testing and first-line treatment with gefitinib for patients with advanced adenocarcinoma of the lung. Cancer. 2012;118(4):1032-1039. [CrossRef] [PubMed]
 
Gold KA, Wistuba II, Kim ES. New strategies in squamous cell carcinoma of the lung: identification of tumor drivers to personalize therapy. Clin Cancer Res. 2012;18(11):3002-3007. [CrossRef] [PubMed]
 
Shiao TH, Chang YL, Yu CJ, et al. Epidermal growth factor receptor mutations in small cell lung cancer: a brief report. J Thorac Oncol. 2011;6(1):195-198. [CrossRef] [PubMed]
 
Smouse JH, Cibas ES, Jänne PA, Joshi VA, Zou KH, Lindeman NI. EGFR mutations are detected comparably in cytologic and surgical pathology specimens of nonsmall cell lung cancer. Cancer. 2009;117(1):67-72. [PubMed]
 
Wu JY, Yu CJ, Chang YC, Yang CH, Shih JY, Yang PC. Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer. Clin Cancer Res. 2011;17(11):3812-3821. [CrossRef] [PubMed]
 
Sriram KB, Tan ME, Savarimuthu SM, et al. Screening for activating EGFR mutations in surgically resected nonsmall cell lung cancer. Eur Respir J. 2011;38(4):903-910. [CrossRef] [PubMed]
 
D’Angelo SP, Park B, Azzoli CG, et al. Reflex testing of resected stage I through III lung adenocarcinomas for EGFR and KRAS mutation: report on initial experience and clinical utility at a single center. J Thorac Cardiovasc Surg. 2011;141(2):476-480. [CrossRef] [PubMed]
 
Warth A, Macher-Goeppinger S, Muley T, et al. Clonality of multifocal non-small cell lung cancer: implications for staging and therapy. Eur Respir J. 2012;39(6):1437-1442. [CrossRef] [PubMed]
 

Figures

Tables

References

Tanner NT, Pastis NJ, Sherman C, Simon GR, Lewin D, Silvestri GA. The role of molecular analyses in the era of personalized therapy for advanced NSCLC. Lung Cancer. 2012;76(2):131-137. [CrossRef] [PubMed]
 
Li C, Fang R, Sun Y, et al. Spectrum of oncogenic driver mutations in lung adenocarcinomas from East Asian never smokers. PLoS ONE. 2011;6(11):e28204. [CrossRef] [PubMed]
 
Pao W, Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncol. 2011;12(2):175-180. [CrossRef] [PubMed]
 
da Cunha Santos G, Shepherd FA, Tsao MS. EGFR mutations and lung cancer. Annu Rev Pathol. 2011;6:49-69. [CrossRef] [PubMed]
 
Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-957. [CrossRef] [PubMed]
 
Keedy VL, Temin S, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: epidermal growth factor receptor (EGFR) mutation testing for patients with advanced non-small-cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy. J Clin Oncol. 2011;29(15):2121-2127. [CrossRef] [PubMed]
 
Travis WD, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011;6(2):244-285. [CrossRef] [PubMed]
 
Togashi Y, Masago K, Fujita S, et al. Differences in adverse events between 250 mg daily gefitinib and 150 mg daily erlotinib in Japanese patients with non-small cell lung cancer. Lung Cancer. 2011;74(1):98-102. [CrossRef] [PubMed]
 
Sequist LV, Heist RS, Shaw AT, et al. Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice. Ann Oncol. 2011;22(12):2616-2624. [CrossRef] [PubMed]
 
Su Z, Dias-Santagata D, Duke M, et al. A platform for rapid detection of multiple oncogenic mutations with relevance to targeted therapy in non-small-cell lung cancer. J Mol Diagn. 2011;13(1):74-84. [CrossRef] [PubMed]
 
Gately K, O’Flaherty J, Cappuzzo F, Pirker R, Kerr K, O’Byrne K. The role of the molecular footprint of EGFR in tailoring treatment decisions in NSCLC. J Clin Pathol. 2012;65(1):1-7. [CrossRef] [PubMed]
 
Travis WD. Pathology of lung cancer. Clin Chest Med. 2011;32(4):669-692. [CrossRef] [PubMed]
 
Dacic S. Molecular diagnostics of lung carcinomas. Arch Pathol Lab Med. 2011;135(5):622-629. [PubMed]
 
de Lima Lopes G Jr, Segel JE, Tan DS, Do YK, Mok T, Finkelstein EA. Cost-effectiveness of epidermal growth factor receptor mutation testing and first-line treatment with gefitinib for patients with advanced adenocarcinoma of the lung. Cancer. 2012;118(4):1032-1039. [CrossRef] [PubMed]
 
Gold KA, Wistuba II, Kim ES. New strategies in squamous cell carcinoma of the lung: identification of tumor drivers to personalize therapy. Clin Cancer Res. 2012;18(11):3002-3007. [CrossRef] [PubMed]
 
Shiao TH, Chang YL, Yu CJ, et al. Epidermal growth factor receptor mutations in small cell lung cancer: a brief report. J Thorac Oncol. 2011;6(1):195-198. [CrossRef] [PubMed]
 
Smouse JH, Cibas ES, Jänne PA, Joshi VA, Zou KH, Lindeman NI. EGFR mutations are detected comparably in cytologic and surgical pathology specimens of nonsmall cell lung cancer. Cancer. 2009;117(1):67-72. [PubMed]
 
Wu JY, Yu CJ, Chang YC, Yang CH, Shih JY, Yang PC. Effectiveness of tyrosine kinase inhibitors on “uncommon” epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer. Clin Cancer Res. 2011;17(11):3812-3821. [CrossRef] [PubMed]
 
Sriram KB, Tan ME, Savarimuthu SM, et al. Screening for activating EGFR mutations in surgically resected nonsmall cell lung cancer. Eur Respir J. 2011;38(4):903-910. [CrossRef] [PubMed]
 
D’Angelo SP, Park B, Azzoli CG, et al. Reflex testing of resected stage I through III lung adenocarcinomas for EGFR and KRAS mutation: report on initial experience and clinical utility at a single center. J Thorac Cardiovasc Surg. 2011;141(2):476-480. [CrossRef] [PubMed]
 
Warth A, Macher-Goeppinger S, Muley T, et al. Clonality of multifocal non-small cell lung cancer: implications for staging and therapy. Eur Respir J. 2012;39(6):1437-1442. [CrossRef] [PubMed]
 
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