0
Point/Counterpoint Editorials |

Point: Should Epidermal Growth Factor Receptor Mutations Be Routinely Tested for in Patients With Lung Cancer? YesTest for EGFR Mutations? Yes FREE TO VIEW

Daniel H. Sterman, MD, FCCP
Author and Funding Information

From the Section of Interventional Pulmonology and Thoracic Oncology, Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Medical Center.

Correspondence to: Daniel H. Sterman, MD, FCCP, Section of Interventional Pulmonology and Thoracic Oncology, Pulmonary, Allergy, and Critical Care Division, 833 W Gates Bldg, University of Pennsylvania Medical Center, Philadelphia, PA 19104-4283; e-mail: daniel.sterman@uphs.upenn.edu


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):597-600. doi:10.1378/chest.12-2546
Text Size: A A A
Published online

Lung cancer is the most common cause of cancer-related death in the United States, with >160,000 new cases per year.1,2 Over the past several years, there have been remarkable developments in the diagnosis, staging, and treatment of lung cancer, including chest CT scan screening for high-risk individuals with proven survival benefit,3 minimally invasive surgical approaches,4 and endobronchial ultrasound (EBUS) as the primary means of mediastinal staging.5 All of these innovations combined will have a dramatic impact on the quality and quantity of life in lung cancer victims.

More than 100 years ago, as bronchogenic carcinoma was first described, the disease was subdivided in pathologic terms based on the cellular appearance under light microscopy into “small cell,” and “non-small cell” carcinomas.6 These morphologic divisions were ultimately verified by the development of immunohistochemical techniques that allowed selective staining of tumor cells with specific antibodies that bound to cell-surface molecules and provided a characteristic pattern of expression. These morphologic and immunohistochemical techniques allowed for the subdivision of non-small cell lung cancers (NSCLCs) into a variety of major subtypes, including adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.1,7

There has, however, been no greater innovation in the past 20 years of lung cancer research than the identification of specific driving mutations that cause the development, proliferation, and metastasis of lung cancer cells.8 One such pathway that has been investigated has been the epidermal growth factor pathway, which has been found to be activated in a significant percentage of lung cancers, particularly adenocarcinomas. The epidermal growth factor receptor (EGFR) (ErbB-1; HER1 in humans) is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands. Mutations that lead to EGFR overexpression or overactivity have been associated with a number of cancers, including lung cancer. The EGFR molecule can be targeted for inhibition by anti-EGFR antibodies (cetuximab) or specific tyrosine kinase inhibitors (TKIs): erlotinib or gefitinib.9

Approximately 10 years ago, investigators at Massachusetts General Hospital, the Dana-Farber Cancer Institute, and the Memorial Sloan-Kettering Cancer Center identified certain populations of patients with lung adenocarcinoma who were exquisitely sensitive to a novel class of drug that had been recently introduced into clinical practice—the EGFR-TKI.10,11 Initially, those patients with dramatic responses to EGFR-TKIs were identified on the basis of epidemiologic characteristics: They were predominantly female nonsmokers, often of Asian origin.12 Ultimately, however, the majority of these responders were found to have specific mutations in the EGFR-tyrosine kinase domain, most commonly in exons 19 and 21.13 Commercial and investigational EGFR-TKIs (gefitinib and erlotinib) were—not surprisingly—shown to bind specifically to these sites of mutation and to inhibit the function of the EGFR, thus directly inhibiting tumor cell growth and promoting tumor cell apoptosis.

Of great importance has been the development of methods to assay for EGFR mutations on small cellular specimens obtained at the time of EBUS-guided fine needle aspiration of primary lung tumors and mediastinal masses. In a report in CHEST in 2007, for example, Nakajima and colleagues14 were able to demonstrate detection of point mutations at or near the hot-spot mutation of EGFR exon 21 on tumor DNA specimens obtained from EBUS-transbronchial needle aspiration of mediastinal lymph nodes. Nakajima and colleagues14 were also able to document a successful treatment of the adenocarcinoma carrying the EGFR mutation with gefitinib therapy, which was initiated only on the basis of the molecular findings on EBUS-transbronchial needle aspiration.

There have been several clinical trials over the past 10 years that have specifically tried to assess the role of novel targeted therapies, such as gefitinib and erlotinib, vs that of traditional cytotoxic chemotherapy agents in NSCLC. On the basis of these studies and others, gefitinib and erlotinib were approved for use in patients with lung cancer by regulatory agencies worldwide. Erlotinib, for example, was approved in the United States in 2004 for treatment of NSCLC after failure of at least one prior chemotherapy regimen. In a review in 2007, Sequist and colleagues15 described the improvement in overall survival for those patients with lung cancer who harbored an EGFR mutation compared with those with wild-type EGFR, even after adjusting for age, sex, and stage at diagnosis.

In the Iressa Pan-Asia Study (IPASS) trial, patients with advanced lung cancer were randomized to receive either gefitinib or standard combination cytotoxic chemotherapy with no a priori testing for EGFR mutations but with inclusion/exclusion criteria that favored patients likely to respond to EGFR-TKIs (female, Asian, nonsmoking patient populations).16 A cohort of those patients randomized in the trial had their primary tumors analyzed post hoc, and those patients who were found to have activating EGFR mutations had significantly prolonged progression-free survival (PFS) compared with those patients with EGFR mutations who were treated with chemotherapy. Contrastingly, those patients who were mutation negative had much worse PFS when treated with gefitinib compared with those who received chemotherapy.16-18

The Optimal Trial was the first randomized, prospective trial of erlotinib vs platinum-based combination chemotherapy in patients with EGFR mutation-positive NSCLC.19 In this study, marked improvements in PFS were seen in the group receiving erlotinib (hazard ratio, 0.16; 95% CI, 0.10-0.26, with log rank P value of .0001). The results of this landmark clinical trial suggested that all Asian patients with advanced NSCLC should be screened for EGFR mutations at diagnosis, irrespective of their histologic subtype, to inform decisions about optimum first-line treatment and that patients whose tumors have confirmed EGFR-activating mutations should receive erlotinib as first-line therapy.19

The European Tarceva vs Chemotherapy (EURTAC) phase 3 randomized trial was the first randomized trial in a non-Asian population of erlotinib vs chemotherapy in chemotherapy-naive patients with advanced NSCLC with EGFR-activating mutations.20 The study results confirmed significant benefit in PFS of first-line erlotinib over standard chemotherapy in this population. The SATURN (Sequential Tarceva in Unresectable NSCLC) study was a double-blinded randomized clinical trial of maintenance erlotinib vs placebo in patients with nonprogressive disease after first-line platinum-based chemotherapy,21 with the finding that patients with NSCLC with activating mutations in EGFR had a 90% reduction in the risk of death or disease progression when treated with erlotinib vs placebo (hazard ratio, 0.10; P <.001).21 Based on these and other phase 3 clinical trials, in 2011 the American Society of Clinical Oncology published a Provisional Clinical Opinion that “patients with NSCLC who are being considered for first-line therapy with an EGFR-TKI should have their tumor tested for EGFR mutations to determine whether an EGFR-TKI or chemotherapy is the appropriate first-line therapy.”22

So, why routinely test for EGFR mutations in patients with lung cancer? The data are clear that EGFR mutations can be easily detected on minimally invasive testing of patients with lung cancer and that the presence of mutations can delineate those who are likely to benefit from therapy with EGFR-TKIs. Results from large phase 3 trials have demonstrated that the best treatment options for patients with advanced lung cancer harboring activating EGFR mutations are EGFR TKIs. Identification of those patients with lung cancer who have EGFR mutations in advance can not only determine which patients will benefit from EGFR TKIs but also identify those patients who will not benefit from standard cytotoxic chemotherapy and also spare them the potential for complications from these drugs. In particular, paclitaxel and gemcitabine have been associated with drug-related hypersensitivity pneumonitis that would be poorly tolerated in the population of patients with advanced NSCLC and marginal pulmonary function. Preliminary data from Memorial Sloan-Kettering Cancer Center and Massachusetts General Hospital suggest that adjuvant EGFR-TKI therapy may also be of benefit in the adjuvant setting to those surgically resected patients who harbor an activating EGFR mutation.

Perhaps most importantly, given the increasing focus on the high costs of cancer care, a recent study from Singapore by de Lima Lopes and colleagues23 demonstrated that high-sensitivity analysis for EGFR mutations and first-line treatment with gefitinib is cost effective in their population of patients with lung cancer when compared with standard practice without testing, first-line treatment with chemotherapy, and second-line treatment with gefitinib. This finding was driven primarily by the savings generated by not providing gefitinib to those patients who are much less likely to derive a clinical benefit because they do not harbor activating EGFR mutations.23

Despite the clearly delineated benefits, I do not advocate testing for EGFR mutations in all patients with lung cancer, as there are subtypes, such as small cell lung cancer and squamous cell carcinoma (SCCa), for which EGFR mutations play a minimal role. Interestingly, data from the Optimal Trial suggest that these benefits of EGFR-TKI therapy are not limited to women and those with adenocarcinomas, as there were patients with SCCa who also demonstrated improved survival. For this reason, the authors recommended that all patients with NSCLC should be tested for EGFR mutations (at least among Chinese populations).19 Other Chinese investigators have also shown that a small subset of patients with SCCa of the lung also harbor EGFR mutations, although the preponderance of those with mutations had adenocarcinomas.24,25 There have even been published reports of patients with small cell lung cancer harboring EGFR mutations, although these may well have been mixed tumors with concomitant adenocarcinoma or SCCa elements.26

Given the available data in the medical literature, I posit that the standard of care should be for routine testing for EGFR mutations in all patients with NSCLC of nonsquamous histology, with strong consideration for EGFR mutation testing in all patients with NSCLC (including those with SCCa) in Asian populations as well as in those Western patients with persistent disease status post first-line platinum-based chemotherapy. This will prove to be a cost-effective and less toxic approach to the treatment of lung cancer and will be the model for personalized therapy of all malignancies in the future.

Abbreviations

EBUS

endobronchial ultrasound

EGFR

epidermal growth factor receptor

NSCLC

non-small cell lung cancer

PFS

progression-free survival

SCCa

squamous cell carcinoma

TKI

tyrosine kinase inhibitor

Litzky LA. The pathology of non–small cell lung carcinoma.. In:Fishman AP, Elias JA, Fishman JA, Grippi MA, Senior RM, Pack AI., eds. Fishman’s Pulmonary Diseases and Disorders.4th ed. New York: McGraw-Hill; 2008:1831-1850.
 
U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999–2008 Incidence and Mortality Web-based Report. Atlanta, GA: Department of Health and Human Services, Centers for Disease Control and Prevention, and National Cancer Institute; 2012.
 
Aberle DR, Adams AM, Berg CD, et al; National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5):395-409. [CrossRef] [PubMed]
 
Andrade RS, Maddaus MA. Thoracoscopic lobectomy for stage I non-small cell lung cancer. Semin Thorac Cardiovasc Surg. 2010;22(1):14-21. [CrossRef] [PubMed]
 
Herth FJ, Eberhardt R, Vilmann P, Krasnik M, Ernst A. Real-time endobronchial ultrasound guided transbronchial needle aspiration for sampling mediastinal lymph nodes. Thorax. 2006;61(9):795-798. [CrossRef] [PubMed]
 
Spiro SG, Silvestri GA. One hundred years of lung cancer. Am J Respir Crit Care Med. 2005;172(5):523-529. [CrossRef] [PubMed]
 
Dubinski W, Leighl NB, Tsao MS, Hwang DM. Ancillary testing in lung cancer diagnosis. Pulm Med. 2012;2012:249082. [PubMed]
 
Strausberg RL, Simpson AJG, Old LJ, Riggins GJ. Oncogenomics and the development of new cancer therapies. Nature. 2004;429(6990):469-474. [CrossRef] [PubMed]
 
Herbst RS, Fukuoka M, Baselga J. Gefitinib—a novel targeted approach to treating cancer. Nat Rev Cancer. 2004;4(12):956-965. [CrossRef] [PubMed]
 
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(21):2129-2139. [CrossRef] [PubMed]
 
Paez JG, Jänne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497-1500. [CrossRef] [PubMed]
 
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(36):13306-13311. [CrossRef] [PubMed]
 
Sequist LV, Bell DW, Lynch TJ, Haber DA. Molecular predictors of response to epidermal growth factor receptor antagonists in non-small-cell lung cancer. J Clin Oncol. 2007;25(5):587-595. [CrossRef] [PubMed]
 
Nakajima T, Yasufuku K, Suzuki M, et al. Assessment of epidermal growth factor receptor mutation by endobronchial ultrasound-guided transbronchial needle aspiration. Chest. 2007;132(2):597-602. [CrossRef] [PubMed]
 
Sequist LV, Joshi VA, Jänne PA, et al. Response to treatment and survival of patients with non-small cell lung cancer undergoing somatic EGFR mutation testing. Oncologist. 2007;12(1):90-98. [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]
 
Mitsudomi T, Morita S, Yatabe Y, et al; West Japan Oncology Group. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11(2):121-128. [CrossRef] [PubMed]
 
Maemondo M, Inoue A, Kobayashi K, et al; North-East Japan Study Group. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362(25):2380-2388. [CrossRef] [PubMed]
 
Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12(8):735-742. [CrossRef] [PubMed]
 
Rosell R, Carcereny E, Gervais R, et al; Spanish Lung Cancer Group in collaboration with Groupe Français de Pneumo-Cancérologie and Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239-246. [CrossRef] [PubMed]
 
Brugger W, Triller N, Blasinska-Morawiec M, et al. Prospective molecular marker analyses of EGFR and KRAS from a randomized, placebo-controlled study of erlotinib maintenance therapy in advanced non-small-cell lung cancer. J Clin Oncol. 2011;29(31):4113-4120. [CrossRef] [PubMed]
 
Keedy VL, Temin S, Somerfield MR, Beasley MB, Johnson DH, McShane LM, Milton DT, Strawn JR, Wakelee HA, Giaccone G. 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]
 
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]
 
Tseng JS, Yang TY, Chen KC, Hsu KH, Chen HY, Chang GC. Retrospective study of erlotinib in patients with advanced squamous lung cancer. Lung Cancer. 2012;77(1):128-133. [CrossRef] [PubMed]
 
Huang YS, Yang JJ, Zhang XC, et al. Impact of smoking status and pathologic type on epidermal growth factor receptor mutations in lung cancer. Chin Med J (Engl). 2011;124(16):2457-2460. [PubMed]
 
Lu HY, Sun WY, Chen B, et al. Epidermal growth factor receptor mutations in small cell lung cancer patients who received surgical resection in China. Neoplasma. 2012;59(1):100-104. [CrossRef] [PubMed]
 

Figures

Tables

References

Litzky LA. The pathology of non–small cell lung carcinoma.. In:Fishman AP, Elias JA, Fishman JA, Grippi MA, Senior RM, Pack AI., eds. Fishman’s Pulmonary Diseases and Disorders.4th ed. New York: McGraw-Hill; 2008:1831-1850.
 
U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999–2008 Incidence and Mortality Web-based Report. Atlanta, GA: Department of Health and Human Services, Centers for Disease Control and Prevention, and National Cancer Institute; 2012.
 
Aberle DR, Adams AM, Berg CD, et al; National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5):395-409. [CrossRef] [PubMed]
 
Andrade RS, Maddaus MA. Thoracoscopic lobectomy for stage I non-small cell lung cancer. Semin Thorac Cardiovasc Surg. 2010;22(1):14-21. [CrossRef] [PubMed]
 
Herth FJ, Eberhardt R, Vilmann P, Krasnik M, Ernst A. Real-time endobronchial ultrasound guided transbronchial needle aspiration for sampling mediastinal lymph nodes. Thorax. 2006;61(9):795-798. [CrossRef] [PubMed]
 
Spiro SG, Silvestri GA. One hundred years of lung cancer. Am J Respir Crit Care Med. 2005;172(5):523-529. [CrossRef] [PubMed]
 
Dubinski W, Leighl NB, Tsao MS, Hwang DM. Ancillary testing in lung cancer diagnosis. Pulm Med. 2012;2012:249082. [PubMed]
 
Strausberg RL, Simpson AJG, Old LJ, Riggins GJ. Oncogenomics and the development of new cancer therapies. Nature. 2004;429(6990):469-474. [CrossRef] [PubMed]
 
Herbst RS, Fukuoka M, Baselga J. Gefitinib—a novel targeted approach to treating cancer. Nat Rev Cancer. 2004;4(12):956-965. [CrossRef] [PubMed]
 
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(21):2129-2139. [CrossRef] [PubMed]
 
Paez JG, Jänne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497-1500. [CrossRef] [PubMed]
 
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(36):13306-13311. [CrossRef] [PubMed]
 
Sequist LV, Bell DW, Lynch TJ, Haber DA. Molecular predictors of response to epidermal growth factor receptor antagonists in non-small-cell lung cancer. J Clin Oncol. 2007;25(5):587-595. [CrossRef] [PubMed]
 
Nakajima T, Yasufuku K, Suzuki M, et al. Assessment of epidermal growth factor receptor mutation by endobronchial ultrasound-guided transbronchial needle aspiration. Chest. 2007;132(2):597-602. [CrossRef] [PubMed]
 
Sequist LV, Joshi VA, Jänne PA, et al. Response to treatment and survival of patients with non-small cell lung cancer undergoing somatic EGFR mutation testing. Oncologist. 2007;12(1):90-98. [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]
 
Mitsudomi T, Morita S, Yatabe Y, et al; West Japan Oncology Group. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11(2):121-128. [CrossRef] [PubMed]
 
Maemondo M, Inoue A, Kobayashi K, et al; North-East Japan Study Group. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362(25):2380-2388. [CrossRef] [PubMed]
 
Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12(8):735-742. [CrossRef] [PubMed]
 
Rosell R, Carcereny E, Gervais R, et al; Spanish Lung Cancer Group in collaboration with Groupe Français de Pneumo-Cancérologie and Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239-246. [CrossRef] [PubMed]
 
Brugger W, Triller N, Blasinska-Morawiec M, et al. Prospective molecular marker analyses of EGFR and KRAS from a randomized, placebo-controlled study of erlotinib maintenance therapy in advanced non-small-cell lung cancer. J Clin Oncol. 2011;29(31):4113-4120. [CrossRef] [PubMed]
 
Keedy VL, Temin S, Somerfield MR, Beasley MB, Johnson DH, McShane LM, Milton DT, Strawn JR, Wakelee HA, Giaccone G. 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]
 
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]
 
Tseng JS, Yang TY, Chen KC, Hsu KH, Chen HY, Chang GC. Retrospective study of erlotinib in patients with advanced squamous lung cancer. Lung Cancer. 2012;77(1):128-133. [CrossRef] [PubMed]
 
Huang YS, Yang JJ, Zhang XC, et al. Impact of smoking status and pathologic type on epidermal growth factor receptor mutations in lung cancer. Chin Med J (Engl). 2011;124(16):2457-2460. [PubMed]
 
Lu HY, Sun WY, Chen B, et al. Epidermal growth factor receptor mutations in small cell lung cancer patients who received surgical resection in China. Neoplasma. 2012;59(1):100-104. [CrossRef] [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

CHEST Journal Articles
CHEST Collections
PubMed Articles
Guidelines
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543