Lung cancer is the second most common cancer and the leading cause of cancer-related deaths in the United States. Moreover, advanced non-small-cell lung cancer (NSCLC) is considered an incurable disease and current treatment approaches provide marginal improvement in overall survival at the expense of substantial morbidity and mortality, highlighting the need for new, less toxic treatment approaches. Tyrosine kinase inhibitors, such as erlotinib (Tarceva®), have been developed and approved as maintenance, second- and third-line treatment options in unselected advanced NSCLC patients (2, 15). However, subgroup analyses from the initial clinical trials consistently showed that patients with epidermal growth factor receptor (EGFR) mutations who received erlotinib had higher rates of response and better progression-free and overall survival, leading to clinical trials specifically focused on the use of tyrosine kinase inhibitors as first-line therapy in these patients. We examined the published literature on the analytic validity, clinical validity, and clinical utility of EGFR mutational testing in guiding first-line therapy use of erlotinib to treat advanced NSCLC and we briefly summarized the current lung cancer screening guidelines. The primary goal was to provide a basic overview of EGFR mutational testing and use of erlotinib as first-line therapy and identify gaps in knowledge and evidence that affect the recommendation and adoption of the test in advanced NSCLC treatment management strategies.
Testing patients with advanced non-small-cell lung cancer (NSCLC) for epidermal growth factor receptor ( EGFR ) mutation status may help determine who is more likely to respond to the tyrosine kinase inhibitor erlotinib. Recent data suggest that patients with EGFR mutations are more responsive to treatment with erlotinib and gefitinib than those without mutations, which may make it possible for doctors and patients to tailor therapy at diagnosis. Nevertheless, several uncertainties remain regarding EGFR , including: (1) the prevalence of this mutation among all patients with NSCLC; (2) the need for a second biopsy, given that testing for EGFR requires volumes of tumor that are often beyond that obtained for diagnosis; and (3) the optimal EGFR testing strategy (i.e., test all patients or confine testing to patients with correlated clinical characteristics. Those issues may strongly influence the effectiveness and cost-effectiveness of EGFR testing as a management strategy for patients with NSCLC.
EGFR mutation analysis detects acquired mutations in the EGFR gene in tumor specimens of patients with NSCLC. There are various polymerase chain reaction (PCR)-methods that can detect the mutations, as well as through the use of direct sequencing, which is currently considered the gold standard.
Public Health Importance
Lung cancer is the second most commonly diagnosed cancer in the United States, with NSCLC accounting for approximately 80% of all lung cancer cases. Lung cancer is the leading cause of cancer-related deaths in both men and women in the U.S.  . Current first-line therapy of advanced NSCLC is platinum-based doublet chemotherapy and is usually limited to four to six cycles. Tyrosine kinase inhibitors, such as erlotinib, have been developed and approved for use in maintenance (i.e., after platinum-based first-line treatment without progression) and second-line treatment of NSCLC   . Approximately 10-20% of NSCLC tumors have a somatic mutation in EGFR , but prevalence varies among patients with different phenotypes (e.g., women, Asians, non-smokers versus smokers, cancer histology).
Published Reviews, Recommendations and Guidelines
Systematic evidence reviews
Recommendations by independent groupNone identified.
Guidelines by professional groups (in order by year of publication)
A summary of all mentioned recommendations and guidelines appear in Table 1 below.
Table 1 . Recommendations by Organization1 as to the Utility of EGFR Mutation Testing for Erlotinib Therapy in NSCLC.
|Treatment: First-line||Treatment: Second-line|
|ASCO||Yes||Recommended in a subset of patients||Yes|
|NCCN||Yes||Recommended in a subset of patients||Yes|
|European Medicines Agency 2||Yes||No||Yes|
|Italian Association of Thoracic Oncology||Yes||Recommended in a subset of patients||Recommended in subset of patients|
Analytic Validity : test accuracy and reliability in detection of EGFR mutations using PCR-based methods (analytic sensitivity and specificity).
Clinical Validity : strength of relationship between test result and patient outcomes (predictive and prognostic value).
Clinical Utility : net benefit of test in improving health outcomes.
As noted earlier, lung cancer is the leading cause of cancer-related deaths, with an estimated 157,300 deaths in the US in 2010  . Moreover, advanced NSCLC is considered an incurable disease and current treatment approaches provide marginal improvement in overall survival at the expense of substantial morbidity and mortality, highlighting the need for new, less toxic treatment approaches.
Tyrosine kinase inhibitors, such as erlotinib, have been developed and approved as maintenance, second- and third-line treatment options in unselected advanced NSCLC patients   . However, subgroup analyses from the initial clinical trials consistently showed that patients with EGFR mutations and correlated clinical and histological characteristics who received erlotinib had higher rates of response and better progression-free and overall survival, leading to clinical trials specifically focused on the use of tyrosine kinase inhibitors as first-line therapy in these patients.
Overall, the available evidence indicates that upfront EGFR mutation testing for patients with advanced NSCLC can help guide treatment decisions (i.e., EGFR mutation status can identify NSCLC patients who are more likely to respond to erlotinib, whereas those with wild-type tumors are unlikely to respond to erlotinib and alternative treatment should be considered). However, there are remaining gaps in the evidence base that make strong conclusions about the clinical utility premature: (1) there are currently no data from prospective randomized clinical trials comparing EGFR mutation testing to usual care;(2) there is a lack of data as to whether EGFR-TKI’s provide an overall survival advantage when compared with platinum-based treatment in patients with EGFR mutations; and (3) the cost-effectiveness of erlotinib as first-line or maintenance therapy, considering the high cost of a monthly supply 4 , has not been adequately assessed.
Last updated: June 13, 2011
The authors would like to thank Dr. Muin Khoury of the Centers for Disease Control and Prevention and Dr. David Veenstra of the University of Washington for their invaluable input and guidance on the content. The authors also acknowledge the contributions of Ms. Camillo Benedicto and Ms. Kelly Bennett of the National Cancer Institute.
This study was funded by CANCERGEN (Comparative Effective Research in Cancer Genomics) through the American Recovery and Reinvestment Act of 2009 by the National Cancer Institute, National Institutes of Health under Agency Award # RC2 CA148570 (Principle Investigator: Scott D. Ramsey).
Josh Carlson has been a consultant to Genentech, Inc. and Biodesix, Inc. All other authors have declared no competing interests exist.
The findings and conclusions are those of the authors and do not necessarily represent the views of the National Institutes of Health (NIH). The information provided in this manuscript does not constitute an endorsement of EGFR mutation testing by NIH nor the Department of Health and Human Services of the U.S. government.
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