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EGFR Expression and Mutational Analysis As a Predictive Test

Thoracic Oncology Program, Department of Surgery, University of California San Francisco, San Francisco, CA

To the Editor:

We read with great interest the article by Hirsch and colleagues on the molecular predictors of outcome with gefitinib in the Iressa Survival Evaluation in Lung Cancer (ISEL) study.¹ This study reported important information on the role of biomarkers in the initiation of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy for advanced stage lung cancer. Clinicians are currently faced with a multitude of clinical factors (never-smoking status, Asian ethnicity, female sex), histologic features (bronchioloalveolar carcinoma), and molecular markers (EGFR by immunohistochemistry [IHC], gene copy number, and mutational analysis) that can be used to identify the minority of patients with lung cancer who will have an objective response to erlotinib or gefitinib. In this study, the authors concluded that increased EGFR copy number predicted response to gefitinib. They also report a statistically significant association between EGFR expression by IHC and clinical response.

The work presented by the authors could have been even more useful for clinical decision making had EGFR analysis techniques been treated as a predictive test and had the authors reported the sensitivity and specificity of the test. Using data reported in the text, the sensitivity and specificity of IHC for objective response to gefitinib was 93% and 32%, with a positive predictive value (PPV) of 8% and negative predictive value (NPV) of 99%. The sensitivity and specificity of gene copy number was 79% and 73%, with a PPV of 16% and a NPV of 97%. The sensitivity and specificity of EGFR mutational analysis was 43% and 92% with a PPV of 38% and a NPV of 97%.

Mutational analysis has the best PPV, and all tests have similar NPV. Given this information, if the clinician has one test to order, it should be mutational analysis. An analysis of combinations of tests might be most useful for clinicians. Perhaps IHC, which is relatively inexpensive, should be the first test ordered. Patients who are negative by IHC should not be treated with an EGFR-TKI, while patients who are positive by IHC should go on to have either fluorescence in situ hybridization or mutational analysis. Likelihood ratio testing could be used to determine post-test probability of treatment response given clinical information, which increases the pretest probability of response to gefitinib, such as smoking status and Asian ethnicity. A decision-making analysis incorporating cost of testing, cost of treatment, and estimated cost of not treating patients with EGFR-TKIs would be very useful to aid lung cancer clinicians and patients in making treatment decisions.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: David M. Jablons, Genentech, Eli Lilly Research Funds: N/A Testimony: N/A Other: N/A

REFERENCE

1. Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al: Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. J Clin Oncol 24: 5034-5042, 2006[Abstract/Free Full Text]

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  Fred R. Hirsch, Marileila Varella-Garcia, Wilbur A. Franklin, Rafal Dziadziuszko, Paul A. Bunn, Jr, Claire Watkins, and Brian Holloway
  JCO 2007 25: 2144-2145 [Full Text]

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