Lung Cancer and EGFR
A substantial percentage of lung cancers express cell surface epidermal growth factor receptors (EGFRs). As activation of these cell surface receptors has been shown in experimental systems to result in the growth and progression of the malignancy, there have been considerable pre-clinical and clinical research efforts directed toward the development of effective inhibitors of the EGFR.
Initial studies with small molecules designed to inhibit the tyrosine kinase (TK) domain of the EGFR, such as gefitinib (Iressa) and erlotinib (Tarceva), demonstrated biologic and clinical activity in only a relatively limited subset of lung cancers.1 Further investigation demonstrated that the highest response rates were seen in patients with somatic mutations within the EGFR-TK domain, 90% of which involve a relatively small number of amino acids within a specific region (exons 19 and 21).2
Although the reasons for the association remain unclear, these mutations are more commonly observed in patients with the following clinical characteristics: (a) adenocarcinoma histology (particularly bronchioloalveolar subtype); (b) no prior history of smoking; (c) female sex; and (d) Asian ethnicity.
Clinical Implications of the Genetic Mutation
The majority of evidence supporting the clinical utility of the evaluation for the presence of mutations in EGFR has been provided from retrospective examinations of previously reported clinical experiences.
Results from a phase III trial evaluating the EGFR-TKI gefitinib demonstrated that only approximately 10% of patients responded well to the therapy, and no survival benefit was conferred.3 Follow-up analysis of tissue samples identified mutations in the TK domain of the EGFR in 8 of 9 responders whereas no mutations were seen in seven patients who did not respond to gefitinib therapy.2 Neverthless, the lack of a significant clinical benefit led to changes in the approval status of gefitinib in the United States; it is now only available for patients who have already demonstrated response to the drug.
Phase III trials with erlotinib demonstrated small but significant improvements in overall survival (6.7 months vs. 4.7 months; P < 0.001) and in progression-free survival (2.2 months vs. 1.8 months; P < 0.001) compared with placebo.4 However, review of 325 tumor-biopsy samples demonstrated that although EGFR expression was associated with response on univariate analysis (P = 0.03), multivariate analysis demonstrated that neither status of EGFR expression, the number of EGFR copies, nor the presence of an EGFR mutation independently predicted survival benefit .5
Based on data from these and other trials, NCCN Clinical Practice Guidelines note that patients with EGFR exon 19 deletion or exon 21 L858R mutation have significantly better response to EGFR-TKIs. However, no formal recommendation is made for altering therapy based on mutation status.6 Additional studies are required before mutation analysis can be considered mandatory or strongly recommended prior to the administration of an EGFR-TKI to a patient with advanced or metastatic non-small cell lung cancer.1,7
Nevertheless, prior to deciding whether to administer an EGFR-TKI to a patient with advanced or metastatic non-small cell lung cancer, it is reasonable to consider having the tumor specimen examined for the presence of mutations within the EGFR-TK domain. But it is also appropriate to note that the decision to follow this course of action will include other considerations, such as: (a) the time available before the management decision must be made; (b) third-party payment for the test; (c) the relative toxicities of alternative therapeutic options in this specific patient; (d) the availability and quality of a clinical laboratory that will be performing the test.
Testing for the Genetic Mutation
Testing for mutations in exons 18 through 21 in the EGFR-TK domain is conducted via PCR analysis of tumor samples (formalin-fixed, paraffin-embedded, unstained slides, or fresh snap frozen biopsy) or via MALDI-TOF mass spectrometry of pretreatment serum samples.
The clinical significance of EGFR gene amplification by fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC) remains unclear.