Purpose: Reliable detection of drug-sensitive activating EGFR mutations is critical in the care of advanced non-small cell lung cancer (NSCLC), but such testing is commonly performed using a wide variety of platforms, many of which lack rigorous analytic validation.Experimental Design: A large pool of NSCLC cases was assayed with well-validated, hybrid capture-based comprehensive genomic profiling (CGP) at the request of the individual treating physicians in the course of clinical care for the purpose of making therapy decisions. From these, 400 cases harboring EGFR exon 19 deletions (Dex19) were identified, and available clinical history was reviewed.Results: Pathology reports were available for 250 consecutive cases with classical EGFR Dex19 (amino acids 743-754) and were reviewed to assess previous non-hybrid capture-based EGFR testing. Twelve of 71 (17%) cases with EGFR testing results available were negative by previous testing, including 8 of 46 (17%) cases for which the same biopsy was analyzed. Independently, five of six (83%) cases harboring C-helical EGFR Dex19 were previously negative. In a subset of these patients with available clinical outcome information, robust benefit from treatment with EGFR inhibitors was observed.Conclusions: CGP identifies drug-sensitive EGFR Dex19 in NSCLC cases that have undergone prior EGFR testing and returned negative results. Given the proven benefit in progression-free survival conferred by EGFR tyrosine kinase inhibitors in patients with these alterations, CGP should be considered in the initial presentation of advanced NSCLC and when previous testing for EGFR mutations or other driver alterations is negative.

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The recent discovery of relevant biomarkers has reshaped our approach to therapy selection for patients with non-small cell lung cancer.The unprecedented outcomes demonstrated with tyrosine kinase inhibitors in molecularly defined cohorts of patients has underscored the importance of genetic profiling in this disease. Despite published guidelines on biomarker testing, successful tumor genotyping faces significant hurdles at both academic and community-based practices. Oncologists are now faced with interpreting large-scale genomic data from multiple tumor types, possibly making it difficult to stay current with practice standards in lung cancer. In addition, physicians' lack of time, resources, and face-to-face opportunities can interfere with the multidisciplinary approach that is essential to delivery of care. Finally, several challenges exist in optimizing the amount and quality of tissue for molecular testing. Recognizing the importance of biomarker testing, a series of advisory boards were recently convened to address these hurdles and clarify best practices. We reviewed these challenges and established recommendations to help optimize tissue acquisition, processing, and testing within the framework of a multidisciplinary approach. The Oncologist 2015; 20:1175-1181 Implications for Practice: Although several professional societies have incorporated biomarker testing recommendations into clinical practice guidelines for the diagnosis and management of non-small cell lung cancer (NSCLC), health care providers still face considerable challenges when establishing and implementing these standards. Developing and instituting protocols to ensure that all appropriate patients are tested for molecular biomarkers requires communication among the various specialists involved in the care of patients with NSCLC. This report provides insights into key challenges and recommendations for molecular testing of patients with metastatic NSCLC, summarized from a multidisciplinary team of experts spanning academic, community, and integrated health systems.

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