Importance of Molecular Features of Non–Small Cell Lung Cancer for Choice of Treatment

Abstract

Lung cancer is the leading cause of cancer-related deaths in the United States. Approximately 85% of lung cancer is categorized as non-small cell lung cancer, and traditionally, non-small cell lung cancer has been treated with surgery, radiation, and chemotherapy. Targeted agents that inhibit the epidermal growth factor receptor pathway have been developed and integrated into the treatment regimens in non-small cell lung cancer. Currently, approved epidermal growth factor receptor inhibitors include the tyrosine kinase inhibitors erlotinib and gefitinib. Molecular determinants, such as epidermal growth factor receptor-activating mutations, have been associated with response to epidermal growth factor receptor tyrosine kinase inhibitors and may be used to guide treatment choices in patients with non-small cell lung cancer. Thus, treatment choice for patients with non-small cell lung cancer depends on molecular features of tumors; however, improved techniques are required to increase the specificity and efficiency of molecular profiling so that these methods can be incorporated into routine clinical practice. This review provides an overview of how genetic analysis is currently used to direct treatment choices in non-small cell lung cancer. Lung cancer is the second most common malignancy (surpassed in incidence only by nonmelanoma skin cancer) and the leading cause of cancer-related death in the United States, with an estimated 219,440 new diagnoses and 159,390 deaths in 2009. 1,2 Between 1996 and 2004, the 5-year survival rate was 15% for patients with lung cancer across all stages of disease-ranging from 2.8% for patients with distant metastases to nearly 50% for those presenting with local disease. 1 Curative-intent surgery is the preferred treatment modality but has limited applicability, given the typical presentation at an unresectable locally ad- Given the clinical burden of lung cancer, with nonsmall cell lung cancer (NSCLC) accounting for approximately 85% of cases, it has become a major platform for the clinical development of biological-targeting agents. To date, targeted agents that have been granted US Food and Drug Administration approval for treating advanced NSCLC are the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab (Avastin; Genentech, South San Francisco, CA), indicated as an adjunct to first-line chemotherapy with paclitaxel/carboplatin [Avastin (bevacizumab) package insert. Genentech, Inc., South San Francisco, CA], and the reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib in chemotherapypretreated patients (Figure 1) [Iressa (gefitinib tablets) package insert. AstraZeneca Pharmaceuticals LP, Wilmington, DE; Tarceva (erlotinib tablets) package insert. Genentech, Inc., South San Francisco, CA]. Erlotinib (Tarceva; Genentech) was initially approved by the US Food and Drug Administration in 2004 for patients with advanced NSCLC failing one chemotherapy regimen, a setting in which the objective response ra...

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