Clinical Information

Targeted cancer therapies are defined as antibody or small molecule drugs that block the growth and spread of cancer by interfering with specific cell molecules involved in tumor growth and progression. Multiple targeted therapies have been approved by the FDA for treatment of specific cancers. Molecular genetic profiling is often needed to identify targets amenable to targeted therapies and to minimize treatment costs and therapy-associated risks. Epidermal growth factor receptor (EGFR) protein is activated by the binding of specific ligands, resulting in activation of the RAS/MAPK pathway. Activation of this pathway induces a signaling cascade, ultimately leading to cell proliferation. Dysregulation of the RAS/MAPK pathway is a key factor in tumor progression for many solid tumors. Targeted therapies directed to tumors harboring activating mutations within the EGFR tyrosine kinase domain (exons 18-21) have demonstrated some success in treating a subset of patients with non-small cell lung cancer (NSCLC). As a result, the mutation status of EGFR can be a useful marker by which patients are selected for EGFR-targeted therapy.

Rearrangements of the anaplastic lymphoma kinase (ALK) locus are found in a subset of lung carcinomas (generally EGFR wildtype tumors) and their identification by fluorescence in situ hybridization (FISH) may guide important therapeutic decisions for the management of these tumors. The fusion of the echinoderm microtubule-associated protein-like 4 (EML4) gene with the ALK gene results from an inversion of chromosome band 2p23. The ALK-EML4 rearrangement has been identified in 3% to 5% of NSCLC with the majority occurring in adenocarcinoma and younger male patients who were light or nonsmokers. Recent studies have demonstrated that lung cancers harboring ALK rearrangements are resistant to EGFR tyrosine kinase inhibitors but may be highly sensitive to ALK inhibitors, like crizotinib (Xalkori). The drug crizotinib works by blocking certain kinases, including those produced by the abnormal ALK gene. Clinical studies have demonstrated that crizotinib treatment of patients with tumors exhibiting ALK rearrangements can halt tumor progression or result in tumor regression. The ALK/EML4 FISH assay is an FDA-approved companion diagnostic test for crizotinib, which was recently approved by the FDA to treat certain patients with late-stage (locally advanced or metastatic), non-small cell lung cancers that harbor ALK gene rearrangements. It is useful for the identification of patients with lung cancer who will benefit from crizotinib therapy.