Molecular profiling in lung cancer specimens leads to targeted therapeutic options in patients with non-small cell lung carcinoma (NSCLC)

After a period of stagnation in lung cancer therapeutics, a remarkable molecular revolution occurred in mid-2000's. Molecular characterization of lung carcinoma coincided with the development, and utilization of targeted therapeutic agents. The discovery of EGFR led the movement: after some false starts (INTACT1 and 2), small molecule tyrosine kinase inhibitors gefitinib and then erlotinib gained FDA-approval. Basic science hypotheses of oncogene addition and the discovery of activating mutations has rapidly transitioned from bench to bedside, resulting in a recommendation for up-front testing of lung cancer patients, and the use of targeted agents as first line therapy. Subsequent drug-target pairs followed, such as crizotinib-ALK-EML rearrangements, and in this case the clinical use approval was followed within days by a separate companion diagnostic, underscoring the need for rethinking of the regulatory review and approval paradigm. At this time, a queue of oncogene targets is forming, and inhibitors are being tested in clinical trials with some success: ROS1, RET, C-Met, and BRAF are among them, although others like KRAS remain difficult to target effectively. Regardless of the molecular target, lesional tissue is required for any analysis, and in this process the diagnosis by a pathologist remains the primary step. The challenge arises as the low morbidity means of tissue procurement result in ever smaller amounts of material, while the numbers and variety of assay platforms necessary to match drugs to targets increases. Given this paradigm only a multiplexed approach is feasible, which consequently enforces a common assay platform. Mutational profiling, such as SNaPshot, which captures all known abnormalities should find its way into regular diagnostic practice, and be included in the planning of all lung cancer trials involving new targeted agents.