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This brief report summarizes Dr. Pao's talk at the 54th Annual Meeting of the Thomas L. Petty Aspen Lung Conference, in Aspen, Colorado, on June 11, 2011. In this talk, Dr. Pao discussed three main topics: (1) DETECT (DNA Evaluation of Tumors for Enhanced Cancer Treatment), (2) MyCancerGenome.org (web-based decision support), and (3) DIRECT (DNA-mutation Inventory to Refine and Enhance Cancer Treatment).
Keywords: lungcancer;drivermutations;targetedtherapy;MyCancerGenome
Lung cancer causes the most cancer-related deaths in the United States and worldwide (1). Five-year overall survival rates are poor, and the maximal benefit of existing chemotherapy has reached a plateau (2).
In the past, the disease has been treated according to histologic criteria (small-cell lung cancer versus non-small-cell lung cancer [NSCLC) (3). However, over the past 40 years, investigators have discovered several key biological principles. First, cancers arise from an accumulation of gain-of-function mutations in oncogenes and loss-of-function mutations in tumor suppressor genes (4). Second, mutations that occur in signaling proteins, most notably kinases, can leave them "stuck" in the "on" position. Finally, despite the presence of multiple mutations in cancer cells, turning "off" a specific "driver" mutant kinase with small molecule inhibitors can be highly effective antitumor therapy (5). This phenomenon has been called "oncogene addiction," conveying the notion that cancer cells have become so "addicted" to signaling from a mutant oncoprotein that they die when the signaling is inhibited (6). Oncogene addiction underlies the move toward rational treatment of cancers with targeted therapies according to the genetic makeup of individual tumors.
NSCLCs harbor many driver mutations (7). Adenocarcinomas can be classified according to "driver mutations" in multiple genes, including EGFR, HER2, KRAS, BRAF, PIK3CA, AKT1, MEK1, ROS1, and ALK. Most of these mutations are mutually exclusive, so a tumor with a mutation in one gene rarely harbors a mutation in another. Mutations within individual genes can be associated with primary drug sensitivity, primary drug resistance, or secondary drug resistance.
Multiple studies have shown that a genotype-driven approach to lung cancer treatment has benefits over the one-size-fits-all approach. This is best exemplified in metastatic EGFR mutant lung cancer. Patients whose tumors harbor EGFR mutations have improved responses rates (z70%), prolonged progressionfree survival, and improved quality of life on an EGFR tyrosine kinase inhibitor versus chemotherapy. Conversely, patients whose...