Lung cancer is the most frequent invasive malignancy and the common cause of cancer death worldwide with an estimated 1.60 million new cases and 1.37 million deaths in 2008.1 Non small-cell lung cancer (NSCLC), the broad category that accounts for approximately 87% of all patients with lung cancer, usually presents at an advanced stage, where the treatment is essentially palliative. The survival improvement for unselected patients with metastatic NSCLC has been modest, with a large surveillance, epidemiology, and end results (SEER) study, from the periods 1990–1993 to 2002–2005, showing increased survivals at 1 and 2 years of 13.2% to 19.4% and 4.5% to 7.8%, respectively.2 More recently, however, there has been a significant improvement in the understanding of the biology of lung cancer, with the discovery of new targets and development of several drugs with novel mechanisms of action. This chapter reviews the current knowledge of cancer genomics, the use of molecular markers, and results from clinical trials that are changing the therapeutic landscape of NSCLC.
Genomics is defined as the study of the entire set of genetic information of a person, encoded in the structure of deoxyribonucleic acid (DNA). Cancer genomics is the study of DNA-associated abnormalities associated with the development of cancer. The DNA in normal cells is constantly damaged by environmental and normal cellular processes. Although the majority of the damage is repaired, a small fraction is converted into fixed mutations. Mutations may be broadly subdivided into germline and somatic. Whereas germline mutations are present in the fertilized egg, inherited from the parents and therefore present in all somatic cells, the somatic mutations are acquired after conception. Although somatic mutations are distributed throughout the genome, a subset of them occurs in key genes. These “driver mutations” are implicated in oncogenesis by allowing the malignant clone to expand more than the normal cells. In contrast, the “passenger mutations” are carried along during clonal expansion, do not contribute to cancer development, and are not associated with growth advantage.3,4
The majority of malignancies is sporadic and occurs as a consequence of the accumulation of genomic alterations that lead to dysregulation of protein-encoding genes. As normal cells evolve to a neoplastic state, they acquire several essential complementary capabilities including sustained proliferative signaling, resistance to apoptosis, evasion of growth suppressors, and induction of angiogenesis, invasion, and metastasis.5 Cancer cells, however, often are physiologically dependent or “addicted to” to the continued activity of specific oncogenes, and this dependency has been explored for drug discovery.6 The pivotal study of chronic myeloid leukemia that showed excellent response rates (RRs) and good tolerability for imatinib in patients who progressed after interferon therapy, validated the concept of targeting driver mutations and essentially started the era of targeted therapy in cancer treatment.7
Recent advances in DNA sequencing have permitted significant advances in cancer genomics. The ...