Pharmacogenetics in lung cancer for the lay doctor

Lung cancer embodies the conundrum of cancer in general: why some patients with apparently similar tumors respond and others progress. In spite of a plethora of knowledge at the investigational level, in daily practice, the physician is still challenged by the lack both of prognostic markers to identify patients with a high risk of relapse and of predictive markers for customizing chemotherapy and targeted therapy. Multiple microarray studies have deciphered the important network of signaling pathways that can lead to the formation of metastasis, and we are not far from being able to predict the risk of metastasis at a particular site (bone, brain or others) according to specific gene profiles. Quantitative PCR has allowed the assessment of mRNA expression levels of key genes, identified mostly by transcriptome analysis. Growing evidence indicates that three-or five-gene signatures by quantitative PCR are highly predictive of metastasis and survival in early-stage non-small cell lung cancer, including stage IB, paving the way for the selection of high-risk patients for adjuvant chemotherapy and for the customization of treatment. A meaningful proportion of lung cancer patients are EGFR-driven, and abundant knowledge has enabled us to identify extensive networks of downstream signals that collapse when drug treatment is effective. Novel mechanisms of resistance to chemotherapy and targeted therapies can be useful for personalizing treatment and can lead to the implementation of novel targeted therapies.