Non-small-cell lung cancers: a heterogeneous set of diseases

Abstract

Next-generation sequencing and other high-throughput analyses have begun to show the many different molecular and genetic subsets of non-small-cell lung cancer (NSCLC) and have drastically altered the clinical evaluation and treatment of patients during the past decade. The pathological features and treatment response of NSCLC are affected by genetic and epigenetic profiles, as well as by the cellular origins of the tumours. Target-specific small-molecule inhibitors, such as epidermal growth factor receptor (EGFR) and echinoderm microtubule-associated protein-like 4 (EML4)–anaplastic lymphoma kinase (ALK) inhibitors, have achieved much greater treatment response and survival advantage compared with conventional chemotherapies. However, the treatment response is often short-lived and survival remains limited. Cellular heterogeneity within the tumour milieu influences tumorigenesis, tumour progression and treatment response. The main components of this dynamic microenvironment include vasculature, immune cells, fibroblasts and tumour cell subpopulations. Immune therapies that aim to rejuvenate antitumour immune responses have shown success in early clinical trials. The combination of immunotherapy with other targeted therapies is anticipated in the near future. Data from the bench on criteria for patient stratification and treatment selection are increasingly being translated into clinical practice.