Emerging Mutations in Lung Cancer and Other Solid Tumors

Published: Tuesday, Jul 31, 2018
lung cancer
Advances within the field of oncogenetics over the past several decades have ushered in a new stage in cancer treatment. Continued discoveries in the realm of gene fusions coupled with innovations in detection technology have since fueled development of targeted therapies. Data have increasingly shown the therapeutic potential of the neurotrophic tyrosine receptor kinase (NTRK) gene mutation as a target for inhibition. Preclinical and clinical studies of recently developed NTRK inhibitors have demonstrated robust response in NTRK-dependent tumors. Additionally, NTRK inhibitors have demonstrated activity in inhibiting anaplastic lymphoma kinase- (ALK) and proto-oncogene receptor kinase- (ROS1) dependent tumors. This supplement chronicles the evolving role of gene mutations within the cancer treatment spectrum, from discoveries in tumor biology and detection technologies, to the development targeted therapies and the clinical impact of pivotal trial data.

Tumor Biology and Treatment Approaches:

Historical Perspective and New Innovations

Decisions regarding cancer therapy have historically been based largely on histologic considerations. For example, lung cancers have typically been categorized into small-cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC) types, the latter of which is then further subdivided into squamous-cell carcinoma, large-cell carcinoma, and adenocarcinoma.1 In the past, platinum-based doublet chemotherapy was the standard treatment for patients with advanced NSCLC; efficacy was limited.1 However, after a study demonstrated better response to pemetrexed than gemcitabine among patients with nonsquamous NSCLC,1 researchers began evaluating whether genetic variations of cancer have a role in treatment selection.

The treatment of lung cancer has become further refined with the emergence of next-generation sequencing (NGS) techniques, along with the availability of verified in-clinic assays for defining molecular subtypes and mutations that may be targeted with therapy. Diagnostic technologies, such as liquid biopsy2 and transcriptome sequencing,3 can assist clinicians in determining which targeted therapy is optimal for their patients. Genomic studies over the past decade have uncovered additional molecular driver mutations in lung cancer, allowing further subdivision of NSCLC classification based on these driver mutations.1 These findings have assisted in the development of targeted therapy.1 For example, recent findings suggest that presence of mutations in the epidermal growth factor receptors (EGFR) strongly predicts the efficacy of EGFR tyrosine kinase inhibitors (TKIs), wherein response rates greater than 70% were seen in multiple studies.1

Molecular alterations in NSCLC can lead to oncogene activation through multiple mechanisms, including point mutations, insertions, deletions, and gene rearrangements.4 Generally, these alterations are mutually exclusive, but all have the propensity to confer oncogene addiction, which describes the phenomenon by which oncogenesis is driven primarily or exclusively by aberrant oncogene signaling.4 The implications of oncogene arrangements have been well described in NSCLC. With respect to oncogenic fusions, in which a 5-inch partner forms an in-frame gene fusion with a 3-inch proto-oncogene, the kinase domain of the proto-oncogene is typically preserved, and the result is expression of a constitutively activated protein whose downstream signaling promotes cell proliferation and survival in a ligand-independent manner.4 Gene fusions often represent markers for specific cancer subtypes. For example, BCR-ABL1 gene fusion has been implicated in chronic myelogenous leukemia.3 Some gene fusions, however, termed multitumor rearrangements, are nonspecific and have been seen in multiple cancer types.3 For example, ETV6-NTRK3 has been linked to secretory breast cancer, congenital fibrosarcoma, acute myeloid leukemia, and other malignancies.3 

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