Abstract
The management of non-small cell lung cancer (NSCLC) has transformed with the discovery of therapeutically tractable oncogenic drivers. In addition to activating driver mutations, gene fusions or rearrangements form a unique sub-class, with anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) targeted agents approved as the standard of care in the first-line setting for advanced disease. There are a number of emerging fusion drivers, however, including neurotrophin kinase (NTRK), rearrangement during transfection (RET), and neuregulin 1 (NRG1) for which there are evolving high-impact systemic treatment options. Brain metastases are highly prevalent in NSCLC patients, with molecularly selected populations such as epidermal growth factor receptor (EGFR) mutant and ALK-rearranged tumors particularly brain tropic. Accordingly, there exists a substantial body of research pertaining to the understanding of brain metastases in such populations. Little is known, however, on the molecular mechanisms of brain metastases in those with other targetable fusion drivers in NSCLC. This review encompasses key areas including the biological underpinnings of brain metastases in fusion-driven lung cancers, the intracranial efficacy of novel systemic therapies, and future directions required to optimize the control and prevention of brain metastases.
Highlights
Non-small cell lung cancer (NSCLC) is a leading cause of cancer death globally [1] and is characterized by a high prevalence of brain metastases (BM) of up to 50% during the course of the disease [2,3]
One such study by Wang et al [30] performed panel-based next-generation sequencing (NGS) of 61 paired primary and resected BM tumors. They found alterations of genes related to cell cycle regulation and phosphatidylinositol 3-kinase (PI3K) pathway signaling were enriched and tumor mutation burden (TMB) was increased in the resected BM compared to the paired primary lung tumors
neurotrophin kinase (NTRK) fusions consist of gene rearrangements involving NTRK1, NTRK2, and NTRK3, which result in constitutive activation of the fusion protein containing the tropomyosin receptor tyrosine kinase (TRK) kinase domain [55]
Summary
Non-small cell lung cancer (NSCLC) is a leading cause of cancer death globally [1] and is characterized by a high prevalence of brain metastases (BM) of up to 50% during the course of the disease [2,3]. With rapidly evolving systemic treatment options including molecular therapies and immunotherapy, patients with BM remain a patient population of special interest. Tyrosine kinase inhibitor (TKI) therapy is standard of care in the first-line setting for advanced disease in patients that harbor such alterations. There are a number of emerging fusion drivers, including neuregulin 1 (NRG1), neurotrophin kinase (NTRK), and rearrangement during transfection (RET), for which there are evolving systemic treatment options. Much less is known on the molecular mechanisms of BM in lung cancers with emerging targetable fusion drivers. This review will encompass key areas including the biological underpinnings of BM in lung cancers harboring an oncogenic fusion driver, the intracranial efficacy of novel systemic therapies, and future directions to optimize the control and prevention of BM
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