A Poor Prognostic ALK Phenotype: A Review of Molecular Markers of Poor Prognosis in ALK Rearranged Nonsmall Cell Lung Cancer

BACKGROUND: Patients with nonsmall cell lung cancer with anaplastic lymphoma kinase (ALK) rearrangements derive a significant and durable clinical benefit from tyrosine kinase inhibitors (TKIs). However, early progression/death on treatment occurs in a subset of patients, which we term the poor prognostic ALK phenotype. This review aims to summarize the known molecular mechanisms that underlie this phenotype with a focus on variant 3 and TP53 mutations. METHODS: A scoping review was performed using scientific databases such as Ovid Medline, Ovid Embase, and Cochrane Central Register of Controlled Trials. Studies included molecular markers of poor prognosis, with a focus on TP53 mutations, variant 3 re-arrangements, and poor clinical response to TKIs. RESULTS: Of 4371 studies screened, 108 were included. Numerous studies implicated a negative prognostic role of variant 3, likely mediated through the acquisition of on-target resistance mutations and TP53 mutations which are associated with greater chromosomal instability and mutational burden. Co-occurring variant 3 and TP53 mutations were associated with even worse survival. Other mediators of early resistance development include aberrations in cell cycle regulators and mutations in cell signaling pathways. Comprehensive genomic analysis from first-line TKI clinical trial data was unable to identify a singular genomic signature that underlies the poor prognostic phenotype but implicated a combination of pathways. CONCLUSIONS: This scoping review highlights that the poor prognostic ALK phenotype is likely composed of a heterogeneous variety of genomic factors. There remains an unmet need for a genomic assay to integrate these various molecular markers to predict this ALK phenotype.