Patients with NSCLCs Harboring Internal Inversions or Deletion Rearrangements of the Gene Have Durable Responses to ALK Kinase Inhibitors. Journal Article

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Authors: Schrock, AB; Madison, R; Rosenzweig, M; Allen, JM; Erlich, RL; Wang, SY; Chidiac, T; Reddy, VS; Riess, JW; Yassa, AE; Shakir, A; Miller, VA; Alexander, BM; Venstrom, J; McGregor, K; Ali, SM
Article Title: Patients with NSCLCs Harboring Internal Inversions or Deletion Rearrangements of the Gene Have Durable Responses to ALK Kinase Inhibitors.
Abstract: Background: fusions are targetable drivers in non-small-cell lung cancer (NSCLC). However, patients with NSCLC harboring rearrangements without a fusion partner identified in DNA have also been shown to respond to ALK inhibitors. We aimed to characterize complex variants that may predict sensitivity to multiple approved ALK inhibitors. Methods: Comprehensive genomic profiling (CGP) of DNA isolated from formalin-fixed paraffin-embedded (FFPE) tumor tissue or blood-based circulating tumor DNA was performed for 39,159 NSCLC patients during routine clinical care. For a subset of cases, RNA sequencing was performed, and prior ALK test results and clinical treatment information were collected from treating physicians. Results: We queried the Foundation Medicine NSCLC database and identified ALK internal inversions, as well as internal deletions, as the sole rearrangements in 6 (0.02%) and 3 (0.01%) of cases, respectively. In cases with internal inversions, RNA testing identified an fusion in 2/2 cases evaluated, and 3/3 patients treated with ALK inhibitors had durable responses. A single patient with an internal deletion and clinical data available responded to multiple ALK inhibitors. RNA data available for a subset of non-NSCLC cases suggest that internal deletions removing a portion of the N-terminus are drivers themselves and do not result in fusions. Fluorescence in situ hybridization (FISH) results were inconsistent for both classes of DNA events. Conclusion: Rare internal inversions of appear to be indicative of fusions, which can be detected in RNA, and response to ALK inhibitors in patients with NSCLC. In contrast, internal deletions are not associated with fusions in RNA but likely represent targetable drivers themselves. These data suggest that CGP of DNA should be supplemented with immunohistochemistry or RNA-based testing to further resolve these events and match patients to effective therapies.
Journal Title: Lung Cancer (Auckland, N.Z.)
Publisher: Unknown  
Date Published: 2020