Clinical Utility of Cell-Free DNA for the Detection of ALK Fusions and Genomic Mechanisms of ALK Inhibitor Resistance in Non–Small Cell Lung Cancer
- 14 June 2018
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 24 (12), 2758-2770
- https://doi.org/10.1158/1078-0432.ccr-17-2588
Abstract
Purpose: Patients with advanced non–small cell lung cancer (NSCLC) whose tumors harbor anaplastic lymphoma kinase (ALK) gene fusions benefit from treatment with ALK inhibitors (ALKi). Analysis of cell-free circulating tumor DNA (cfDNA) may provide a noninvasive way to identify ALK fusions and actionable resistance mechanisms without an invasive biopsy. Patients and Methods: The Guardant360 (G360; Guardant Health) deidentified database of NSCLC cases was queried to identify 88 consecutive patients with 96 plasma-detected ALK fusions. G360 is a clinical cfDNA next-generation sequencing (NGS) test that detects point mutations, select copy number gains, fusions, insertions, and deletions in plasma. Results: Identified fusion partners included EML4 (85.4%), STRN (6%), and KCNQ, KLC1, KIF5B, PPM1B, and TGF (totaling 8.3%). Forty-two ALK-positive patients had no history of targeted therapy (cohort 1), with tissue ALK molecular testing attempted in 21 (5 negative, 5 positive, and 11 tissue insufficient). Follow-up of 3 of the 5 tissue-negative patients showed responses to ALKi. Thirty-one patients were tested at known or presumed ALKi progression (cohort 2); 16 samples (53%) contained 1 to 3 ALK resistance mutations. In 13 patients, clinical status was unknown (cohort 3), and no resistance mutations or bypass pathways were identified. In 6 patients with known EGFR-activating mutations, an ALK fusion was identified on progression (cohort 4; 4 STRN, 1 EML4; one both STRN and EML4); five harbored EGFR T790M. Conclusions: In this cohort of cfDNA-detected ALK fusions, we demonstrate that comprehensive cfDNA NGS provides a noninvasive means of detecting targetable alterations and characterizing resistance mechanisms on progression. Clin Cancer Res; 24(12); 2758–70. ©2018 AACR.Keywords
Other Versions
Funding Information
- University of Colorado Lung Cancer SPORE (P50CA058187)
This publication has 54 references indexed in Scilit:
- Crizotinib versus Chemotherapy in AdvancedALK-Positive Lung CancerNew England Journal of Medicine, 2013
- Genomic Landscape of Non-Small Cell Lung Cancer in Smokers and Never-SmokersCell, 2012
- Mechanisms of Resistance to Crizotinib in Patients with ALK Gene Rearranged Non–Small Cell Lung CancerClinical Cancer Research, 2012
- Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trialThe Lancet Oncology, 2012
- Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysisThe Lancet Oncology, 2011
- Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic ScreeningNew England Journal of Medicine, 2011
- Gefitinib or Carboplatin–Paclitaxel in Pulmonary AdenocarcinomaNew England Journal of Medicine, 2009
- Somatic mutations affect key pathways in lung adenocarcinomaNature, 2008
- Multiplex Reverse Transcription-PCR Screening for EML4-ALK Fusion TranscriptsClinical Cancer Research, 2008
- Cloning of Human Striatin cDNA (STRN), Gene Mapping to 2p22–p21, and Preferential Expression in BrainGenomics, 1998