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

Caroline E. McCoach, Collin M. Blakely, Kimberly C. Banks, Benjamin Levy, Ben M. Chue, Victoria M. Raymond, Anh T. Le, Christine E. Lee, Joseph Diaz, Saiama N. Waqar, William T. Purcell, Dara L. Aisner, Kurtis D. Davies, Richard B. Lanman, Alice T. Shaw, Robert C. Doebele

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2758-2770
Number of pages13
JournalClinical Cancer Research
Volume24
Issue number12
DOIs
StatePublished - Jun 15 2018

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

McCoach, C. E., Blakely, C. M., Banks, K. C., Levy, B., Chue, B. M., Raymond, V. M., Le, A. T., Lee, C. E., Diaz, J., Waqar, S. N., Purcell, W. T., Aisner, D. L., Davies, K. D., Lanman, R. B., Shaw, A. T., & Doebele, R. C. (2018). 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. Clinical Cancer Research, 24(12), 2758-2770. https://doi.org/10.1158/1078-0432.CCR-17-2588