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. - PubMed - NCBI
Clin Cancer Res. 2018 Mar 29. pii: clincanres.2588.2017. doi: 10.1158/1078-0432.CCR-17-2588. [Epub ahead of print]
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.
McCoach CE1,
Blakely CM2,
Banks KC3,
Levy B4,
Chue BM5,
Raymond VM6,
Le A7,
Lee CE3,
Diaz J3,
Waqar SN8,
Purcell WT9,
Aisner DL10,
Davies KD11,
Lanman RB3,
Shaw AT12,
Doebele RC13.
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 non-invasive way to identify ALK fusions and actionable resistance mechanisms without biopsy. EXPERIMENTAL DESIGN:
The Guardant360 (G360) de-identified 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, 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 - 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 non-invasive means of detecting targetable alterations, and characterizing resistance mechanisms on progression. Copyright ©2018, American Association for Cancer Research.
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