Clinical utility of next-generation sequencing-based ctDNA testing for common and novel ALK fusions Journal Article


Authors: Mondaca, S.; Lebow, E. S.; Namakydoust, A.; Razavi, P.; Reis-Filho, J. S.; Shen, R.; Offin, M.; Tu, H. Y.; Murciano-Goroff, Y.; Xu, C.; Makhnin, A.; Martinez, A.; Pavlakis, N.; Clarke, S.; Itchins, M.; Lee, A.; Rimner, A.; Gomez, D.; Rocco, G.; Chaft, J. E.; Riely, G. J.; Rudin, C. M.; Jones, D. R.; Li, M.; Shaffer, T.; Hosseini, S. A.; Bertucci, C.; Lim, L. P.; Drilon, A.; Berger, M. F.; Benayed, R.; Arcila, M. E.; Isbell, J. M.; Li, B. T.
Article Title: Clinical utility of next-generation sequencing-based ctDNA testing for common and novel ALK fusions
Abstract: Objectives: Liquid biopsy for plasma circulating tumor DNA (ctDNA) next-generation sequencing (NGS) can detect ALK fusions, though data on clinical utility of this technology in the real world is limited. Materials and Methods: Patients with lung cancer without known oncogenic drivers or who had acquired resistance to therapy (n = 736) underwent prospective plasma ctDNA NGS. A subset of this cohort (n = 497) also had tissue NGS. We evaluated ALK fusion detection, turnaround time (TAT), plasma and tissue concordance, matching to therapy, and treatment response. Results: ctDNA identified an ALK fusion in 21 patients (3%) with a variety of breakpoints and fusion partners, including EML4, CLTC, and PON1, a novel ALK fusion partner. TAT for ctDNA NGS was shorter than tissue NGS (10 vs. 20 days; p < 0.001). Among ALK fusions identified by ctDNA, 93% (13/14, 95% CI 66%–99%) were concordant with tissue evaluation. Among ALK fusions detected by tissue NGS, 54% (13/24, 95% CI 33%–74%) were concordant with plasma ctDNA. ctDNA matched patients to ALK-directed therapy with subsequent clinical response, including four patients matched on the basis of ctDNA results alone due to inadequate or delayed tissue testing. Serial ctDNA analysis detected MET amplification (n = 2) and ALK G1202R mutation (n = 2) as mechanisms of acquired resistance to ALK-directed therapy. Conclusion: Our findings support a complementary role for ctDNA in detection of ALK fusions and other alterations at diagnosis and therapeutic resistance settings. © 2021 Elsevier B.V.
Keywords: next generation sequencing; circulating tumor dna; alk fusion; liquid biopsy
Journal Title: Lung Cancer
Volume: 159
ISSN: 0169-5002
Publisher: Elsevier Ireland Ltd.  
Date Published: 2021-09-01
Start Page: 66
End Page: 73
Language: English
DOI: 10.1016/j.lungcan.2021.06.018
PROVIDER: scopus
PUBMED: 34311346
PMCID: PMC8594131
DOI/URL:
Notes: Article -- Erratum issued, see DOI: 10.1016/j.lungcan.2021.09.016 -- Export Date: 1 September 2021 -- Source: Scopus
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MSK Authors
  1. Ronglai Shen
    205 Shen
  2. Daniel R Gomez
    242 Gomez
  3. Jamie Erin Chaft
    290 Chaft
  4. Gregory J Riely
    603 Riely
  5. Andreas Rimner
    527 Rimner
  6. Michael Forman Berger
    768 Berger
  7. Maria Eugenia Arcila
    669 Arcila
  8. Alexander Edward Drilon
    634 Drilon
  9. Charles Rudin
    493 Rudin
  10. Pedram Razavi
    183 Razavi
  11. Rym Benayed
    188 Benayed
  12. David Randolph Jones
    418 Jones
  13. Bob Tingkan Li
    279 Li
  14. James Michael Isbell
    128 Isbell
  15. Michael David Offin
    172 Offin
  16. Gaetano Rocco
    132 Rocco
  17. Chongrui Xu
    8 Xu
  18. Alex Makhnin
    19 Makhnin
  19. Hai-Yan Tu
    7 Tu
  20. Emily Schapira Lebow
    49 Lebow