Sebastian Mondaca1, Emily S Lebow2, Azadeh Namakydoust3, Pedram Razavi3, Jorge S Reis-Filho4, Ronglai Shen5, Michael Offin3, Hai-Yan Tu6, Yonina Murciano-Goroff3, Chongrui Xu6, Alex Makhnin3, Andres Martinez3, Nick Pavlakis7, Stephen Clarke7, Malinda Itchins7, Adrian Lee7, Andreas Rimner2, Daniel Gomez2, Gaetano Rocco8, Jamie E Chaft3, Gregory J Riely3, Charles M Rudin3, David R Jones8, Mark Li9, Tristan Shaffer9, Seyed Ali Hosseini9, Caterina Bertucci9, Lee P Lim9, Alexander Drilon3, Michael F Berger10, Ryma Benayed4, Maria E Arcila4, James M Isbell8, Bob T Li11. 1. Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, USA; Department of Hematology and Oncology, Pontificia Universidad Católica de Chile, Diagonal Paraguay 362 6th Fl, Rm 609, Santiago, Chile. Electronic address: spmondac@uc.cl. 2. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, USA. 3. Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, USA. 4. Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, USA. 5. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering, 1275 York Avenue, New York, NY, USA. 6. Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, USA; Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, 106 Zhongshan Er Road, Guangzhou, China. 7. GenesisCare (formerly Northern Cancer Institute), University of Sydney, Macquarie University NSW 2109, Australia. 8. Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, USA. 9. Resolution Bioscience, 550 Kirkland Way #200, Kirkland, WA, USA. 10. Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, USA; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York NY, USA. 11. Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, USA. Electronic address: lib1@mskcc.org.
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.
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.
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