Clinical value of next generation sequencing of plasma cell-free DNA in gastrointestinal stromal tumors
Por:
Serrano, C, Vivancos, A, Lopez-Pousa, A, Matito, J, Mancuso, FM, Valverde, C, Quiroga, S, Landolfi, S, Castro, S, Dopazo, C, Sebio, A, Virgili, AC, Menso, MM, Martin-Broto, J, Sanso, M, Garcia-Valverde, A, Rosell, J, Fletcher, JA, George, S, Carles, J, Arribas, J
Publicada:
5 feb 2020
Resumen:
Background Gastrointestinal stromal tumor (GIST) initiation and evolution is commonly framed by KIT/PDGFRA oncogenic activation, and in later stages by the polyclonal expansion of resistant subpopulations harboring KIT secondary mutations after the onset of imatinib resistance. Thus, circulating tumor (ct)DNA determination is expected to be an informative non-invasive dynamic biomarker in GIST patients. Methods We performed amplicon-based next-generation sequencing (NGS) across 60 clinically relevant genes in 37 plasma samples from 18 GIST patients collected prospectively. ctDNA alterations were compared with NGS of matched tumor tissue samples (obtained either simultaneously or at the time of diagnosis) and cross-validated with droplet digital PCR (ddPCR). Results We were able to identify cfDNA mutations in five out of 18 patients had detectable in at least one timepoint. Overall, NGS sensitivity for detection of cell-free (cf)DNA mutations in plasma was 28.6%, showing high concordance with ddPCR confirmation. We found that GIST had relatively low ctDNA shedding, and mutations were at low allele frequencies. ctDNA was detected only in GIST patients with advanced disease after imatinib failure, predicting tumor dynamics in serial monitoring. KIT secondary mutations were the only mechanism of resistance found across 10 imatinib-resistant GIST patients progressing to sunitinib or regorafenib. Conclusions ctDNA evaluation with amplicon-based NGS detects KIT primary and secondary mutations in metastatic GIST patients, particularly after imatinib progression. GIST exhibits low ctDNA shedding, but ctDNA monitoring, when positive, reflects tumor dynamics.
Filiaciones:
Serrano, C:
Vall Hebron Univ Hosp, Med Oncol Dept, P Vall Hebron 119, Barcelona 08035, Spain
Vall Hebron Inst Oncol, Preclin Res Program, Barcelona, Spain
Vivancos, A:
Vall Hebron Inst Oncol, Canc Genom Grp, Natzaret 115, Barcelona 08035, Spain
Lopez-Pousa, A:
St Pau Univ Hosp, Med Oncol, Barcelona, Spain
Matito, J:
Vall Hebron Inst Oncol, Canc Genom Grp, Natzaret 115, Barcelona 08035, Spain
Mancuso, FM:
Vall Hebron Inst Oncol, Canc Genom Grp, Natzaret 115, Barcelona 08035, Spain
Valverde, C:
Vall Hebron Univ Hosp, Med Oncol Dept, P Vall Hebron 119, Barcelona 08035, Spain
Quiroga, S:
Vall Hebron Univ Hosp, Radiol Dept, Barcelona, Spain
Landolfi, S:
Vall Hebron Univ Hosp, Pathol Dept, Barcelona, Spain
Castro, S:
Vall Hebron Univ Hosp, Surg Oncol Div, Barcelona, Spain
Dopazo, C:
Vall Hebron Univ Hosp, Surg Oncol Div, Barcelona, Spain
Sebio, A:
St Pau Univ Hosp, Med Oncol, Barcelona, Spain
Virgili, AC:
St Pau Univ Hosp, Med Oncol, Barcelona, Spain
Menso, MM:
St Pau Univ Hosp, Radiol Dept, Barcelona, Spain
Martin-Broto, J:
Virgen del Rocio Hosp, Med Oncol, Seville, Spain
Sanso, M:
Vall Hebron Inst Oncol, Canc Genom Grp, Natzaret 115, Barcelona 08035, Spain
Garcia-Valverde, A:
Vall Hebron Inst Oncol, Preclin Res Program, Barcelona, Spain
Rosell, J:
Vall Hebron Inst Oncol, Preclin Res Program, Barcelona, Spain
Fletcher, JA:
Harvard Med Sch, Brigham & Womens Hosp, Pathol Dept, Boston, MA 02115 USA
George, S:
Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, Boston, MA 02115 USA
Carles, J:
Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, Boston, MA 02115 USA
Arribas, J:
Vall Hebron Inst Oncol, Preclin Res Program, Barcelona, Spain
ICREA, Barcelona, Spain
Gold, Green Published
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