Clinical value of next generation sequencing of plasma cell-free DNA in gastrointestinal stromal tumors.

Autor: Serrano C; Medical Oncology Department, Vall d'Hebron University Hospital, P. Vall d'Hebron 119, 08035, Barcelona, Spain. cserrano@vhio.net.; Preclinical Research Program, Vall d'Hebron Institute of Oncology, Barcelona, Spain. cserrano@vhio.net., Vivancos A; Cancer Genomics Group, |Vall d'Hebron Institute of Oncology, Natzaret 115, 08035, Barcelona, Spain. avivancos@vhio.net., López-Pousa A; Medical Oncology, Sant Pau University Hospital, Barcelona, Spain., Matito J; Cancer Genomics Group, |Vall d'Hebron Institute of Oncology, Natzaret 115, 08035, Barcelona, Spain., Mancuso FM; Cancer Genomics Group, |Vall d'Hebron Institute of Oncology, Natzaret 115, 08035, Barcelona, Spain., Valverde C; Medical Oncology Department, Vall d'Hebron University Hospital, P. Vall d'Hebron 119, 08035, Barcelona, Spain., Quiroga S; Radiology Department, Vall d'Hebron University Hospital, Barcelona, Spain., Landolfi S; Pathology Department, Vall d'Hebron University Hospital, Barcelona, Spain., Castro S; Surgical Oncology Division, Vall d'Hebron University Hospital, Barcelona, Spain., Dopazo C; Surgical Oncology Division, Vall d'Hebron University Hospital, Barcelona, Spain., Sebio A; Medical Oncology, Sant Pau University Hospital, Barcelona, Spain., Virgili AC; Medical Oncology, Sant Pau University Hospital, Barcelona, Spain., Menso MM; Radiology Department, Sant Pau University Hospital, Barcelona, Spain., Martín-Broto J; Medical Oncology, Virgen del Rocío Hospital, Sevilla, Spain., Sansó M; Cancer Genomics Group, |Vall d'Hebron Institute of Oncology, Natzaret 115, 08035, Barcelona, Spain., García-Valverde A; Preclinical Research Program, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Rosell J; Preclinical Research Program, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Fletcher JA; Pathology Department, Brigham and Women's Hospital/Harvard Medical School, Boston, USA., George S; Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston, USA., Carles J; Medical Oncology Department, Vall d'Hebron University Hospital, P. Vall d'Hebron 119, 08035, Barcelona, Spain., Arribas J; Preclinical Research Program, Vall d'Hebron Institute of Oncology, Barcelona, Spain.; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
Jazyk: angličtina
Zdroj: BMC cancer [BMC Cancer] 2020 Feb 05; Vol. 20 (1), pp. 99. Date of Electronic Publication: 2020 Feb 05.
DOI: 10.1186/s12885-020-6597-x
Abstrakt: 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.
Databáze: MEDLINE
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