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• W2890882686 abstract "11513 Background: Most patients with mGIST initially benefit from IM therapy with durable disease control (DC), i.e. objective responses and stable disease, with median duration of approximately two years. We reported exceptional long-term benefit (LTB) with DC and overall survival (OS) >14 years in a subset of mGIST pts treated with IM. We aimed to characterize tumor and normal genomes of exceptional LTB pts treated with IM and compare with short-term benefit (STB) pts. Methods: Among 87 mGIST pts enrolled between July 2000 and June 2001 in the B2222 trial of IM and followed prospectively at the Dana Farber Cancer Institute, we identified 10 LTB (>14 years of DC) pts, and 6 STB (<2 years of DC) pts on IM. Targeted genotyping ( KIT/PDGFRA)was performed in all tumors (n=16). Whole exome sequencing (WES) was performed on archival FFPE tumor samples from LTB and STB pts prior to any IM treatment. We compared WES results from LTB with STB pts to identify unique features of long-term DC and OS with IM. Results: KIT mutation in LTB pts were as follows: exon 11(6 pts), exon 9 (3 pts), and SDH-deficient with KIT/PDGFRA wild type (1 pt). In STB pts, mutated KITwas found 4 pts (exon 11) and 2 pts (exon 9). WES was successful in six LTB (five exon 11, one exon 9) and three STB (two exon 11, one exon 9) pts. A total of 1211 somatic mutations were observed (546 missense, 37 nonsense, 256 silent, 285 indels, 36 splice mutations). The mean somatic mutational burden was 3.42 mutations/Mb (range 1.18-4.93) and 3.34 mutations/Mb (range 1.06-6.68) among LTB and STB, respectively. Genes mutated in LTB but not in STB were MUC7 (4 pts), H1F0 (3 pts), ZKSCAN1 (3 pts), SLC24A1 (3 pts) and USP4 (2 pts). Conclusions: KRAB domain containing zinc finger (KRAB-ZNF) gene expression signatures have been associated with prediction of response to IM, and a possible role in response modulation to tyrosine kinase inhibitors in GIST. We found variants in ZKSCAN1, a gene encoding a transcriptional regulator of the KRAB subfamily of zinc finger, to be present in LTB but not in STB. KRAB-ZNF family of genes may be linked to LTB and exceptional survival with IM in mGIST; functional analyses will be important to test such hypotheses." @default.
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• W2890882686 date "2017-05-20" @default.
• W2890882686 modified "2023-10-02" @default.
• W2890882686 title "Whole exome analysis of patients (pts) with metastatic GIST (mGIST) demonstrating exceptional survival with imatinib (IM) therapy compared to those with short term benefit." @default.
• W2890882686 doi "https://doi.org/10.1200/jco.2017.35.15_suppl.11513" @default.
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