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Pretreatment Tumor DNA Sequencing of KIT and PDGFRA in Endosonography-Guided Biopsies Optimizes the Preoperative Management of Gastrointestinal Stromal Tumors

Journal article
Authors Per Hedenström
C. Andersson
Henrik Sjövall
F. Enlund
O. Nilsson
B. Nilsson
R. Sadik
Published in Molecular Diagnosis & Therapy
Pages 14
ISSN 1177-1062
Publication year 2020
Published at Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
Pages 14
Language en
Links dx.doi.org/10.1007/s40291-020-00451...
Keywords neoadjuvant/adjuvant imatinib mesylate, phase-ii trial, tyrosine kinase, dose imatinib, free survival, follow-up, mutations, risk, gist, diagnosis, Genetics & Heredity, Pharmacology & Pharmacy
Subject categories Pharmacology and Toxicology

Abstract

Background Neoadjuvant tyrosine kinase inhibitor (TKI) therapy increases the chance of organ-preserving, radical resection in selected patients with gastrointestinal stromal tumors (GISTs). We aimed to evaluate systematic, immediate DNA sequencing of KIT and PDGFRA in pretreatment GIST tissue to guide neoadjuvant TKI therapy and optimize preoperative tumor response. Methods All patients who were candidates for neoadjuvant therapy of a suspected GIST [the study cohort (SC)] were prospectively included from January 2014 to March 2018. Patients were subjected to pretreatment endosonography-guided fine-needle biopsy (EUS-FNB) or transabdominal ultrasound-guided needle biopsy (TUS-NB), followed by immediate tumor DNA sequencing (< 2 weeks). A historic (2006-2013) reference cohort (RC) underwent work-up without sequencing before neoadjuvant imatinib (n = 42). The rate of optimal neoadjuvant therapy (Therapy(OPTIMAL)) was calculated, and the induced tumor size reduction (Tumor Regression(MAX), %) was evaluated by computed tomography (CT) scan. Results The success rate of pretreatment tumor DNA sequencing in the SC (n = 81) was 77/81 (95%) [EUS-FNB 71/74 (96%); TUS-NB 6/7 (86%)], with mutations localized in KIT (n = 58), PDGFRA (n = 18), or neither gene, wild type (n = 5). In patients with a final indication for neoadjuvant therapy, the Therapy(OPTIMAL) was higher in the SC compared with the RC [61/63 (97%) versus 33/42 (79%), p = 0.006], leading to a significantly higher Tumor Regression(MAX) in patients treated with TKI (27% vs. 19%, p = 0.015). Conclusions Pretreatment endosonography-guided biopsy sampling followed by immediate tumor DNA sequencing of KIT and PDGFRA is highly accurate and valuable in guiding neoadjuvant TKI therapy in GIST. This approach minimizes maltreatment with inappropriate regimens and leads to improved tumor size reduction before surgery.

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