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

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.

The Diagnosis of Small Gastrointestinal Subepithelial Lesions by Endoscopic Ultrasound-Guided Fine Needle Aspiration and Biopsy

“…Recently, the selection of neoadjuvant TKI therapy using EUS-FNB sample was reported [112]. They evaluated DNA sequencing of C-kit and PDGFRA in pretreatment GIST tissue.…”

Early Prediction and Monitoring of Treatment Response in Gastrointestinal Stromal Tumors by Means of Imaging: A Systematic Review

“…Articles that were excluded based on imaging criteria included, for example, the use of radiotracers other than [ 18 F]FDG [ 20 ]. Additionally, some articles discussed the use of molecular genotyping and DNA sequencing to predict or determine response and therefore did not involve the use of any imaging modality [ 21 ]. Other excluded articles discussed the efficacy of a specific TKI treatment but did not quantify the efficacy of imaging features in predicting or monitoring response [ 22 , 23 ].…”