Abstract
The majority of patients diagnosed with advanced gastrointestinal stromal tumors (GISTs) are successfully treated with a combination of surgery and tyrosine kinase inhibitors (TKIs). However, it remains challenging to monitor treatment efficacy and identify relapse early. Here, we utilized a sequencing strategy based on molecular barcodes and developed a GIST-specific panel to monitor tumor-specific and TKI resistance mutations in cell-free DNA and applied the approach to patients undergoing surgical treatment. Thirty-two patients with GISTs were included, and 161 blood plasma samples were collected and analyzed at routine visits before and after surgery and at the beginning, during, and after surgery. Patients were included regardless of their risk category. Our GIST-specific sequencing approach allowed detection of tumor-specific mutations and TKI resistance mutations with mutant allele frequency < 0.1%. Circulating tumor DNA (ctDNA) was detected in at least one timepoint in nine of 32 patients, ranging from 0.04% to 93% in mutant allele frequency. High-risk patients were more often ctDNA positive than other risk groups (P < 0.05). Patients with detectable ctDNA also displayed higher tumor cell proliferation rates (P < 0.01) and larger tumor sizes (P < 0.01). All patients who were ctDNA positive during surgery became negative after surgery. Finally, in two patients who progressed on TKI treatment, we detected multiple resistance mutations. Our data show that ctDNA may become a clinically useful biomarker in monitoring treatment efficacy in patients with high-risk GISTs and can assist in treatment decision making.
Highlights
Gastrointestinal stromal tumor (GIST) is the most common abdominal sarcoma with a yearly incidence rate of 15 per 1,000,000 [1,2]
We developed patient-specific SiMSen-Seq panels that target the patient’s tumor-specific mutation in either KIT or PDGFRA, as well as mutations related to imatinib and sunitinib resistance (Fig. 1B)
We developed a gastrointestinal stromal tumor (GIST)-specific sequencing approach to monitor treatment efficacy by analyzing both the patients’ tumor-specific mutation and sequences related to tyrosine kinase inhibitors (TKIs) resistance
Summary
Gastrointestinal stromal tumor (GIST) is the most common abdominal sarcoma with a yearly incidence rate of 15 per 1,000,000 [1,2]. 80 % have a mutation in KIT and 10 % in PDGFRA, resulting in tyrosine kinase activation and tumor cell proliferation [3,4,5]. Risk stratification is based on tumor size, location, and mitotic count, according to the National Institute of Health (NIH) consensus classification system [8,9,10,11]. For patients with tumors in the very low-, low- and intermediate-risk groups, surgical resection is often curative. For patients with high-risk tumors and treatment-sensitive mutations, tyrosine kinase inhibitors (TKIs), imatinib, may be used both as neoadjuvant and adjuvant treatments [11,12,13]
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