Correlation of Long-term Results of Imatinib in Advanced Gastrointestinal Stromal Tumors With Next-Generation Sequencing Results
Bibliographic record
Abstract
IMPORTANCE: After identification of activating mutations of the KIT gene in gastrointestinal stromal tumor (GIST)-the most common sarcomaof the gastrointestinal tract-a phase 2 study demonstrated efficacy of imatinib mesylate in patients with metastatic GIST harboring a KIT exon 11 mutation. Initial results of long-term follow-up have found a survival benefit in this subgroup of patients. OBECTIVE: To assess the long-term survival of patients with GIST who were treated in SWOG study S0033 and to present new molecular data regarding treatment outcomes. DESIGN, SETTING, AND PARTICIPANTS: In this follow-up of randomized clinical trial participants (from December 15, 2000, to September 1, 2001), patients were required to have advanced GIST that was not surgically curable. Postprotocol data collection occurred from August 29, 2011, to July 15, 2015. Using modern sequencing technologies, 20 cases originally classified as having wild-type tumors underwent reanalysis. This intergroup study was coordinated by SWOG, a cooperative group member within the National Clinical Trials Network, with participation by member/affiliate institutions. This follow-up was not planned as part of the initial study. INTERVENTIONS: Patients were randomized to 1 of 2 dose levels of imatinib mesylate, including 400 mg once daily (400 mg/d) vs 400 mg twice daily (800 mg/d), and were treated until disease progression or unacceptable toxic effects of the drug occurred. MAIN OUTCOMES AND MEASURES: The primary end point was overall survival. Updated survival data were correlated with clinical and molecular factors, and patterns of postprotocol therapies were enumerated and described in long-term survivors. RESULTS: Of 695 eligible patients (376 men [54.1%]; 319 women [45.9%]; mean [SD] age, 60.1 [14.0] years), 189 survived 8 years or longer, including 95 in the 400-mg/d dose arm and 94 in the 800-mg/d arm. The 10-year estimate of overall survival was 23% (95% CI, 20%-26%). Among 142 long-term survivors, imatinib was the sole therapy administered in 69 (48.6%), with additional systemic agents administered to 54 patients (38.0%). Resequencing studies of 20 cases originally classified as KIT/PDGFRA wild-type GIST revealed that 17 (85.0%) harbored a pathogenic mutation, most commonly a mutation of a subunit of the succinate dehydrogenase complex. CONCLUSIONS AND RELEVANCE: A subset of patients with metastatic GIST experiences durable, long-term overall survival with imatinib treatment. Although this study provides guidance for management of GIST harboring the most common KIT and PDGFRA mutations, optimal management of other genotypic subtypes remains unclear. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00009906.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.009 | 0.017 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".