Association between locoregional failure and <i>NFE2L2/KEAP1/CUL3 </i>pathway mutations in NRG/RTOG 9512: A randomized trial of hyperfractionation vs. conventional fractionation in T2N0 glottic squamous cell carcinoma (SCC).
Bibliographic record
Abstract
6054 Background: Radiotherapy (RT) is the primary treatment for patients with T2N0 glottic SCC. ~30% of these patients experience locoregional relapse despite dose escalation. Mutations in the NFE2L2/KEAP1/CUL3 pathway have been linked to radioresistance preclinically and in small retrospective studies. We tested the hypothesis that patients with T2 glottic SCCs having these mutations would show radioresistance and more local (LF) and locoregional failures (LRF) when treated with RT compared to those without, using samples from a phase III trial. Methods: Of 250 randomized patients with T2N0 glottic SCC receiving definitive RT in RTOG 9512, 119 had available biospecimens that were subjected to amplicon-based next generation sequencing (appropriate to low-input DNA from biopsy specimens) to assess for presence of NFE2L2/KEAP1/CUL3 mutations without regard to outcomes. The association between binary mutation status and LF, LRF, disease-free survival (DFS), and overall survival (OS) was assessed using (cause-specific) Cox models (2-sided alpha of 0.05). LR/LRF rates were estimated by the cumulative incidence method and DFS/OS rates by the Kaplan-Meier method. Results: Nineteen of 119 patients (16.0%; 95% confidence interval [CI] 9.4, 22.6) had mutations in the NFE2L2/KEAP1/CUL3 pathway. Patient and tumor characteristics were similar between those with and without mutation.There were 32 LF, 37 LRF, and 80 DFS events, and 52 deaths. Patients with mutation compared to those without had significantly higher LF and LRF rates (Table). Median DFS was 0.9 years (95% CI 0.4, not reached) for the mutation group compared to 4.2 years (95% CI 3.2, 6.4) for those without. The hazard ratio (HR) for DFS was significantly higher for the mutated compared to the non-mutated group in the first 2 years after randomization but declined thereafter (Table), likely due to limited events after 2 years in the mutation group. There was no significant difference in OS between the two groups (HR = 0.76; 95% CI 0.35, 1.6; p = 0.48). Conclusions: NFE2L2/KEAP1/CUL3 pathway mutations may predict radiation treatment failure in T2N0 glottic cancer. They may also be a prognostic biomarker for DFS, but the current evidence supports the harmful effect of these mutations only during the first 2 years from randomization. Clinical trial information: NCT00002727 . [Table: see text]
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.004 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.004 | 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".