An analysis of the prognostic and predictive importance of K-ras mutation status in the National Cancer Institute of Canada Clinical Trials Group BR.21 study of erlotinib versus placebo in the treatment of non-small cell lung cancer
Bibliographic record
Abstract
7005 Background: BR.21 demonstrated a significant survival benefit for patients with advanced non-small cell lung cancer (NSCLC) who received erlotinib vs. placebo (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.58–0.85, p<0.001). Tyrosine kinase (TK) domain mutations and high EGFR gene copy number by fluorescent in situ hybridization (FISH) have been associated with significantly higher response rates to erlotinib, while high gene copy number is a better predictor of survival benefit than mutations. K-ras mutation has been associated with non-responsiveness to EGFR TK inhibitors and poorer outcome for patients treated with erlotinib and chemotherapy. The survival impact of K-ras mutation on single agent erlotinib therapy in NSCLC patients remains unknown. Methods: 731 patients were randomized to BR.21 (488 erlotinib, 243 placebo). K-ras mutation analysis was conducted by sequencing in 246 patient samples. Results: K-ras analysis was successful in 206 patients; 30 (14.6%) demonstrated oncogenic mis-sense mutations on codon 12 or 13 (22 on the erlotinib arm and 8 on the placebo arm). For all 206 patients with known K-ras genotype, the HR for erlotinib was 0.77 (95% CI 0.57–1.06, p=0.06). For the 176 K-ras wild type patients, the univariate HR for erlotinib was 0.69 (95% CI 0.49–0.97, p=0.03). In contrast, the HR for the thirty K-ras mutant patients was 1.67 (95% CI 0.62–4.5, p=0.31), with an interaction p value of 0.09. Overall response rates were 5% (1/20) in K-ras mutant patients, and 10.2% (10/98) in K-ras wild type patients. In patients with K-ras genotype known, the multivariate Cox regression model showed that K-ras mutation was significantly associated with shorter survival (HR 1.63, 95% CI 1.06–2.51, p=0.03). Conclusion: In BR.21, patients with K-ras mutation do not appear to derive any survival benefit from erlotinib therapy. However, the numbers of patients are small and results need to be confirmed in other studies. (Supported by the Canadian Cancer Society, Ontario Cancer Research Network, the Jacqueline Seroussi Memorial Foundation for Cancer Research and OSI Pharmaceuticals). [Table: see text]
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.005 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".