Subgroup analysis of a phase III trial of doxorubicin vs doxorubicin plus tesmilifene in advanced breast cancer (ABC): Tesmilifene survival benefit focused on patients with more aggressive disease
Bibliographic record
Abstract
756 Background: Tesmilifene (DPPE), a novel chemopotentiating small molecule, conferred a substantial (50%+) increase in median survival in MA.19, a 305 patient randomized trial in ABC (doxorubicin alone, 15.6 m; doxorubicin + DPPE, 23.6 m; p<0.03; J Clin Oncol 22: 269–276, 2004). Response rates and median progression free survival (PFS) were not different, however. Methods: YM Biosciences conducted an unplanned subgroup analysis of the MA.19 database to determine whether some subsets of patients might benefit differentially from the addition of DPPE. Results: Tally of post-trial treatments revealed minimal differences in exposure to a range of chemotherapy (CT) including taxanes; therefore, post-trial treatments do not explain the large survival (OS) difference. The only important prognostic factor maldistribution was the disease free interval (DFI) from original diagnosis to entry on trial, median 20 m (doxorubicin) vs 26 m (doxorubicin + DPPE). Although independently prognostic this DFI difference could not account for the OS difference (Cox proportional hazards, J Clin Oncol, ibid). By tertiles, only patients with a DFI >36 m were maldistributed and this subgroup actually demonstrated no survival benefit. A very large survival benefit (MST doxorubicin 12.2 m; doxorubicin + DPPE 29.7 m, p=0.0016) was evident in the two thirds of patients with DFI ≤36 m. Furthermore, a large, highly significant, OS benefit was seen in ER negative (p=0.003) but not ER positive patients, and in the ±80% of chemotherapy responders (CR, PR) and stabilizers (SD) (p<0.007) but not in chemorefractory (PD) patients; additionally, these CR/PR/SD patients exhibited a significant improvement in time to disease progression (p= 0.0204). Conclusions: These subset analyses, although unplanned, raise interesting hypotheses including the suggestions that a differential effect on a minority population of mdr+ cells explains the late (survival) benefit in the absence of an early (response, PFS) benefit for DPPE. This hypothesis is being further explored in a currently ongoing trial of EC vs EC plus DPPE in ABC patients with early recurring disease. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration YM Biosciences Pfizer, YM Biosciences YM Biosciences YM Biosciences YM Biosciences
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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 | 0.004 | 0.005 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.003 | 0.007 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 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 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".