Effect of continuous statistically standardized measures of estrogen and progesterone receptors on disease-free survival in NCIC CTG MA.12 Trial and BC Cohort
Bibliographic record
Abstract
INTRODUCTION: We hypothesized improved inter-laboratory comparability of estrogen receptor (ER) and progesterone receptor (PgR) across different assay methodologies with adjunctive statistical standardization, akin to bone mineral density (BMD) z-scores. We examined statistical standardization in MA.12, a placebo-controlled pre-menopausal trial of adjuvant tamoxifen with locally assessed hormone receptor +/- tumours, and in a cohort of post-menopausal British Columbia (BC) tamoxifen-treated patients. METHODS: ER and PgR were centrally assessed for both patient groups with real time quantitative reverse transcription polymerase chain reaction (qPCR) and immunohistochemistry (IHC). Effects on disease-free survival (DFS) were investigated separately for 345 MA.12 and 673 BC patients who had both qPCR and IHC assessments. Comparisons utilized continuous laboratory units and statistically standardized z-scores. Univariate categorization of ER/PgR was by number of standard deviations (SD) above or below the mean (z-score ≥1.0 SD below mean; z-score <1.0 SD below mean; z-score ≤1.0 SD above mean; z-score >1.0 SD above mean). Exploratory multivariate examinations utilized step-wise Cox regression. RESULTS: Median follow-up for MA.12 was 9.7 years; for BC patients, 11.8 years. For MA.12, 101 of 345 (29%) patients were IHC ER-PgR-. ER was not univariately associated with DFS (qPCR, P = 0.19; IHC, P = 0.08), while PgR was (qPCR, P = 0.09; IHC, P = 0.04). For BC patients, neither receptor was univariately associated with DFS: for ER, PCR, P = 0.36, IHC, P = 0.24; while for PgR, qPCR, P = 0.17, IHC, P = 0.31. Multivariately, MA.12 patients randomized to tamoxifen had significantly better DFS (P = 0.002 to 0.005) than placebo. Meanwhile, jointly ER and PgR were not associated with DFS whether assessed by qPCR or by IHC in all patients, or in the subgroup of patients with IHC positive stain, for pooled or separate treatment arms. Different results by type of continuous unit supported the concept of ER level being relevant for medical decision-making. For postmenopausal BC tamoxifen patients, higher qPCR PgR was weakly associated with better DFS (P = 0.06). CONCLUSIONS: MA.12 pre-menopausal patients in a placebo-controlled tamoxifen trial had similar multivariate prognostic effects with statistically standardized hormone receptors when tumours were assayed by qPCR or IHC, for hormone receptor +/- and + tumours. The BC post-menopausal tamoxifen cohort did not exhibit a significant prognostic association of ER or PgR with DFS. Adjunctive statistical standardization is currently under investigation in other NCIC CTG endocrine trials.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".