Abstract P4-11-11: CADER prognostic gene signature for disease free survival in hormone receptor positive breast cancer: NCIC CTG MA.12 phase III placebo-controlled tamoxifen trial
Bibliographic record
Abstract
Abstract Background: The copy number aberration derived endocrine response (CADER) gene signature was developed as a prognostic marker for hormone receptor positive breast cancer; it combines information derived from both gene expression and copy number aberration and was trained on samples from both the neoadjuvant and adjuvant settings (see separate CADER nanostring assay methodology abstract, Luo et al). We examined the effects of CADER on outcome in the MA.12 trial to evaluate the association of CADER and PAM 50 with relapse. Methods: From 1993 to 2000, MA.12 accrued 672 women to a placebo-controlled pre-menopausal trial of adjuvant tamoxifen with locally assessed hormone receptor +/- tumors. The 9.7 years median follow-up was used here. A secondary endpoint was disease free survival (DFS), defined as time from randomization to the earliest date of recurrence or death; censoring was at the last date the patient was known to be alive. Stratification factors were type of chemotherapy (CMF vs CEF vs AC), hormone receptor status (ER and/or PgR positive vs ER and PgR negative), and nodal status (0 vs 1–3 vs 4–9 vs 10+). Exact Fisher tests were used to compare baseline characteristics of those assessed, or not, for CADER. We examined the effects of the CADER classifications (sensitive, indeterminate, resistant) for hormone receptor positive patients. The prognostic effects of CADER, and preexisting qPCR PAM50 ROR-S, and PAM50 intrinsic subtype (Chia et al, CCR 16, 4465, 2012) on DFS were examined with stratified multivariate Cox regression, adjusted for treatment and baseline patient characteristics. An interaction test with treatment was used to assess evidence for CADER as a predictive signature. Graphical depiction was with adjusted Cox survivor plots. Results: CADER was assessed in 434 (65%) of the 672 patients: 213 patients on the tamoxifen arm; 221, on the placebo arm. Proportionately more patients profiled for CADER underwent CEF adjuvant chemotherapy (p=0.03) so we performed only stratified analyses. Of the 434 patients, 317 (73%) had hormone receptor breast tumors. The CADER classifications significantly impacted DFS (p=0.04): hazard ratio (HR) of indeterminate CADER to sensitive=2.29 (95% CI 0.93-5.62; p=0.07); HR of resistant to sensitive=3.72 (95% CI 1.33-10.42, p=0.01). Patients with low ROR-S had longer DFS (p=0.04), while PAM50 intrinsic subtype did not significantly impact DFS (p=0.51). CADER and ROR-S were not predictive factors. Conclusions: In MA.12 hormone-receptor patients, both CADER and ROR-S had significant prognostic effects on disease free survival. Neither CADER nor PAM50 ROR were predictive in this placebo-controlled tamoxifen trial. We confirmed here the earlier clinical prognostic relevance of CADER that was seen during the signature’s development. Citation Format: Matthew J Ellis, Bingshu Chen, Judy-Anne W Chapman, Jingqin Luo, Diana Ma, Lois Shepherd, Jeremy Hoog, Samuel Leung, Elaine Mardis, Sherri R Davies, Torsten O Nielsen, Vivien Bramwell. CADER prognostic gene signature for disease free survival in hormone receptor positive breast cancer: NCIC CTG MA.12 phase III placebo-controlled tamoxifen trial [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-11.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| 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 | 0.002 |
| 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".