Abstract P3-06-01: Nuclear β-catenin negativity predicts for late relapse in ER+, tamoxifen-treated breast cancer
Bibliographic record
Abstract
Abstract Background: The annual recurrence rates of post-menopausal ER-positive breast cancers persist beyond the first 5 years of diagnosis and treatment and the mortality rates in this period are higher versus ER-negative cancers. Extended endocrine therapy past 5 years has been shown to be of benefit but is associated with increased toxicity and cost thus the ability to predict patients who are at highest risk of late relapse would be of significant benefit in clinical decision making in this context. β-catenin is an intracellular protein that undergoes Wnt-mediated nuclear translocation where it transactivates genes implicated in tumour development and progression. We have also previously reported that β-catenin can play a role in aggressive resistance that accompanies prolonged endocrine treatment in vitro. In this study, we thus investigated whether β-catenin expression in ER+ breast cancer was predictive of recurrence beyond 5 years in an analysis of three separate endocrine-treated cohorts. Methods: Associations between β-catenin gene expression and relapse free survival (RFS) were performed using the online KMplotter tool. Immunostaining for total β-catenin was performed on tissue samples from 3 ER+ primary breast cancer series with long-term follow-up data: Nottingham 2000 (n=384, tamoxifen-only); ABC (n=570; tamoxifen only); transATAC (n=743; tamoxifen or ansatrozole). The association between subcellular (nuclear or cytoplasmic) β-catenin expression and RFS was determined in (i) the entire cohort, (ii) the first 5 years of tamoxifen treatment versus post-5 years. Results: KMplotter analysis of β-catenin in ER+, tamoxifen-treated patient samples (n=665) revealed a significant relationship with improved RFS in the post-five year cohort [HR: 0.48 (0.34-0.68); p=0.000019) versus the first 5 years [HR: 0.91 (0.61-1.36; p=0.64)]. No significant association was observed in untreated ER+ patients. In the Nottingham series, nuclear β-catenin positivity was significantly associated with improved survival in the 20-year follow-up for tamoxifen-treated patients (p=0.047) but not in the first five years (p=0.239). Cytoplasmic β-catenin did not associate with survival. Further analysis in the ABC series revealed an association between nuclear β-catenin positivity and improved survival for tamoxifen-treated patients in the entire cohort (HR: 0.52 (0.18, 0.55); p=0.00005). However, nuclear β-catenin was more strongly associated with improved outcome in the post 5-year treatment group (HR: 0.30 (0.14, 0.66); p=0.01) versus the first five years of treatment (HR: 0.33 (0.15,0.73); p=0.06). No significant associations were seen with cytoplasmic β-catenin. The transATAC trial material again revealed an association between presence of nuclear β-catenin and reduced distant recurrence in the post 5-years endocrine-treated cohort (HR: 0.54 (0.33, 0.91): x2=5.52, p=0.018) versus years 1-5 (HR: 1.16 (0.67, 2.01); x2=0.29, p=0.59). Conclusions: This is the first study to demonstrate that nuclear β-catenin may represent a predictive biomarker for late relapse following tamoxifen treatment in ER+ breast cancer where, contrary to traditional hypotheses and pre-clinical data, its nuclear expression is strongly associated with good outcome post-five years of treatment. Citation Format: Stephen Hiscox, Chris Smith, Robert I Nicholson, Julia Gee, Adrian Harris, Judith Bliss, Eleftheria Kalaizak, Ivana Sestak, Mitch Dowsett, Jack Cuzick, Ian Ellis, Peter Barrett-Lee. Nuclear β-catenin negativity predicts for late relapse in ER+, tamoxifen-treated breast cancer [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 P3-06-01.
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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 | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| 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) | 0.003 | 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".