Abstract P3-06-03: Downregulation of histone H2A and H2B pathways is associated with anthracycline sensitivity in breast cancer
Bibliographic record
Abstract
Abstract Background: Meta-analyses performed by the Early Breast Cancer Trialists Collaborative Group demonstrated a significant increase in disease free and overall survival through the addition of anthracyclines to polychemotherapy. Anthracyclines have, however, significant toxicities including cardiotoxicity and leukaemia. It is, therefore, imperative to identify those patients who will benefit from adjuvant anthracycline treatment; other patients could then be spared unnecessary toxicities and be considered for alternative adjuvant therapy. Several markers that may predict anthracycline benefit have been explored in patient cohorts (HER2, TOP2A, Ch17CEP and TIMP1) with limited success. Methods: To identify markers that are clinically-relevant, we generated MDA-MB-231, MCF7, SKBR3 and ZR-75-1 breast cancer cell lines sensitive and resistant to epirubicin to identify pathways contributing to anthracycline resistance. A complementary approach including gene expression analyses to identify molecular pathways involved in resistance, and small-molecule inhibitors to reverse resistance were performed. RNA was extracted from patients in the BR9601 adjuvant trial evaluating the addition of epirubicin (E) to CMF and analysed through Nanostring technology. Log-rank analyses explored the predictive values of the signatures on distant relapse-free survival (DRFS). Cox-regression models tested independent predictive value on DRFS in the presence of treatment, age, tumour size, nodal status, ER status and grade, and treatment by marker interactions. Results: Gene expression analysis identified upregulaton of a histone gene module in all four cell lines which was validated by qRT-PCR. Histone deacetylase small-molecule inhibitors reversed resistance and were cytotoxic for epirubicin-resistant cell lines, with IC50's ranging from 0.1-3.69µM, confirming that histone pathways are associated with epirubicin resistance. Gene expression analysis of the 18-gene histone module in the BR9601 clinical cohort revealed that patients whose tumour had low expression had an increased DRFS (HR: 0.35, 95%CI 0.17-0.73, p=0.005) when treated with E-CMF compared with patients treated with CMF alone. Conversely, there was no apparent benefit of E-CMF vs CMF in patients with high histone module expression (HR: 0.96, 95%CI 0.58-1.59, p=0.87). After multivariate analysis and adjustment for HER2 status, nodal status, age, grade and ER status, the treatment by marker interaction was 0.35 (95%CI 0.13-0.96, p=0.042) for DRFS. Conclusion: Histone gene expression was an independent predictor of anthracycline benefit in terms of DRFS. In vitro data demonstrated that resistance could be reversed with histone deacetylase small-molecule inhibitors. The histone signature identified could be a potential theranostic candidate for patients with early breast cancer. Citation Format: Spears M, Braunstein M, Liao L, Yao C, Lyttle N, Lobo N, Taylor KJ, Krzyzanowski PM, Kalatskaya I, Marcellus R, Stein L, Boutros P, Twelves CJ, Bartlett JMS. Downregulation of histone H2A and H2B pathways is associated with anthracycline sensitivity in breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-06-03.
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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 | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.003 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 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".