Abstract 644: Tumor circadian dysfunction is associated with improved survival in breast cancer patients on neoadjuvant chemotherapy (NAC)
Bibliographic record
Abstract
Abstract Introduction Previous studies highlighted the relevance of circadian rhythms for carcinogenesis and therapy in breast cancer. These rhythms are generated in each cell by a molecular clock. We have developed a machine-learning approach (TimeTeller) and constructed an algorithm to measuring circadian clock functionality from the expression levels of clock genes in a single tissue sample (Vlachou et al. Rxiv 2020). Methods TimeTeller was used to analyse tumor molecular clock dysfunction in biopsies from 226 breast cancer patients prior to NAC. Tumour transcriptome was determined using the Affymetrix U133A (Giacchetti et al. EJC 2017). A measure Θ of the level of dysfunction of the cellular clock was computed using TimeTeller, based on the relative mRNA expressions of 16 clock genes, which displayed largest circadian expressions in healthy mouse and human tissues sampled at > 6 circadian times. Thus Θ < 0.1 was indicative of a functional clock in humans irrespective of sampling time. To determine the prognostic value of continuous Θ for breast cancer patients'survival at ten years, we calculated the hazard ratios (HRs) associated with overall survival (OS) and disease-free survival (DFS) of the 226 patients receiving NAC, using the Cox proportional hazards model. HR1/10 corresponded to the risk of an earlier death or relapse for a change of 0.1 in Θ. Results: The breast cancer Θ values ranged from 0.02 to 0.29, with a median of 0.058 [IQR, 0.09]. As compared to patients whose tumor Θ was < median, patients with tumor Θ>median had higher survival rate (71% vs 81%, p = 0.01) and DFS rate, 65% vs 74%, p = 0.02) at 10-years. Multivariate analyses identified continuous Θ as an independent prognostic factor for both OS (HR1/10, 0.38 [0.17-0.84] (p = 0.016) and DFS (HR1/10, 0.46 [0.27-0.80] (p = 0.005), jointly with tumor size for OS (HR1/10, 1.73 [1.12-2.70], p =0.014) and HER2 for DFS (HR1/10, 0.43 [0.23-0.79], p = 0.007). The relevance of Θ was further explored in the three main breast cancer categories. In the HER2+ subset, the HR associated with Θ was 0.19 for OS (p=0.058) and 0.22 for DFS (p=0.048, single significant prognostic factor). The HR1/10 increased to 0.45 for OS and 0.57 for DFS in the HER2-/hormonal receptors + subset, and to 0.45 and 0.46 respectively for the TN group (p>0.10), suggesting a lesser independent prognostic effect of Θ in these subsets. The patients who achieved pCR had a higher median Θ as compared to those who did not (p = 0.035), supporting increased chemosensitivity of those tumors with clock dysfunction to conventional NAC Conclusion: In this population of women on NAC for primary breast cancer, tumor circadian clock dysfunction, as computed by the TimeTeller algorithm, was the strongest independent predictor of survival. Thus, conventional chemotherapy efficacy may be enhanced in tumors with deregulated metabolism and proliferation, as a result of circadian clock dysfunction. Citation Format: Sylvie Giacchetti, Denise Vlachou, Georg A. Bjarnason, David A. Rand, Francis A. Levi. Tumor circadian dysfunction is associated with improved survival in breast cancer patients on neoadjuvant chemotherapy (NAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 644.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.010 | 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".