Abstract 644: Tumor circadian dysfunction is associated with improved survival in breast cancer patients on neoadjuvant chemotherapy (NAC)
Notice bibliographique
Résumé
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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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,010 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».