title: Wrist actimetry circadian rhythm as a robust predictor of colorectal cancer patients survival.
abstract: The disruption of the circadian timing system (CTS), which rhythmically controls cellular metabolism and proliferation, accelerated experimental cancer progression. A measure of CTS function in cancer patients could thus provide novel prediction information for outcomes, and help to identify novel specific therapies. The rest-activity circadian rhythm is a reliable and non-invasive CTS biomarker, which was monitored using a wrist watch accelerometer for 2 days in 436 patients with metastatic colorectal cancer. The relative percentage of activity in-bed versus out-of-bed (I < O) constituted the tested CTS measure, whose prognostic value for overall survival (OS) and progression-free survival (PFS) was determined in a pooled analysis of three patient cohorts with different treatment exposures. Median OS was 21.6 months [17.8-25.5] for patients with I < O above the median value of 97.5% as compared to 11.9 months [10.4-13.3] for those with a lower I < O (Log-rank p < 0.001). Multivariate analyses retained continuous I < O as a joint predictor of both OS and PFS, with respective hazard ratios (HR) of 0.954 (p < 0.001) and 0.970 (p < 0.001) for each 1% increase in I < O. HRs had similar values in all the patient subgroups tested. The circadian physiology biomarker I < O constitutes a robust and independent quantitative predictor of cancer patient outcomes, that can be easily and cost-effectively measured during daily living. Interventional studies involving 24-h schedules of clock-targeted drugs, light intensity, exercise and/or meals are needed for testing the relevance of circadian synchronization for the survival of patients with disrupted rhythms.
authors.affiliation: Biological Rhythms and Cancers, INSERM, UMRS , Villejuif Cedex , France .
authors.forename: Francis
authors.initials: F
authors.lastname: Lévi
authors.forename: Pierre-Antoine
authors.initials: PA
authors.lastname: Dugué
authors.forename: Pasquale
authors.initials: P
authors.lastname: Innominato
authors.forename: Abdoulaye
authors.initials: A
authors.lastname: Karaboué
authors.forename: Garance
authors.initials: G
authors.lastname: Dispersyn
authors.forename: Arti
authors.initials: A
authors.lastname: Parganiha
authors.forename: Sylvie
authors.initials: S
authors.lastname: Giacchetti
authors.forename: Thierry
authors.initials: T
authors.lastname: Moreau
authors.forename: Christian
authors.initials: C
authors.lastname: Focan
authors.forename: Jim
authors.initials: J
authors.lastname: Waterhouse
authors.forename: David
authors.initials: D
authors.lastname: Spiegel
mesh_terms: D000054:Acceleration; D056044:Actigraphy / Q000379:methods*; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D002940:Circadian Rhythm; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018670:Monitoring, Ambulatory / Q000379:methods*; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D016896:Treatment Outcome; D014953:Wrist / Q000503:physiopathology*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers
keywords: Biomarkers; cancer; circadian clock; rest-activity rhythm; survival