title: Diurnal cortisol rhythm as a predictor of breast cancer survival.
abstract: BACKGROUND
  : Abnormal circadian rhythms have been observed in patients with cancer, but the prognostic value of such alterations has not been confirmed. We examined the association between diurnal variation of salivary cortisol in patients with metastatic breast cancer and subsequent survival. We explored relationships between cortisol rhythms, circulating natural killer (NK) cell counts and activity, prognostic indicators, medical treatment, and psychosocial variables.
  
  
  METHODS
  Salivary cortisol levels of 104 patients with metastatic breast cancer were assessed at study entry at 0800, 1200, 1700, and 2100 hours on each of 3 consecutive days, and the slope of diurnal cortisol variation was calculated using a regression of log-transformed cortisol concentrations on sample collection time. NK cell numbers were measured by flow cytometry, and NK cell activity was measured by the chromium release assay. The survival analysis was conducted by the Cox proportional hazards regression model with two-sided statistical testing.
  
  
  RESULTS
  Cortisol slope predicted subsequent survival up to 7 years later. Earlier mortality occurred among patients with relatively "flat" rhythms, indicating a lack of normal diurnal variation (Cox proportional hazards, P =. 0036). Patients with chest metastases, as opposed to those with visceral or bone metastases, had more rhythmic cortisol profiles. Flattened profiles were linked with low counts and suppressed activity of NK cells. After adjustment for each of these and other factors, the cortisol slope remained a statistically significant, independent predictor of survival time. NK cell count emerged as a secondary predictor of survival.
  
  
  CONCLUSIONS
  Patients with metastatic breast cancer whose diurnal cortisol rhythms were flattened or abnormal had earlier mortality. Suppression of NK cell count and NK function may be a mediator or a marker of more rapid disease progression.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, KY 40292-0001, USA. sephton@louisville.edu
authors.forename: S E
authors.initials: SE
authors.lastname: Sephton
authors.forename: R M
authors.initials: RM
authors.lastname: Sapolsky
authors.forename: H C
authors.initials: HC
authors.lastname: Kraemer
authors.forename: D
authors.initials: D
authors.lastname: Spiegel
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000401:mortality / Q000523:psychology / Q000628:therapy; D002940:Circadian Rhythm; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D007457:Iodine Radioisotopes; D007694:Killer Cells, Natural / Q000378:metabolism; D018655:Lymphocyte Count; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D011863:Radioimmunoassay; D012463:Saliva / Q000378:metabolism*; D012944:Social Support; D016019:Survival Analysis
chemical_list: D007457:Iodine Radioisotopes; D006854:Hydrocortisone