Aberrant nocturnal cortisol and disease progression in women with breast cancer
- 422 Downloads
While a relationship between disruption of circadian rhythms and the progression of cancer has been hypothesized in field and epidemiologic studies, it has never been unequivocally demonstrated. We determined the circadian rhythm of cortisol and sleep in women with advanced breast cancer (ABC) under the conditions necessary to allow for the precise measurement of these variables. Women with ABC (n = 97) and age-matched controls (n = 24) took part in a 24-h intensive physiological monitoring study involving polysomnographic sleep measures and high-density plasma sampling. Sleep was scored using both standard clinical metrics and power spectral analysis. Three-harmonic regression analysis and functional data analysis were used to assess the 24-h and sleep-associated patterns of plasma cortisol, respectively. The circadian pattern of plasma cortisol as described by its timing, timing relative to sleep, or amplitude was indistinguishable between women with ABC and age-matched controls (p′s > 0.11, t-tests). There was, however, an aberrant spike of cortisol during the sleep of a subset of women, during which there was an eightfold increase in the amount of objectively measured wake time (p < 0.004, Wilcoxon Signed-Rank). This cortisol aberration was associated with cancer progression such that the larger the aberration, the shorter the disease-free interval (time from initial diagnosis to metastasis; r = −0.30, p = 0.004; linear regression). The same aberrant spike was present in a similar percent of women without ABC and associated with concomitant sleep disruption. A greater understanding of this sleep-related cortisol abnormality, possibly a vulnerability trait, is likely important in our understanding of individual variation in the progression of cancer.
KeywordsCortisol Breast cancer Survival Sleep Circadian
This work was supported by the National Cancer Institute (R01CA118567) and the National Center for Research Resources (UL1RR025744) at the National Institutes of Health. We thank our research participants for their time, wisdom, and willingness to participate, and the Dr. Susan Love Research Foundation’s Love/Avon Army of Women Program for their assistance in recruitment. We also wish to thank the nursing staff of the Clinical Translational Research Unit for staffing the studies, Ms. Chung-Ping Liao and Mr. Ryan Fisicaro for conducting the cortisol assays, and Mr. Daniel East for scoring the sleep data. We wish to thank Dr. Youngmee Kim for suggesting valuable edits to the manuscript.
Compliance with ethical standards
Conflict of interest
The authors have no conflicts of interest to declare.
- 7.Stevens RG, Hansen J, Costa G, Haus E, Kauppinen T, Aronson KJ, Castano-Vinyals G, Davis S, Frings-Dresen MH, Fritschi L, Kogevinas M, Kogi K, Lie JA, Lowden A, Peplonska B, Pesch B, Pukkala E, Schernhammer E, Travis RC, Vermeulen R, Zheng T, Cogliano V, Straif K (2011) Considerations of circadian impact for defining ‘shift work’ in cancer studies: IARC Working Group Report. Occup Environ Med 68:154–162CrossRefPubMedGoogle Scholar
- 9.Czeisler CA, Klerman EB (1999) Circadian and sleep-dependent regulation of hormone release in humans. Rec Prog Hormone Res 54:97–132Google Scholar
- 18.Karnofsky DA, Burchenal JH (1949) The clinical evaluation of chemotherapeutic agents in cancer. In: MacLeod CM (ed) evaluation of chemotherapeutic agents. Columbia University Press, New York, pp 191–205Google Scholar
- 23.Spielberger C, Gorusch RI, Lushene R, Vagg PR, Jacobs GA (1983) State-Trait Anxiety Inventory for Adults. Consulting Psychologists Press Inc, Palo AltoGoogle Scholar
- 24.Weathers FW, Litz BT, Huska JA, Keane TM (1994) PTSD Checklist - Civilian Version. National Center for PTSD, Behavioral Science Division, BostonGoogle Scholar
- 27.Mifflin MD, St.Jeor ST, Hill LA, Scott BJ, Daugherty SA, Koh YO (1990) A new predictive equation for resting energy expenditure in healthy individuals. Amer J Clin Nutrition 51:241–247Google Scholar
- 29.Development Core Team R (2010) R: A language and environment for statistical computing, version Vienna. R Foundation for Statistical Computing, AustriaGoogle Scholar
- 31.Rechtschaffen, A. and Kales, A. (1968) A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects. Washington D.C.: US Department of Health, Education, and Welfare, Government Printing OfficeGoogle Scholar
- 33.Cohen L, Cole SW, Sood AK, Prinsloo S, Kirschbaum C, Arevalo JMG, Jennings NB, Scott S, Vence L, Wei Q, Kentor D, Radvanyi L, Tannir N, Jonasch E, Tamboli P, Pisters L (2012) Depressive symptoms and cortisol rhythmicity predict survival in patients with renal cell carcinoma: role of inflammatory signaling. PLoS One 7:e42324CrossRefPubMedPubMedCentralGoogle Scholar
- 35.Thaker PH, Han LY, Kamat AA, Arevalo JM, Takahashi R, Lu C, Jennings NB, Armaiz-Pena G, Bankson JA, Ravoori M, Merritt WM, Lin YG, Mangala LS, Kim TJ, Coleman RL, Landen CN, Li Y, Felix E, Sanguino AM, Newman RA, Lloyd M, Gershenson DM, Kundra V, Lopez-Berestein G, Lutgendorf SK, Cole SW, Sood AK (2006) Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med 12:939–944CrossRefPubMedGoogle Scholar