Diurnal cortisol and survival in epithelial ovarian cancer
Introduction
Ovarian cancer is the second most commonly diagnosed gynecologic malignancy and the most deadly, with five year survival rates of 44% for all patients, and 27% for patients with metastatic disease (American Cancer Society, 2014). Recent research has demonstrated effects of neuroendocrine signaling on a variety of pathways implicated in ovarian tumor growth including angiogenesis, invasion, anoikis, and promotion of inflammation in the tumor microenvironment (Cole and Sood, 2012). To date, mechanisms that have been characterized predominantly involve beta-adrenergic signaling. Neuroendocrine signals from the hypothalamic-pituitary-adrenal (HPA) axis regulate endogenous inflammation and metabolic activity, via the release of glucocorticoids (Tsigos and Chrousos, 2002). Although glucocorticoids are known to play a regulatory role in other cancers, little is known about the role of the HPA axis in the context of ovarian cancer.
Cortisol, a glucocorticoid, is released into circulation by the adrenal cortex following upstream signaling from the pituitary and hypothalamus (Rhen and Cidlowski, 2005). Cortisol follows a diurnal cycle; levels typically peak in the morning and reach a nadir during the second half of the night, though significant inter-individual differences are common even in apparently healthy people (Chrousos, 1995, Stone et al., 2001, Clow et al., 2010). Excess circulating cortisol provides negative feedback to the hippocampus and hypothalamus, however, under conditions of chronic inflammation the feedback system can become unresponsive, resulting in abnormal diurnal cortisol rhythms (Silverman and Sternberg, 2012).
Glucocorticoids have a variety of effects in cancer; they have been shown to inhibit apoptosis in breast, cervical and ovarian cancer cell lines and in animal models of breast cancer (Volden and Conzen, 2013). Incubation of ovarian cancer cells with cortisol has been shown to reduce expression of tumor-suppressor genes SLIT2 and ROBO1 (Dickinson et al., 2011), as well as to suppress the cytotoxic effects of paclitaxel, a drug commonly used in ovarian cancer chemotherapy (Flint et al., 2009). Moreover, flattened diurnal cortisol rhythms have been linked to decreased survival in breast, lung, and renal cell carcinoma patients, adjusting for clinical and demographic characteristics (Sephton et al., 2000, Sephton et al., 2013, Cohen et al., 2012). For example, in a recent study of renal cell carcinoma patients, flatter cortisol slope was associated with an approximately two-fold greater likelihood of death (HR = 1.9, 95% CI 1.3, 3.0) adjusting for a variety of disease characteristics (Cohen et al., 2012).
We have previously observed an altered cortisol diurnal rhythm in ovarian cancer patients prior to surgery compared to that of pre-surgical patients with benign disease and healthy controls not facing surgery. Ovarian cancer patients show elevated afternoon and nocturnal cortisol, resulting in blunted diurnal cortisol variability (Weinrib et al., 2010). These patterns of dysregulation have been associated with elevated measures of systemic inflammation in ovarian cancer patients (Lutgendorf et al., 2008, Schrepf et al., 2013). This inflammation is hypothesized to be tumor-derived (Edgell et al., 2010). Furthermore, inflammation in the tumor microenvironment is strongly linked to ovarian cancer progression (Kulbe et al., 2012). Animal models have demonstrated that tumor growth can activate the HPA axis and induce systemic inflammatory signaling (Lamkin et al., 2011, Yang et al., 2014). However, HPA activity has not been investigated in the context of survival in ovarian cancer. Moreover, the relationship between HPA activity and inflammation measured in the vicinity of the tumor has not been previously characterized in the clinical setting of ovarian cancer.
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Participants
Participants were 113 women at least 18 years of age, with no auto-immune disease or systemic steroid use (i.e. prednisone) and no previous history of cancer. Participants were eligible if histology confirmed primary invasive epithelial ovarian, primary peritoneal, or fallopian tube carcinoma. Patients were excluded if diagnosis was a primary cancer of another organ, an ovarian tumor of non-epithelial origin, a tumor of low malignant potential, or benign disease. Included patients had surgery
Sample characteristics
Patients were approximately 58 years old (on average) at the time of study entry, married/living with a partner, and college educated. Demographic and clinical information is presented in Table 1. Patients who participated in the study did not differ significantly from those who declined to supply cortisol (n = 49) on demographics (all p < .19) or disease characteristics including disease stage (p = .60), tumor grade (p = .84), cytoreduction (p = .50) tumor histology (p = .10), initial cycles of
Discussion
The key finding of this study is that dysregulated function of the HPA axis, evidenced by reduced diurnal cortisol variability, flattened diurnal cortisol slope, and elevated night cortisol, is associated with decreased survival time in ovarian cancer patients, controlling for relevant clinical and demographic covariates. This is the first study demonstrating that HPA function at the time of surgery is associated with significant differences in survival for ovarian cancer. It should be noted
Role of the funding source
This research was funded in part by grants CA88293 (Lutgendorf), CA104825 (Lutgendorf), CA140933 (Lutgendorf), CA109298 (Sood), CA116778 (Sood), and P50CA083639 (Sood), from the National Cancer Institute. The National Cancer Institute had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.
Conflict of interest
The authors declare that they have no conflict of interest.
Acknowledgements
The authors gratefully acknowledge the assistance of Lauren Clevenger, Desire Christensen, Amy Nichols, Katherine Collins, Heena Maiseri, the Gynecologic Oncology faculty and staff at all institutions, and the time and efforts of the patients who participated in this study. This research was funded in part by grants CA88293 (Lutgendorf), CA104825 (Lutgendorf), CA140933 (Lutgendorf), CA109298 (Sood), CA116778 (Sood), and P50CA083639 (Sood), from the National Cancer Institute.
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