Veneris JT, Darcy KM, Mhawech-Fauceglia P, et al. High glucocorticoid receptor expression predicts short progression-free survival in ovarian cancer [published online ahead of print April 26, 2017]. Gynecol Oncol. 2017.
To determine the association between tumor glucocorticoid receptor (GR) expression and clinical characteristics, progression-free survival (PFS), and overall survival (OS) in patients with ovarian cancer.
The patient population consisted of 481 women with ovarian cancer treated between 1995 and 2010 and 4 patients with benign ovarian conditions. Glucocorticoid receptor expression was analyzed from tissue microarrays of ovarian specimens derived at the time of cytoreductive surgery. Of these cases, the analysis focused on 341 specimens from patients who received debulking surgery before beginning chemotherapy and who had complete clinical follow-up data. The median age was 59 years (range 24-89 years), and the majority of tumors (70.9%) were serous carcinomas. Most (91.2%) tumors were high grade (grade 2 or 3) and advanced stage (International Federation of Gynecology and Obstetrics [FIGO] III or IV) (71.8%).
The GR expression was correlated with tumor histology, tumor grade, tumor stage, PFS, and OS.
High GR expression (defined as over 1% tumor cells with 2+ or 3+ intensity staining) was present in 39% of tumors; the highest prevalence was in serous tumors and the lowest in endometrioid tumors. Furthermore, high GR expression was correlated with higher grade (P<0.001) and advanced stage at diagnosis (P=0.037 early vs advanced). High GR expression was associated with a 66% increased risk of disease progression (hazard ratio [HR]=1.66; 95% confidence interval [CI]=1.29-2.14) and 15 months shorter median PFS compared to tumors with low GR expression (20.4 vs 36.0 months respectively, P<0.001). There was no significant difference in OS by GR expression.
The lack of an association with OS may have been obscured by the fact that there was only a weak association between GR expression and advanced high grade serous cancers—the most predominant subgroup in the study. Finally, in a multivariate analysis, high GR expression was an independent predictor of PFS (HR=1.41; 95% CI 1.08-1.84, P=0.012).
This study provides further evidence of a link between glucocorticoids and ovarian cancer prognosis. In this study, GR expression was positively correlated with attributes of aggressive tumor behavior (grade and stage) and, not surprisingly, with PFS. The GR is a nuclear hormone receptor that is activated by endogenous cortisol and synthetic glucocorticoids. Tumor cells with greater GR expression are, therefore, more susceptible to the effects of hypercortisolemia, a physiologic state associated with prolonged and/or severe physical and psychosocial stress. The implication of this association suggests that stress may drive more aggressive ovarian cancer subtypes.
Simply stated, elevated stress hormones are associated with aggressive ovarian cancer.
The link between stress and ovarian cancer prognosis is not new. Prior work by Guillermo and colleagues found that norepinephrine, a stress-induced catecholamine, activates the Src pro-survival pathway in ovarian cancer cells.1 Catecholamines have also been found to increase prostaglandin E2 levels in ovarian cancer cells, resulting in inflammation, which in turn drives tumor proliferation and metastasis.2
Additionally, Lutgendorf et al found that patients with depression, chronic stress, and low social support have elevated matrix metalloproteinase-9 (MMP-9) in tumor-associated macrophages.3 Expression of MMP-9 is associated with increased tumor proliferation and metastasis. Furthermore, norepinephrine and cortisol directly enhance macrophage production of MMP-9. Sood et al demonstrated that norepinephrine at levels compatible with those seen in situations of psychosocial stress increases in vitro invasiveness of ovarian cancer cells by 89% to 198%.4 Blockage of b-adrenergic receptors by b-adrenergic antagonist propranolol abrogates this effect, recently demonstrated clinically with the perioperative use of propranolol resulting in reduced tumor burden (as measured by cancer antigen [CA] 125).5
While the mechanisms underlying the connection between stress hormones and ovarian cancer prognosis are now well-elucidated, the clinical implications of this connection have yet to be fully realized. Simply stated, elevated stress hormones are associated with aggressive ovarian cancer. Most women diagnosed with ovarian cancer respond to first-line surgery and chemotherapy; however, subsequent recurrence adversely affects survival. Thus, it is imperative to assess ongoing psychosocial stress in women diagnosed with ovarian cancer. In addition to direct queries, objective measurement of cortisol with a 4-point cortisol test or a one-time cortisol sample at bedtime is indicated. Altered circadian rhythms, specifically elevated nocturnal cortisol, flattened diurnal cortisol slope, and reduced cortisol variability are each associated with lower overall survival in women with ovarian cancer.6
Further, among women with ovarian cancer, higher levels of nocturnal cortisol are associated with fatigue and with vegetative depression (low energy, apathy, social withdrawal, and hypersomnia).7 Thus, the presence of these physical and psychological symptoms should trigger investigation into impaired hypothalamic-pituitary-adrenal (HPA) axis and nocturnal cortisol, specifically.
Of note, the diurnal cortisol dysregulation among cancer patients does not necessarily occur as a result of heightened sensitivity to stress per se, but may be due to impaired HPA axis feedback inhibition, which affects one’s resilience rather than reactivity. In addition, impaired sleep due to cortisol dysregulation can result in upregulation of many inflammatory pathways, leading to progression of disease.8
Assessment is most relevant when it leads to specific treatment interventions. If a patient with ovarian cancer is found to have elevated cortisol and/or HPA axis dysfunction, interventions to support the restoration of HPA diurnal rhythm are well-justified. Of course, central to naturopathic practice is the use of herbal adaptogens. Most adaptogens increase adrenocorticotropic hormone (ACTH) and cortisol with single, high-dose administration and normalize ACTH and cortisol with longer-term administration and when given prior to stressors.9,10 A key mechanism of adaptogens is the restoration of hypothalamic and pituitary sensitivity to the negative feedback of cortisol, thus lowering nocturnal cortisol.11 Adaptogenic plants such as Eleutherococcus senticosus (Siberian ginseng), Rhodiola rosea (Rhodiola), Withania somnifera (Ashwagandha), and Ocimum sanctum (Holy basil) are a few of many to consider.
Social support is also critical in lowering stress catecholamines. Low social support accompanied by depressive symptoms is associated with elevated intratumoral norepinephrine levels. Conversely, patients with ovarian cancer with higher levels of perceived social support have lower inflammatory cytokines, including interleukin (IL)-6, lower MMP-9, and increased tumor-infiltrating lymphocytes.12 Not surprisingly, greater social attachment is associated with a lower likelihood of death (HR: 0.87; 95% CI: 0.77-0.98; P=.018) in patients with ovarian cancer.13
An exciting finding related to lowering tumor norepinephrine in patients with epithelial ovarian cancer concerns eudaimonic well-being. Eudaimonic well-being describes experiencing a deeper sense of meaning in life, a sense of fulfilling one’s potential, and deep self-acceptance. In an observational study by Davis et al, eudaimonic well-being was associated with lower tumor norepinephrine, independent of positive affect and psychological distress.14 These findings suggest that a deeper sense of well-being in patients with ovarian cancer may be more physiologically protective than being positive or simply being stress-free. Interventions that specifically support eudaimonic well-being such as mindfulness interventions, positive psychology, and gratitude practices may have profound physiologic effects.
Finally, reinstating optimal HPA axis diurnal rhythmicity to lower elevated nocturnal cortisol is a direct way to modulate the impact of stress hormones and ovarian cancer prognosis. The master regulator of circadian rhythm is melatonin, itself influenced by light/dark cycle. Nighttime light and consequent disruption in melatonin production therefore has a profound uncoupling effect on circadian timing.15 In addition to darkening the night environment, exogenous supplementation of melatonin at night can facilitate restoration of the circadian timing.16
[See the article in this issue on camping as a way to reset melatonin production.]
Overall, the body of evidence supporting a link between elevated stress hormones and worse ovarian cancer prognosis is becoming more definitive. Interventions to reduce norepinephrine and cortisol deserve a place in the integrative standard of care for women diagnosed with ovarian cancer.
- Guillermo A-P, Allen J, Cruz A, et al. Src activation by b-adrenoreceptors is a key switch for tumour metastasis. Nat Commun. 2013;4:1403.
- Nagaraja AS, Dorniak PL, Sadaoui NC, et al. Sustained adrenergic signaling leads to increased metastasis in ovarian cancer via increased PGE2 synthesis. Oncogene. 2016;35(18):2390-2397.
- Lutgendorf SK, Lamkin DM, Jennings NB, et al. Biobehavioral influences on matrix metalloproteinase expression in ovarian carcinoma. Clin Cancer Res. 2008;14(21):6839-6846.
- Sood AK, Bhatty R, Kamat AA, et al. Stress hormone – mediated invasion of ovarian cancer cells. Clin Cancer Res. 2006;12(2):369-375.
- Jang HI, Lim SH, Lee YY, et al. Perioperative administration of propranolol to women undergoing ovarian cancer surgery: a pilot study. Obstet Gynecol Sci. 2017; 60(2):170-177.
- Schrepf A, Thaker PH, Goodheart MJ, et al. Diurnal cortisol and survival in epithelial ovarian cancer. Psychoneuroendocrinology. 2015;53:256-267.
- Weinrib AZ, Sephton SE, DeGeest Koen, et al. Diurnal cortisol dysregulation, functional disability, and depression in women with ovarian cancer. Cancer. 2010;116(18):4410-4419.
- Eismann EA, Lush E, Sephton SE. Circadian effects in cancer-relevant psychoneuroendocrine and immune pathways. Psychoneuroendocrinology. 2010;35(7):963-976.
- Panossian A, Wagner H. Stimulating effect of adaptogens: an overview with particular reference to their efficacy following single dose administration. Phytother Res. 200;19(10):819-838.
- Kimura Y, Sumiyoshi M. Effects of various Eleutherococcus senticosus cortex on swimming time, natural killer activity and corticosterone level in forced swimming stressed mice. J Ethnopharmacol. 2004;95(2-3):447-453.
- Panossian A, Wikman G. Evidence-based efficacy of adaptogens in fatigue, and molecular mechanisms related to their stress-protective activity. Curr Clin Pharmacol. 2009;4(3):198-219.
- Lutgendorf SK, De Geest K, Dahmoush L, et al. Social isolation is associated with elevated tumor norepinephrine in ovarian carcinoma patients. Brain Behav Immun. 2010;25:250-255.
- Lutgendorf SK, DeGeest K, Bender D. Social influences on clinical outcomes of patients with ovarian cancer. J Clin Oncol. 2012;30(23):2885-2890.
- Avis LZ, Siavich GM, Thaker PH, et al. Eudaimonic well-being and tumor norepinephrine in patients with epithelial ovarian cancer. Cancer. 2015;121(19):3543-3550.
- Emens JS, Burgess HJ. Effect of light and melatonin and other melatonin receptor agonists on human circadian physiology. Sleep Med Clin. 2015;10(4):435-453.
- Ferracioli-Oda E, Qawasmi A, Bloch MH. Meta-analysis: melatonin for the treatment of primary sleep disorders. PLoS One. 2013;8(5):e63773