Depressive Symptoms and Cortisol Rhythmicity Predict Survival in Patients with Renal Cell Carcinoma: Role of Inflammatory Signaling

Abstract

PurposeEvidence has supported the association between psychological factors and cancer biology; however, findings are equivocal on the role of psychosocial factors in cancer progression. This study generates a hypothesis of mechanistic variables by examining the clinical effects of psychosocial factors and cortisol dysregulation in patients with metastatic renal cell carcinoma (RCC) and examines associated activation of transcription control pathways.MethodsPatients with metastatic RCC (n = 217) were prospectively enrolled in this study. Patients completed questionnaires (Centers for Epidemiologic Studies – Depression; SF-36 Health Status Survey; Duke Social Support Index; Coping Operations Preference Enquiry; organized and non-organized religious activity; and intrinsic religiosity), and provided blood and saliva samples. Cortisol levels and whole genome transcriptional profiling were assessed to identify potential alterations in circadian rhythms and genomic pathways.ResultsSeparate Cox regression models, controlling for disease risk category, revealed that CES-D scores (p = 0.05, HR = 1.5, 95% CI for HR: 1.00–2.23) and cortisol slope (p = 0.002; HR = 1.9; 95%CI for HR: 1.27–2.97) were significantly associated with decreased survival. Only cortisol slope and risk category remained significant in the complete model. Functional genomic analyses linked depressive symptoms to increased expression of pro-inflammatory and pro-metastatic genes in circulating leukocytes. 116 transcripts were found to be upregulated by an average of 50% or more in high CES-D patients, and 57 transcripts downregulated by at least 50%. These changes were also found in the tumor in a subset of patients.ConclusionThese findings identify depressive symptoms as a key predictor of survival in renal cell carcinoma patients with potential links to dysregulation of cortisol and inflammatory biology.

Salivary diurnal cortisol profiles in patients suffering from chronic breathlessness receiving supportive and palliative care services: A cross-sectional study

“…The association between flatter diurnal cortisol slopes and higher MRC dyspnoea grade is consistent with the growing literature demonstrating flatter diurnal slopes in association with shorter survival in cancer (Sephton et al, 2000;Cohen et al, 2012;Sephton et al, 2013). It is also consistent with the strong evidence in the literature for a relationship between DCS and functional impairment in older adults.…”

“…Such dysregulation has been observed in a wide range of chronic diseases, both malignant (Abercrombie et al, 2004) and non-malignant (Hackett et al, 2014), and has been associated with negative disease outcomes and characteristics. Flatter diurnal rhythms have been shown to predict mortality secondary to cancer (Sephton et al, 2000;Cohen et al, 2012;Sephton et al, 2013) and cardiovascular disease (Kumari et al, 2011 ). They have also been associated with more advanced cancer stages (Sephton et al, 2000;Sephton et al, 2013), greater functional disability in cancer (Weinrib et al, 2011;Sephton et al, 2013) and worse physical performance in older adulthood (Gardner et al, 2013).…”

Depression in cancer: The many biobehavioral pathways driving tumor progression

“…For instance, depression has been associated with shorter survival in patients with renal carcinoma 62 . Of note, a subgroup analysis revealed that increased gene expression related to inflammatory pathways and oxidative stress as well as greater activity of the nuclear transcriptional factor NF-kB in circulating leucocytes, were positively associated with depressive symptoms' severity 62 . In keeping with this view, elevated concentrations of cytokines (e.g., IL-6 and TNF-α) have been associated with later cancer stages, poor differentiation and tumor size/volume across a variety of malignancies.…”

Distress, circadian rhythms, immunity, and survival in presurgical breast cancer patients.

“…Among those with metastatic renal cell carcinoma, salivary cortisol slope was significantly associated with survival (Cohen et al, 2012). In women with metastatic breast cancer, similar results were observed, such that those with flattened diurnal salivary cortisol slopes had shorter length of survival (Sephton, Sapolsky, Kraemer, & Spiegel, 2000).…”