Contents lists available at ScienceDirect Psychoneuroendocrinology journal homepage: www.elsevier.com/locate/psyneuen Eveningsalivarycortisolasasinglestressmarkerinwomenwithmetastatic breast cancer Santiago Allende a, *,JohnnaL.Medina b , David Spiegel b ,JamieM.Zeitzer b a PGSP-Stanford Psy.D. Consortium, Palo Alto University, 1791 Arastradero Road, Palo Alto, CA 94304, United States b Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road Stanford, CA 94305-5717, United States ARTICLEINFO Keywords: Metastatic breast cancer Salivary cortisol Diurnal cortisol HPA-axis ABSTRACT Background: Flattened diurnal salivary cortisol patterns predict shorter subsequent survival with breast, lung, and renal cell carcinomas. The underlying cause of this fattened slope is undetermined, though it has been hypothesizedtobesecondarytoadefcitintheamplitudeofthecircadianclock.Togaingreaterinsightintothe portionsofthediurnalsalivarycurvethatareassociatedwithcancersurvival,weexamined(1)whichpointsin thediurnalcurvearepredictiveoftheslopeofthecurveand(2)whetherelevatedeveningcortisollevelsalone are associated with reduced HPA-axis feedback inhibition (i.e., decreased sensitivity to the dexamethasone suppression test). Method: Weexaminedstudyhypothesesonadultwomenwithadvancedbreastcancer(age=54.3±9.58years; n =99) using non-parametric Wilcoxon’s rank-sum tests, Spearman correlation coefcients and an accuracy formulabasedonaconfusionmatrix.Cortisolwassampled fvetimesperday forthreeconsecutivedays,with dexamethasone administered late on the second day. Results: Salivary cortisol concentrations did not vary between those with fat and steep slopes during the morning(p’s>.05),butdidvaryintheevening(p’s<0.05).Furthermore,theconcentrationofthe2100halone was 86% accurate in discriminating between individuals classifed as having “fat” or “steep” slopes. Dexamethasone suppression was only associated with diurnal salivary cortisol slope (p =.0042). Conclusions: Eveningcortisollevelsareasensitiveindicatorfatteneddiurnalcortisolslope,suggestingevening cortisolmayalsobeausefulpredictorofbreastcancersurvival.Futureresearchshouldfocusondeterminingthe causes of abnormally increased evening cortisol. 1. Introduction Extant research has capitalized on the strong association between free (unbound) plasma cortisol and salivary cortisol concentrations, which ostensibly suggests that assessment of salivary cortisol is an ac- curate, indirect measure of the underlying physiologically active plasma cortisol (Kirschbaum and Hellhammer, 1989). One commonly used technique involving salivary cortisol is the examination of its diurnal slope – the typical decline in salivary cortisol concentrations across the waking day. To determine this slope, salivary cortisol is ty- picallysampledtwo-to-fvetimesperday, fortwo-to-threeconsecutive days (Kraemer et al., 2006). Under normal, non-pathological condi- tions, the main driver of this slope is the suprachiasmatic nucleus, the locationofthehumancircadianclock,whichalterscortisolproduction such that concentrations begin to rise prior to wake, peaking 30−45minpost-wake, and continuously decreasing thereafter, reaching a nadir at night, before beginning to rise again (Weitzman et al., 1971). The slope can also be altered by one of the many homeostatic regulators among the numerous physical, psychological, metabolic, neuroendocrine, epigenetic, molecular and infammatory processes that regulate the HPA axis (Llahana et al., 2019). Diurnalcortisolsamplingisbeingincreasinglyimplementedinfeld andepidemiologicalstudies,withconsistentreportsthat flatter diurnal salivary cortisol slopes are associated with negative physical and mental health outcomes. For example, fatter cortisol slopes predict shorter survival from breast (Sephton et al., 2000), ovarian (Schrepf et al., 2015; Weinrib et al., 2010), renal cell (Cohen et al., 2012)and lung(Sephton et al., 2013) cancer, as well as poorer prognosis in cor- onary artery disease (Kumarietal.,2011). In mental health disorders, fatter diurnal cortisol slopes are observed in those with posttraumatic stress disorder (PTSD) (Yehuda et al., 2005),inadultwomenwithde- pression (Jarcho et al., 2013) and refect the presence of early https://doi.org/10.1016/j.psyneuen.2020.104648 Received16September2019;Receivedinrevisedform3March2020;Accepted4March2020 ⁎ Corresponding author. E-mail addresses: sallende@paloaltou.edu, sallende@stanford.edu (S. Allende). Psychoneuroendocrinology 115 (2020) 104648 0306-4530/ © 2020 Published by Elsevier Ltd. T