ORIGINAL ARTICLE

Stress, Coping, and Circadian Disruption Among WomenAwaiting Breast Cancer Surgery

Eric Dedert, Ph.D. & Elizabeth Lush, M.S. &Anees Chagpar, M.D. & Firdaus S. Dhabhar, Ph.D. &Suzanne C. Segerstrom, Ph.D. & David Spiegel, M.D. &Ehab Dayyat, M.D. & Meagan Daup, M.A. &Kelly McMasters, M.D. & Sandra E. Sephton, Ph.D.

Published online: 27 March 2012# The Society of Behavioral Medicine 2012

AbstractBackground Psychological distress and coping related to abreast cancer diagnosis can profoundly affect psychological ad-justment, possibly resulting in the disruption of circadian rest/activity and cortisol rhythms, which are prognostic for earlymortality inmetastatic colorectal and breast cancers, respectively.Purpose This study aims to explore the relationships ofcancer-specific distress and avoidant coping with rest/activityand cortisol rhythm disruption in the period between diagnosisand breast cancer surgery.Methods Fifty-seven presurgical breast cancer patients provid-ed daily self-reports of cancer-specific distress and avoidantcoping as well as actigraphic and salivary cortisol data.

Results Distress and avoidant coping were related to rest/activity rhythm disruption (daytime sedentariness, inconsis-tent rhythms). Patients with disrupted rest/activity cycleshad flattened diurnal cortisol rhythms.Conclusions Maladaptive psychological responses tobreast cancer diagnosis were associated with disruptionof circadian rest/activity rhythms. Given that circadiancycles regulate tumor growth, we need greater understandingof possible psychosocial effects in cancer-related circadiandisruption.

Keywords Breast cancer . Circadian rhythm . Actigraphy .

Cortisol . Rest/activity . Sleep

E. DedertVeterans Affairs Medical Center,Durham, NC, USA

E. DedertDepartment of Psychiatry and Behavioral Sciences,Duke University Medical Center,Durham, NC, USA

E. Lush :M. Daup : S. E. Sephton (*)Department of Psychological and Brain Sciences,University of Louisville,2301 South Third Street, 317 Life Sciences,Louisville, KY 40292, USAe-mail: sephton@louisville.edu

A. ChagparDepartment of Surgery,Yale University School of Medicine,New Haven, CT, USA

F. S. Dhabhar :D. SpiegelDepartment of Psychiatry and Behavioral Sciences,Stanford University School of Medicine,Stanford, CA, USA

F. S. DhabharInstitute for Immunity, Transplantation, and Infection,Stanford University School of Medicine,Stanford, CA, USA

S. C. SegerstromDepartment of Psychology, University of Kentucky,Lexington, KY, USA

E. DayyatDepartment of Pediatrics, University of Louisville,Louisville, KY, USA

K. McMastersDivision of Surgical Oncology, School of Medicine,University of Louisville,Louisville, KY, USA

K. McMasters : S. E. SephtonJames Graham Brown Cancer Center,Louisville, KY, USA

ann. behav. med. (2012) 44:10–20DOI 10.1007/s12160-012-9352-y

Introduction

Receiving a breast cancer diagnosis can be very stressful.Patients often report distress including unwanted intru-sive thoughts (intrusions) about cancer despite theirefforts to focus on other topics [1]. Patients who experi-ence intrusions are more likely to suffer subsequentanxiety and depression during the months after diagnosis[2]. Though some findings are contradictory, data gener-ally suggest that reacting to a cancer diagnosis withavoidant coping styles (avoidance) also predicts poorerpsychological adjustment later in the course of treatment[3, 4]. Avoidant coping strategies include denial, repres-sion, distraction, and disengagement that reduce one’sability to process difficult thoughts and feelings [5].Early stage breast cancer patients who report usingavoidance also tend to report more distress [6] and fearof recurrence a year later [4]. Very little is known aboutthe behavioral and physiological correlates of these po-tentially maladaptive responses to cancer.

Psychological distress is known to dysregulate endo-crine function including circadian cortisol rhythms. Cor-tisol levels typically peak during the hour afterawakening, descend throughout the day, and reach theirlowest point during sleep [7–9]. Elevations of cortisol oraccentuated diurnal rhythms may reflect short-termstress. Among healthy women with no breast cancerhistory, intrusive thoughts about this much-feared diseasehave been linked with heightened cortisol responses todaily stressors [10]. In contrast, flattened diurnal cortisolprofiles are a hallmark of chronic uncontrollable, trau-matic, and physically threatening stressors [11]. Bothearly stage and advanced stage breast cancer patientsdisplay flattened cortisol rhythms [12, 13]. Advancedbreast cancer patients have the most dysregulated cortisolrhythms, and many also demonstrate profound circadiandisruption that extends to rest/activity, metabolic, andimmune cell rhythms [14]. In particular, disrupted rest/activity rhythms co-occur with poor functional and phys-ical quality of life prior to breast cancer chemotherapy[15]. Rhythm disruption may be exacerbated by chemo-therapy [16] and may partly underlie chemotherapy-related fatigue, depression, and mood disturbance [17].Importantly, poor circadian coordination of rest/activityrhythms and flattening of the diurnal cortisol rhythmhave both proven prognostic for early mortality amongmetastatic colorectal and breast cancer patients, respec-tively [18–21].

Data are accumulating to suggest that central circadiandisruption can accelerate tumor progression [14]. Centrallymediated circadian rhythms regulate sleep/wake, rest/activity,metabolic, endocrine, and immune function. In particular, thecentrally mediated glucocorticoid rhythm serves as a major

signal from the suprachiasmatic nucleus of the hypothalamusthat helps to coordinate the circadian clocks that exist in thevast majority of peripheral tissues. Glucocorticoid rhythmscoordinate the circadian rhythms of proliferative cycles, apo-ptosis, cell trafficking, and cytokine secretion. Stress- ordisease-related disruption of cortisol secretion patterns couldhave permissive effects on tumor progression by uncouplingtumor cell proliferation cycles from central circadian control[14, 22]. While other hormones including melatonin are alsoimplicated in tumor growth [14], glucocorticoid regulation ofperipheral cell division [23, 24] and aspects of antitumorimmunity [14] make them a strong candidate mediator ofcircadian effects on tumor progression. Importantly, robustcircadian coordination has proven to be a prognostic indicatorin cancer survival [18, 20, 21].

The aim of this study is to explore potential pathways bywhich stress and coping might relate to tumor progressionbased on our previously published model of circadianeffects in cancer progression [14]. We chose three positedassociations for testing: relationships between psychosocialfactors and circadian disruption (arrow C [14]), betweenpsychosocial factors and endocrine activation (arrow D[14]), and between circadian and endocrine disruption (ar-row A [14]). Specifically, we hypothesized interrelation-ships between stress (intrusions) and coping (avoidantcoping), circadian disruption (rest/activity and salivary cor-tisol rhythm), and endocrine activation (cortisol awakeningresponse [CAR], mean saliva cortisol levels). Rest/activityand salivary cortisol rhythms were chosen as circadian dis-ruption measures because of their demonstrated prognosticsignificance in cancer [18, 20, 21].

Materials and Methods

Subjects

Eligible participants included women scheduled for surgeryfor incident or recurrent breast cancer (stages I–IV). Otherinclusion criteria were English proficiency, biopsy-provenbreast cancer diagnosis, and the ability to complete 4 daysof data collection prior to surgical treatment. Patientswere recruited from two breast care clinics in Louisville,Kentucky. Thirty-eight patients (66% of the sample) wererecruited from the James Graham Brown Cancer Center.Nineteen patients (33%) were recruited from Norton Health-care in Louisville, Kentucky.

Procedures

Eligible patients were introduced to the study during aclinical visit with their breast surgeon, Dr. Anees Chagpar.A small number of Dr. Chagpar’s patients who were not

ann. behav. med. (2012) 44:10–20 11

invited during their clinic visit were later approached byresearch staff. After providing informed consent and HIPAAResearch Authorization, participants collected data at homeover the following four days. They provided data on demo-graphics, medical history, medications, menopausal status,and use of oral contraceptives and hormone replacementtherapy. Actigraphic recordings and saliva samples werecollected daily during the assessment period. Data on dis-ease status (diagnostic testing, age at diagnosis, time sincediagnosis, stage, and grade) were collected via medical chartreview. The study protocol was approved by all appropriateinstitutional review boards.

Assessments

The daily impact of intrusive thoughts specific to the diag-nosis of breast cancer was assessed using the seven-itemintrusions subscale of the Impact of Event Scale (IES [25]).On each of the four consecutive mornings of data collection,patients were instructed to rate intrusions over the past 24 h.Questionnaire instructions were modified so that participantstargeted symptoms occurring on only the day prior.

Avoidant coping was assessed by summing the “denial,”“self-distraction,” and “behavioral disengagement” sub-scales [26] of the Brief COPE [27]. Participants completedthis measure on four consecutive mornings, reporting on theprevious day’s efforts to cope with “stressful events related tohaving breast cancer.” The assessment author has supportedthe adaptation of this measure to research applications [27],and this method has been used previously in breast cancerstudies [28]. All participants provided complete data on intru-sions and avoidance.

Rest/activity rhythms were measured via actigraphy us-ing a wrist-worn movement-recording device [29]. Bodymovements were recorded consecutively for three daysand four nights. Participants only removed the actigraphydevice to keep it dry when bathing, showering, etc., and theyself-reported removal times. On each of three mornings,they noted for the prior night’s sleep the time they got intoin bed, time they fell asleep, time they awoke, and time theygot out of bed. On the fourth morning, they reported onlytheir time into bed and time they fell asleep. Thus, for eachof the 57 participants, there were 14 instances in which self-report and actigraph data were compared and used to set sleepintervals for further analyses. When self-reports and actigra-phy records differed by more than five min, actigraphy datawere used. This occurred in 13% of 798 reports evaluated.

Commercially available software was used to score all 1-min epochs and provided the following rest/activity rhythmmeasures: 24-h autocorrelation coefficient, a dichotomy in-dex for nighttime restfulness and a dichotomy index fordaytime sedentariness. These three variables were obtainedfor 55 participants. Data from two subjects were lost due to

device malfunction and participant error. The autocorrela-tion coefficient was calculated by correlating each epoch ofactivity during the first day of collection with each epoch ofactivity at that same time on the other two days. The auto-correlation coefficient is a measure of circadian consistency,the similarity of rest/activity patterns across days. Partici-pants with a strong circadian rhythm are expected to exhibitsimilar activity levels at similar times of day, yielding a highautocorrelation. Two dichotomy indices were calculated tocompare activity levels when in bed and out of bed.

Nighttime restfulness indicates the percentage of activitywhen the patient is in bed that fell below the median level ofactivity when out of bed. Conversely, daytime sedentarinessindicates the percentage of activity when out of bed that fellbelow the median level of activity while in bed. In both cases,a higher percentage score indicates more frequent inactivity.Greater nighttime restfulness is consistent with strong circa-dian rhythmicity, while greater daytime inactivity is consistentwith circadian disruption.

In the results of studies among cancer patients, two of thethree activity rhythm measures have demonstrated significantprognostic value. Specifically, the autocorrelation coefficientpredicts early mortality among metastatic colorectal cancerpatients [18], while nighttime inactivity has shown exception-ally strong prognostic value in a large, separate multisitesample of these patients [20].

During the 4-day period when activity recordings werecollected, participants provided a series of 12 saliva sampleson 3 consecutive days at waking, 30 min after waking(+30 min), at 4 p.m., and immediately prior to going tobed. Medication Event Monitoring System (MEMS) bottlesand caps [30] were used to store cotton saliva collectionswabs and record the exact time and date the bottle wasopened. Participants were asked not to eat, drink, brush theirteeth, use mouthwash, chew gum, or smoke for 30 minutesprior to saliva sample collection. Upon completion of datacollection, a research assistant centrifuged, aliquoted, andstored saliva samples at −80°C. Assays were conductedusing an enzyme immunoassay developed for use in saliva[31]. The sensitivity of the assay was 0.007 μg/dL. Theinter-assay coefficient of variation was 10.45% for lowand 4.03% for high controls.

The MEMS and self-reported saliva collection were high-ly correlated (Spearman’s r00.962), suggesting that partic-ipant reports were reliable, as in previous studies amongmedically ill or older samples [32]. Collection timesrecorded by MEMS devices were used in the analyses,except in the case of three subjects who recorded salivacollection times on palm pilot devices when MEMS wereunavailable. MEMS data indicated that one subject tookextra samples to substitute for missed collections on theprevious day. The substituted data were excluded, whilecollections from that participant’s other two days were

12 ann. behav. med. (2012) 44:10–20

retained. All data from an additional subject were excludedbecause of probable effects of her shift work schedule oncircadian measures. Fifty-seven patients with some usablecortisol data were included in the analyses.

Because the CAR is highly time-sensitive, waking and+30 min sample collection times were closely scrutinized.Post-waking samples were excluded if they were collected<15 min or more than 45 min after the waking sample (10 ofthe 672 total samples collected, or 1.5% of the cortisol data).In cases in which the self-reported collection time differedby more than 10 min from MEMS times, MEMS collectiontimes were used. Actigraphy data were examined to corrob-orate the timing of waking and bedtime sample collection.Seventy-three samples (10.9% of the data) were determinednot to have been collected at actual waking or bedtime andwere excluded. Additionally, data for which collection timeor cortisol values were >4 standard deviations from themean were considered outliers and were deleted (n09,1.3%). In sum, 13.7% (92 of 672) samples were excludedbased on these concerns. Nevertheless, the use of 3 days ofsaliva collection improves the reliability of the estimates ofcortisol parameters and allows for the calculation of sum-mary variables in most cases, even when single data pointsare missing [32].

Cortisol values were log-transformed. The CAR wascalculated as the unstandardized beta of natural log-transformed cortisol regressed on collection time, includingonly the waking and +30 min samples. The diurnal cortisolslope was calculated excluding +30 min samples as theunstandardized beta of log-transformed cortisol regressedon collection time. The diurnal mean cortisol level wascalculated using all 12 log-transformed values. Mean wak-ing and bedtime cortisol were calculated using log-transformed values. Because it was based on only six salivacollection points, the CAR was the most vulnerable tomissing data, while the diurnal mean and slope were morerobust. We obtained diurnal mean cortisol for all 57 patients,diurnal slope for 56 patients, and CAR responses for 44patients.

Statistical Analysis

Hierarchal linear regressions were used to examine the rela-tionships of cancer-related intrusions and avoidant copingwith circadian disruption measures. All regression analysesadjusted for age at diagnosis, cancer stage, and income. Ageand stage were chosen because of theorized relationships withboth distress and circadian disruption. Income was chosenbecause it was expected to describe both the socioeconomicstatus of the patients and the two disparate clinics from whichpatients were recruited. The number of covariates was limitedto three because of the limited sample size.

Control variables were entered in the first block witheither intrusion or avoidant coping scores entered in thesecond block as predictors of actigraphy (autocorrelationcoefficient and the two dichotomy indices for activity inand out of bed) and salivary cortisol profiles (diurnal corti-sol slope, CAR, diurnal mean cortisol, and mean log wakingand bedtime levels). Two-tailed Spearman rank correlationsexplored the relationships between actigraphic and salivarycircadian measures.

Sensitivity analyses examined relationships among studyvariables after removing patients with recurrent breast can-cer, given that their perception of the diagnosis wasexpected to be substantively different. To evaluate thepotential influence of missing samples on the data, weexamined correlations between the number of missing cor-tisol samples and cortisol summary variables. Potentialassociations of disease status, distress, and coping styleswith adherence to the data collection protocol were ex-amined. Additional analyses examined the influence onthe results of potentially confounding variables includingtumor size, tumor grade, estrogen receptor status, currentmedications, basal metabolic index, medical comorbidities,and recruitment site.

Results

Sample Characteristics

Ninety-one potentially eligible patients were referred to thestudy. Five patients were unable to be contacted, 25 patientsdeclined to participate due to response burden of the studyand/or time constraints, 1 declined because she was uncom-fortable consenting to medical records reviews, and 3 agreedto participate but were then unable to because of acuteillness or events prior to surgery. Fifty-seven women partic-ipated in this study. Mean and SD age was 52 years [13],with a range from 21 to 79 years. Participants entered thestudy an average of 19 days (SD021; range, 0–122 days)after their initial breast cancer diagnosis and completed thestudy an average of 24 days (SD031.76; range, 4–189 days)prior to beginning any treatment.

Additional demographic and medical characteristics ofthe sample are presented in Table 1. Fifty-four participantsreceived primary breast cancer diagnoses and three hadrecurrent breast cancer but had not received treatment withinthe past year. Six patients elected lumpectomy and theremainder chose to undergo mastectomy or neoadjuvanttreatment. Three participants were recruited based on imag-ing data suggesting invasive (stage 1 or greater) tumors, butwere subsequently shown to have ductal carcinoma in situ(DCIS; stage 0 cancer). One participant was excluded fromcortisol analyses due to the use of an oral anti-inflammatory

ann. behav. med. (2012) 44:10–20 13

steroid known to affect cortisol levels. Of the reportedcomorbidities, the most prevalent were hypertension (26%)and diabetes (18%). Other comorbidities occurred in <5% ofthe sample (three or fewer patients).

Daily Assessments

Descriptive statistics for daily assessments are presented inTable 2. The mean daily IES score (M09.2, SD05.5) waslower than those seen previously in samples within 1 year ofbreast cancer diagnosis [33] but similar to levels reported inbreast cancer patients >1 year after diagnosis [34].

Multilevel modeling of potential within-subject effects orday-to-day differences in reports of intrusions and avoid-ance revealed that neither of these factors varied substan-tially across the three days of collection. The intraclasscorrelation coefficient (ICC) for intrusions within subjectsacross days was 0.82, and that for avoidance was 0.86.These ICC values far exceed the usual criterion for a “trait”variable. Thus, it would not have been informative to test

the hypotheses with regard to within-subject effects, soanalyses tested associations between persons.

Intrusive Thoughts and Rest/Activity Rhythm Disruption

Intrusive thoughts about cancer were associated with theautocorrelation coefficient, a measure of the consistency ofrest/activity rhythms over several days; and this result wasindependent of age at diagnosis, cancer stage, and income(Table 3). Patients who reported more intrusive thoughts hadlower autocorrelation coefficients (partial r0−0.42), or inother words, less consistent rest/activity rhythms. Intrusivethoughts were also associated with daytime sedentarinessindicating that inactivity during the day was greater relativeto activity while in bed (partial r00.37). Intrusive thoughtswere not related to nighttime inactivity.

Avoidant Coping and Rest/Activity Rhythm Disruption

Avoidant coping was associated with the autocorrelation coef-ficient, independent of age at diagnosis, cancer stage, andincome (Table 4). Patients who reported using more avoidantcoping techniques had a lower autocorrelation coefficient (par-tial r0−0.32), indicative of less consistent rest/activity rhythms.Avoidant coping was also significantly associated with daytimeinactivity, indicating greater daytime restfulness (partial r00.38). Avoidant coping was not independently related to night-time inactivity or any of the salivary cortisol measures.

No Significant Associations of Intrusions or Avoidance withCortisol Measures

Neither intrusions nor avoidance were significantly relatedto any of the salivary cortisol measures.

Correlations Between Actigraphy and Salivary Cortisol

When analyzing the relationships between the actigraphyand salivary cortisol measures, a higher autocorrelation co-efficient was found to be significantly correlated with asteeper decline in the diurnal cortisol slope (rs0−0.41,p00.003), both indications of circadian rhythmicity. This rela-tionship is illustrated in Fig. 1.

Results of Secondary Analyses

Sensitivity analyses yielded a similar pattern of results tothose reported above, so the three participants with recurrentbreast cancer are included in the results reported here. Thenumber of missing cortisol samples was not significantlycorrelated with cortisol summary variables including thediurnal slope, diurnal mean cortisol, or CAR.

Table 1 Demographiccharacteristics of thesample

Variable Percent

Ethnicity

White/Caucasian 57.9

African American 36.8

Other 5.3

Years of education

High school or less 71.0

College or more 29.0

Income

<$20,000 39.2

$20,000–$39,999 25.5

$40,000–$59,999 9.8

$60,000–$79,999 7.8

$80,000–$99,999 7.8

>$100,000 9.8

Menopausal status

Premenopausal 40.4

Perimenopausal 7.0

Postmenopausal 52.6

Stage

Stage 0 (DCIS) 7.0

Stage I 42.1

Stage IIA 12.3

Stage IIB 7.0

Stage IIIA 17.5

Stage IIIB 1.8

Stage IIIC 5.3

Stage IV 7.0

14 ann. behav. med. (2012) 44:10–20

Independent samples t tests comparing patients with andwithout data sufficient to calculate the CAR revealed nosignificant association between disease status indicators(age at diagnosis, Karnofsky rating, tumor stage) and miss-ing cortisol data. Similarly, neither intrusions nor avoidancewere related to missing cortisol data.

Exploratory Spearman correlations suggested that neitherhypertension nor diabetes were significantly associated withany of the actigraphy or cortisol variables. Independent

samples t tests showed no significant association of recruit-ment site with intrusions, avoidance, or household income.

Discussion

When a person is first diagnosed with cancer, they mustformulate a psychological response to the diagnosis. Theresponse they choose will likely be manifested in their

Table 2 Descriptive data fordaily measures Variable Number Mean (SD) Range

Intrusive thoughts 57 9.22 (5.47) 0 to 21

Avoidant coping 57 11.23 (4.07) 6 to 20.33

Actigraphy

24 h autocorrelation coefficient 55 0.27 (0.17) −0.07 to 0.72

Nighttime inactivity (%) 55 97.3 (3.3) 84.5 to 100

Daytime inactivity (%) 55 6.1 (5.5) 0.5 to 22.2

Salivary cortisol

Mean waking cortisol log(μg/dL) 54 −1.28 (0.51) −2.60 to −0.09

Cortisol awakening response log(μg/dL)/h 43 0.10 (0.47) −0.89 to 1.65

Diurnal cortisol slope log(μg/dL)/h 54 −0.07 (0.09) −0.26 to 0.18

Diurnal mean cortisol log(μg/dL) 55 −1.20 (0.39) −1.94 to −0.06

Mean bedtime cortisol log(μg/dL) 54 −2.83 (1.05) −5.43 to −0.63

Table 3 Summary of hierarchalregression analyses of intrusivethoughts and actigraphy

f2 is the effect size (by convention,0.0120small, 0.150medium,0.350large)

*p<0.05, **p<0.01

Variable B SE B β R2 ΔR2 p of ΔR2 N f2

Autocorrelation coefficient

Block 1 0.208 0.208 0.015 48

Age 0.002 0.002 0.166

Stage 0.006 0.011 0.078

Income 0.041 0.012 0.443**

Block 2 0.344 0.136 0.005 48 0.52

Intrusive thoughts −0.012 0.004 −0.388**

Nighttime restfulness

Block 1 0.075 0.075 0.326 48

Age 0.001 0.039 0.004

Stage 0.138 0.246 0.084

Income 0.524 0.288 0.265

Block 2 0.083 0.009 0.526 48 0.09

Intrusive thoughts −0.064 0.099 −0.098

Daytime sedentariness

Block 1 0.161 0.161 0.050 48

Age −0.068 0.061 −0.159

Stage 0.060 0.382 0.022

Income −1.214 0.447 −0.377*

Block 2 0.273 0.112 0.014 48 0.38

Intrusive thoughts 0.371 0.144 0.353*

ann. behav. med. (2012) 44:10–20 15

behavior and possibly their physiology. This study showsthat two potentially maladaptive psychological responses tobreast cancer diagnosis are associated with a behavioralindicator of circadian disruption, rest/activity rhythm.

Moreover, it shows that circadian behavior is related todiurnal physiology: presurgical breast cancer patients withdisrupted rest/activity rhythms also had disrupted cortisolrhythms.

In particular, intrusions and avoidance were related todaytime sedentariness. In this newly diagnosed sample,intrusion-related inactivity during the daytime might be anindication that patients were seeking emotional numbnessby disengaging from their environments and remaining sed-entary. As indicated in the avoidance literature, this disen-gagement has the paradoxical effect of increasing distress.While these patients might have sought emotional numbnessthrough avoidance during the day, intrusions and avoidancewere not related to disruption of nighttime activity rhythms,when activity would be less influenced by consciousattempts to avoid.

Other studies have demonstrated that activity rhythmdisruption is related to poor physical, emotional, and socialfunctioning in breast [17] and metastatic colorectal cancerpatients [19, 20, 35]. Pain, sleep habits, and sleep cognitionsmay affect the rest/activity rhythms of cancer patients [36];however, these data demonstrate that distress and copingspecific to the cancer diagnosis are also significantly relatedto activity rhythm disruption. Early intervention may proveespecially helpful in helping patients learn to managecancer-related distress and formulate productive copingstrategies. These data suggest that such interventions may

Table 4 Summary of hierarchicalregression analyses of avoidantcoping with actigraphy

f2 is the effect size (by convention,0.0120small, 0.150medium,0.350large)

*p<0.05, **p<0.01

Variable B SE B β R2 ΔR2 p of ΔR2 N f2

Autocorrelation coefficient

Block 1 0.208 0.208 0.015 48

Age 0.002 0.002 0.166

Stage 0.006 0.011 0.078

Income 0.041 0.012 0.443*

Block 2 0.288 0.079 0.034 48 0.40

Avoidant coping −0.012 0.005 −0.300*

Nighttime restfulness

Block 1 0.075 0.075 0.326 48

Age 0.001 0.039 0.004

Stage 0.138 0.246 0.084

Income 0.524 0.288 0.265

Block 2 0.132 0.057 0.099 48 0.15

Avoidant coping −0.212 0.126 −0.255

Daytime sedentariness

Block 1 0.161 0.161 0.050 48

Age −0.068 0.061 −0.159

Stage 0.060 0.382 0.022

Income −1.214 0.447 −.377**

Block 2 0.285 0.124 0.009 48 0.40

Avoidant coping 0.507 0.186 0.374**

Fig. 1 Mean and 95% confidence interval raw salivary cortisol levelsfor patients who fell below (poor rhythm) versus above (strong rhythm)the median autocorrelation coefficient (N054). A median split wasperformed on the autocorrelation data for descriptive but not analyticpurposes

16 ann. behav. med. (2012) 44:10–20

benefit the patient not only by reducing psychologicalcomorbidities, but also possibly by helping maintain coor-dinated rest/activity patterns, which are prognostic for longersurvival in some cancers [19, 20, 35].

Although the directional nature of the relationships in thisstudy were not examined, systemic inflammation related totumor processes could underlie the psychological, behavior-al, and physiological changes noted here [37]. Patients withhead and neck and non-small cell lung cancer exhibit greaterrest/activity rhythm disruption than controls [38–40]. Sig-nificantly, inflammation evidenced by elevated proinflam-matory cytokine levels has been linked with poorcoordination of rest/activity rhythms among metastatic co-lorectal cancer patients [19], and three studies have demon-strated the prognostic value of rest/activity disruptionamong these patients [19, 20, 35]. Further research is neededto examine the possible contribution of inflammatory medi-ators, to better understand the interplay between psycholo-gy, activity rhythms, and tumor-resistant physiology, and toexamine the potential contribution of these factors to tumorprogression rates. An examination of multiple indices ofinflammation (e.g., proinflammatory cytokines) would be im-portant in this context because excess inflammation couldpromote tumor emergence and progression, while also con-tributing to hypothalamic–pituitary–adrenal axis and circadianrhythm disruption as well as to components of distress such asthe development of depressive symptoms.

It is interesting to note that distress and coping weresignificantly associated with rest/activity but not cortisolrhythm disruption, especially given the finding of a signif-icant association between the behavioral and endocrinemeasures of rhythm. It is possible that, given a larger samplesize, psychosocial associations with the diurnal cortisolrhythm may become apparent, as such relationships havebeen noted in numerous other studies [10]. It is also possiblethat the effects of distress and coping on activity couldmanifest soon after initial cancer diagnosis, while the effectson endocrine function may take longer to develop. Giventhat the bulk of research examining circadian disruption incancer patients has been conducted in the context of laterstage disease, it is noteworthy that we observed activityrhythm disruption associated with the psychology of diag-nosis and early breast cancer treatment. Future researchshould examine longitudinal relationships between cancer-specific distress and coping, circadian disruption, and medicaloutcomes.

Some previous cancer studies have not found an associ-ation of activity or sleep patterns with diurnal cortisolrhythm disruption [18], while others have [41]. Significantcorrelations between the timing of the sleep/wake cycle andthe cortisol rhythm have been noted in healthy subjects [42].In particular, we found poor coordination of activityrhythms measured over several days associated with

flattening of the diurnal salivary cortisol rhythm and theresponse to awakening measured over the same period. Thisfinding is intriguing in light of the notion that diurnal andawakening cortisol levels may be influenced by independentregulatory mechanisms within the suprachiasmatic nucleus[43]. Figure 1 suggests that the flattening of cortisol rhythmsin those with poor circadian rhythmicity of activity levelsmay be due to both decreased morning cortisol levels andelevated evening cortisol levels. Both of these findings standin contrast to typical circadian cortisol profiles. Taken to-gether, these findings support the notion that rest/activityand diurnal cortisol rhythms are related phenomena that mayinfluence one another. This interrelated disruption of rest/activity and cortisol secretion patterns suggests the possibilityof central circadian disruption, which could have permissiveeffects on tumor progression by a number of mechanisms thathave recently been reviewed [14, 22].

Our data were gathered from two cancer clinics, one ofwhich served mainly lower-income patients, many of whomdid not have medical insurance. As expected, subjectsreporting lower household incomes had greater rest/activitydisruption evidenced by poorly coordinated rhythms (auto-correlation) and greater inactivity when out of bed. Previousreports have noted associations between socioeconomicstatus, measured as a composite of income and education,with poor sleep quality and lower physical activity levels inadults [44]. Environmental factors may contribute to thisrelationship, as may stress related to poverty, poor healthcare access, and health behavior [45].

Results should be interpreted with caution because ofseveral limitations. It is possible that refusal to participatein the study could have been related to the primary inde-pendent variables, stress and coping. Indeed, anecdotally,some patients who refused were feeling overwhelmed withdiagnosis and surgery planning. Interpretation of theseresults is also limited by the small sample size. Assumingthree covariates accounted for a total R200.2 of the vari-ance, the statistical power of our sample size of 57 to detectthe effect size of f 200.7 found in similar analyses [46] is63%.

These results are also limited by the cross-sectional na-ture of the design and lack of a control group. Data wereanalyzed using an exploratory approach in order to maxi-mize the depth of investigation and provide direction forfuture research [47]. However, since this study did not makeany adjustments for multiple comparisons, caution in inter-preting the results is merited to protect against the increasedrisk of type 1 error.

These results suggest that, after diagnosis and prior tobreast cancer treatment, distress and coping related specifi-cally to the cancer diagnosis are reflected in disruption ofrest/activity rhythms. Given the known prognostic value ofrest/activity rhythm disruption in colorectal cancer and

ann. behav. med. (2012) 44:10–20 17

cortisol rhythm disruption in breast cancer [18–21], futureattention should be focused on circadian disruption as apathway that may underlie some of the noted effects ofpsychosocial factors on cancer progression [48]. In a previ-ous study, actigraphic recordings linked sleep disruptionwith flattened diurnal cortisol rhythms as well as heightenedsympathetic activity in metastatic breast cancer patients[42]. Thus, sleep may be protective of both parasympathetictone and circadian glucocorticoid rhythms. The potentialimportance of these findings is highlighted by recent animaland cellular data demonstrating mechanisms by which sym-pathetic activation may facilitate tumor growth [49, 50].

Investigating the relationships between cancer-specificdistress, avoidant coping, and circadian disruption may beof clinical relevance to breast cancer patients since both rest/activity and cortisol rhythm disruption have been associatedwith shorter survival. Converging evidence from human andanimal research strongly suggests that the central circadianclock regulates tumor growth (proliferation cycle timing andoverall tumor growth rates) as well as aspects of antitumorimmunity.

In this study, measures of intrusions and avoidance onthree consecutive days did not vary sufficiently within sub-jects to be subjected to multilevel modeling analyses. Theapparent stability of these maladaptive factors during thepresurgical period has implications, both for research andclinical practice among breast cancer patients.

Test–retest reliability for the intrusions subscale of theIES is reflected in the ICC ranging between 0.94 and 0.56,with reliability increasing with proximity to the stressfulevent and as the time between tests is shortened [51]. Sincewe repeated assessments on consecutive days shortly afterbreast cancer diagnosis, high ICCs within subjects are notsurprising.

We measured avoidant coping by summing the “denial,”“self-distraction,” and ‘behavioral disengagement’ subscalesof the Brief COPE [28]. These subscales demonstrated hightest–retest reliability in a sample of 37 Malaysian breastcancer patients from whom data were collected at 2–3 and10 weeks post surgery, yielding ICCs of 0.97, 0.5, and 1.0,respectively [52]. Coping was stable across consecutivedays in this study. This should be viewed within the contextthat cancer coping strategies change with the trajectory ofillness from initial diagnosis, preparation for surgery, recov-ery, initiation of adjuvant treatment, the difficulties of adjuvanttreatment, and finally, release from the medical system [53].Our study measured coping on 3 days presurgery, when thedemands of illness did not change. Given this, high stabilitywithin subjects across days seems reasonable.

Intrusive thoughts and avoidant coping are expected tochange over the resolution of a cancer diagnosis, however,change is likely to occur over weeks or months rather thandays.

Future studies on within-subject associations betweenpsychological and physiological responses to cancer shouldlook to psychological measures that display greater day-to-day variability, and sample during different phases of cancerdiagnosis and treatment. Distress should be targeted inclinical psychological interventions during the presurgicalperiod.

Psychosocial interventions for breast cancer patients haverarely been directed at the initial stages of diagnosis andtreatment. Early intervention may prove especially helpfulin helping patients learn to manage cancer-related distressand formulate productive coping strategies. Such health-promoting psychological and behavioral adjustments couldnot only have beneficial effects during the early stages oftreatment and recovery, but could also have long-term bene-ficial effects by setting the patient on a healthier psychophys-iological trajectory right from the time of initial diagnosis. Itis plausible that reducing psychologically based disruption ofcircadian cycles could also protect tumor defense mecha-nisms that are regulated by the central clock, including tumorcell proliferation cycles and antitumor immunity.

Acknowledgments We would like to thank the women who partic-ipated in this research despite numerous other time demands. We alsothank all of the nursing staff and research assistants who worked onrecruitment and data collection and management. This study wasfunded by the University of Louisville Internal Research IncentiveGrant for Research on Women.

Conflict of Interest Statement The authors have no conflict of interestto disclose.

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