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ORIGINAL ARTICLES |
From the University of North Carolina at Chapel Hill (L.S.P., M.M., V.N., M.B., E.P.), and Duke University Medical Center (M.S.S.), Durham, NC.
Address correspondence to: Laura Porter, PhD, Box 3159, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710. Email: Laura.Porter{at}duke.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONNOTESACKNOWLEDGMENTSREFERENCES |
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METHODS: Participants were 33 breast cancer survivors (3–5 years postdiagnosis) and 21 women with no history of cancer who were scheduled for a routine follow-up mammogram. The first assessment occurred for 3 consecutive days 1 month before the mammogram, and the second assessment occurred on the day before, the day of, and the day after the mammogram. On each of these days, women completed questionnaires and collected saliva samples 6 times/day.
RESULTS: Results indicated that breast cancer survivors had higher levels of cortisol at baseline than controls. There were no group differences in diurnal slopes in cortisol concentration or cortisol responses to wakening. There were group differences in cortisol responses to the mammogram: In breast cancer survivors, cortisol levels decreased from the 3-day baseline period to the 3-day period around the mammogram, whereas in the control subjects mean daily cortisol levels increased around the mammogram. Among cancer survivors, there were no significant associations between cortisol measures and general stress ratings, although there were some associations with specific psychological responses to mammography.
CONCLUSIONS: Results of this pilot study indicate that breast cancer survivors show elevated levels of basal cortisol and suppressed cortisol response to a cancer-related stressor several years after completing treatment. Future research is needed to understand whether these patterns of hypothalamic-pituitary-adrenal functioning are a result of physiologic stress associated with cancer treatment or disease process, psychological stress associated with fear of recurrence, or a combination of both.
Key Words: breast cancer, • cortisol, • cancer survivorship, • stress.
Abbreviations: HPA = hypothalamic-pituitary-adrenal;; NA = negative affect;; PA = positive affect;; PCQ = Psychological Consequences Questionnnaire.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONNOTESACKNOWLEDGMENTSREFERENCES |
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Mammography is often mentioned as one of the most salient and powerful triggers of recurrence fears. Breast cancer survivors as long as 15 years after treatment reported anxiety during routine mammography (9) as well as distress related to fear of future diagnostic tests (3). Returning for mammogram and checkups triggered flashbacks, physiological responses, and high anxiety in many women (15). In contrast, women without a history of breast cancer generally do not experience significant distress when undergoing routine mammography screening (16).
For breast cancer survivors, frequent and repeated exposure to stressors such as mammograms, along with the perception of threat and feelings of anticipation and worry, may lead to decreases in quality of life as well as important biologic effects. There is ample evidence that individuals experiencing other long-term stressors undergo downregulation of the immune system and adverse health outcomes (17). Chronic stress has also been associated with abnormalities in the functioning of the hypothalamic-pituitary-adrenal (HPA) axis, which may promote an increased vulnerability to develop stress-related disorders (18). In particular, hypocortisolism (defined as a deficiency in cortisol including reduced adrenocortical secretion at least temporarily during the circadian cycle as well as reduced adrenocortical reactivity to stress) has been associated with conditions of chronic stress (19).
Dysregulation of the HPA axis is also evident in cortisol reactivity to acute stressors. Activation of the HPA axis and the subsequent release of cortisol in response to psychological stress is a well-documented phenomenon (20–23). In particular, situations that are experienced as unpredictable, uncontrollable, and threatening have been shown to be closely associated with increased cortisol output (22–23). However, individuals under chronic stress have been found to demonstrate decreased cortisol reactivity (18). Thus, although it is likely that for most women the experience of having a mammogram triggers significant increases in cortisol, there may also be subgroups of women such as breast cancer survivors who demonstrate an attenuated cortisol response. For cancer survivors, the mammogram may serve as a proxy for numerous but more randomly occurring experiences that tend to trigger fears about recurrence. Their responses to the mammogram may thus be representative of their physiologic responses to other cancer-related stressors.
The purpose of this study was to compare baseline cortisol levels, diurnal cortisol slopes, and cortisol reactivity to a mammogram in breast cancer survivors and women without a history of cancer. Alterations in cortisol levels, reactivity, and diurnal cycles have been observed in patients with breast cancer (24, 25). One study found that women with metastatic breast cancer had higher basal cortisol levels but attenuated cortisol responses to a laboratory stressor in comparison to healthy women; these results were attributed to the physiologic stress associated with the presence of a tumor (25). Among patients with metastatic breast cancer, flattened diurnal cycles and low morning levels of cortisol have been associated with measures of repressed emotion (26), and have also been found to predict shortened survival time (27). However, it is not known whether breast cancer survivors show alterations in cortisol after treatment, and the effect on the HPA axis of the psychological stressors associated with cancer survivorship is also not known. By characterizing survivors’ baseline levels and diurnal cycles of cortisol as well as their patterns of response to an acute stressor, we may be able to identify individuals who are most at risk.
The present study tested two major hypotheses: 1) At baseline, there will be differences in diurnal slopes in cortisol concentration between breast cancer survivors and women with no history of cancer (controls), with breast cancer survivors showing decreased morning levels and/or flattened cycles. Cancer survivors may also have lower average basal levels of cortisol than controls do, similar to the hypocortisolism seen in other groups of chronically stressed individuals. 2) The pattern of cortisol response to the mammogram will vary by group, with breast cancer survivors demonstrating a blunted cortisol response in comparison to controls. A secondary aim of the study was to explore patterns of associations between demographic/medical and psychological variables and cortisol levels, diurnal slopes, and reactivity to the mammogram in the breast cancer survivors.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONNOTESACKNOWLEDGMENTSREFERENCES |
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Exclusion criteria included factors known to influence cortisol including pregnancy, night-shift work, use of medications known to affect cortisol levels, and active cancer or treatment for cancer (excluding tamoxifen).
Procedures
Data were collected in two phases, for a total of six days. The baseline assessment (Phase 1) occurred 1 month before the time at which the woman was scheduled for a routine mammogram and consisted of 3 consecutive days of sampling. Phase 2 consisted of the day before mammogram, the day of the mammogram, and the day after. On each of the assessment days, women completed questionnaires and collected saliva samples at 6 times: on awakening, 30 minutes after awakening, 60 minutes after awakening, midmorning (10–11 AM), midafternoon (3–4 PM), and evening (8–10 PM). The timing of the samples was chosen in order to be able to 1) characterize the diurnal cycle (22); 2) capture the morning cortisol response to wakening, which is a reliable biological marker for HPA activity (28–31); and 3) assess cortisol reactivity to the mammogram (D. H. Hellhammer, personal communication, April 7, 2000).
On the day of the mammogram, women were assessed immediately after the examination (while waiting for the results) in place of either the midmorning or midafternoon assessment. All participants received the results of their mammogram on the day of the examination. An investigator called participants the day before the start of each phase of data collection in order to answer questions, encourage continued completion of questionnaires and saliva samples, and deal with any gaps in the data that might result. Saliva samples and questionnaires were picked up from the participants’ homes at the end of their data collection period. Participants received $20 worth of gasoline coupons at the end of the study.
Measures
Demographics and medical information
Information on age, ethnicity, years of education, family history of breast cancer, history of mammography screening, smoking status, and current medication use was collected from all subjects. For breast cancer survivors, time since diagnosis, staging, and treatment for breast cancer (including tamoxifen) was also collected.
Risk perception
Perceptions regarding risk of breast cancer were assessed with 3 items addressing participants’ perceptions of their lifetime risk for breast cancer or breast cancer recurrence, and their perceived likelihood of receiving positive results at the current mammography screening. Risk perception was assessed on the first study day as well as on the morning of the mammogram. These items have been used in numerous previous studies and have been associated with psychological distress in women undergoing mammograms (32, 33).
Mood
Mood was assessed 3 times a day (midmorning, midafternoon, and evening) by 4 adjectives describing positive affect (PA) (happy, joyful, enjoyment/fun, pleased) and 5 adjectives describing negative affect (NA) (depressed/blue, unhappy, angry/hostile, frustrated, worried/anxious). The adjectives were rated on a scale of 0 to 6 (0 = not at all, 6 = extremely). The psychometric properties of this scale are satisfactory (34, 35), and it has been used previously in daily studies (36, 37). Items are summed onto two scales, PA and NA.
Stress
Daily stress was measured at the end of each day by asking participants to rate how stressful their day was from 0 "not at all stressful" to 100 "as stressful as you can imagine" (38).
Psychological consequences questionnaire
The Psychological Consequences Questionnaire (39) was developed to measure the consequences of screening mammography. There are 2 scales: 1 assessing negative consequences (12 items) and 1 assessing positive consequences (10 items). In each scale, items assess the effect of screening on functioning in 3 life domains: emotional, social, and physical. The PCQ has demonstrated adequate reliability and validity and has been used in numerous studies investigating distress associated with mammography (16). Participants completed the PCQ on the evening after they had their mammogram.
Salivary cortisol
Saliva was collected using the "Salivette" device (Salimetrics, State College, PA), which are small cotton rolls that participants placed in their mouths for several minutes, put in special plastic tubes marked with the participant’s subject number and the time and date, and stored in the freezer for the duration of the study. Detailed guidelines regarding saliva collection and storage were provided.
Samples were centrifuged for 15 minutes at 3000 rpm, and aliquots were frozen at -70°C. Cortisol levels were assessed by high-sensitivity enzyme immunoassay (as recommended by Salimetrics, State College, PA). Intra-assay coefficients of variation on 3 different saliva pools averaged 5.7%, and the interassay coefficient was 6.8%. Assay sensitivity was 0.007 µg/dl.
Statistical Analyses
Mixed linear models (PROC MIXED in SAS) were used to analyze differences in baseline levels, morning responses to wakening, and diurnal slopes in cortisol concentration (Hypothesis 1) and cortisol reactivity (Hypothesis 2) between the breast cancer survivor and control groups. The mixed model readily accommodates the nested structure of repeated observations within individuals by modeling the covariance structure within subjects. It also incorporates statistical strategies to control for missing data and serial dependency, which preclude the necessity to supply values for missed assessments (40). Fixed effects for group, day, time of day, group*day, group*time, and group*day*time were modeled. Subjects were a random factor nested within group.
Group differences in cortisol reactivity to the mammogram were tested by contrasting cortisol levels during the baseline phase (days 1–3) with those during the stress phase (days 4–6). While we considered examining rapid changes in cortisol that may have occurred at the time point after the mammogram, we ultimately concluded that reactivity would be more accurately represented in a broader context that incorporated anticipatory and recovery phases (represented by days 4 and 6) as well as this acute response. This is consistent with McEwen’s (19) definition of allostatic load, which includes the body’s response to the anticipation of challenges, as well as the ability to shut off the response after the stress is terminated. These processes seem particularly important in the context of an event such as a mammogram, which is likely to elicit anticipatory anxiety as well as a prolonged response in a subset of women.
In addition, correlation analyses were performed to examine associations between demographic/medical and psychological variables and cortisol levels, diurnal slopes, and reactivity. Mean baseline cortisol levels were calculated by averaging cortisol values over the first 3 days of the study for each participant. Diurnal slopes were calculated for each participant by regressing the 18 baseline cortisol values (6 samples x 3 days) on the time of sample collection, resulting in a coefficient representing the slope of diurnal change in the cortisol level. Steeper slopes are represented by smaller ß values for the slope of the regression, which indicate cortisol declining more rapidly. Flatter slopes (larger ß values) indicate slower declines, abnormally timed peaks, or increasing levels during the day (27). Reactivity coefficients were calculated for each subject by computing a change score regressing average stress (Phase 2) cortisol levels on average baseline (Phase 1) cortisol levels. Higher values indicate greater increases in cortisol from Phase 1 to Phase 2.
Because the distribution of raw cortisol values is typically skewed, all analyses were performed on log transformed values of the raw data. Mixed linear analyses were performed with and without age, smoking status, race, and education as covariates; results were nearly identical. Those reported here were conducted without the covariates.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONNOTESACKNOWLEDGMENTSREFERENCES |
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The mean age of the breast cancer survivors was 56.3 (SD = 10.8). Ninety-four percent were white, and 85% were college graduates. On average they were 3.9 (SD = 1.1) years after diagnosis for breast cancer. Thirteen percent (N = 4) had been diagnosed with ductal carcinoma in situ, 58% (N = 18) were Stage I, 26% (N = 8) were Stage II, and 3% (N = 1) were Stage III. Thirty-six percent had had mastectomies, 70% had lumpectomies, and 15% had reconstructive surgery. Twenty-four percent were treated with chemotherapy, 73% with radiation, and 88% with hormone therapy. Hormone therapy was taken by 68.8% at the time of the study. The mean age of the control subjects was 54.4 (SD = 10.0). Seventy-five percent were white, and 57% were college graduates. Sixty-seven percent had no family history of cancer, and 86% had no first-degree relatives with breast cancer. On average they reported that they had had 4.6 (SD = 2.2) mammograms in the past 5 years. There were no significant differences between the groups with regard to age, race, or education.
Compliance with Data Collection
A total of 1918 saliva samples were collected from the 54 subjects. Breast cancer survivors completed an average of 35.2 samples (range = 30–36) of 36, and control subjects completed an average of 34.3 (range = 27–36) samples. This difference was not statistically significant.
Daily Measures of Stress and Mood
Mean daily levels of stress and mood are depicted in Figures 1 and 2 
, respectively. Group differences in baseline levels of stress and mood were tested using mixed linear models. Fixed effects for group, day, and group*day, were modeled. Subjects were a random factor nested within group. There were no significant group differences in baseline stress or NA (p values > .67). The group difference in baseline PA approached significance [F(1,47) = 2.42, p = .13], with breast cancer survivors reporting somewhat higher PA than controls. In addition, mixed linear models were used to analyze group differences in response to the mammogram by contrasting stress and mood levels during Phase 1 (days 1–3) with those during Phase 2 (days 4–6), and by contrasting stress levels during Phase 1 with those on the day 5. The group difference for the contrast in stress ratings between baseline and day 5 approached significance [F(1,47) = 2.27, p = .14], with breast cancer survivors reporting somewhat higher stress on the day of the mammogram. All other contrasts were nonsignificant (p values > .26).
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Hypothesis 2: Group Differences in Cortisol Reactivity
Mixed linear models were used to analyze group differences in response to the mammogram by contrasting cortisol levels during Phase 1 (days 1–3) with those during Phase 2 (days 4–6). There was a significant group*phase interaction [F(1,239) = 3.95, p < .05]. As shown in Figure 3, cortisol levels in breast cancer survivors decreased from Phase 1 to Phase 2, whereas in control subjects, cortisol levels increased, particularly on the day of the mammogram.
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With regard to psychological variables, negative social responses to the mammogram on the PCQ were associated with steeper diurnal slopes at baseline, and positive emotional responses to the mammogram were associated with greater decreases in cortisol from Phase 1 to Phase 2. Two correlations approached significance (r values > 0.30, p < .10): Greater perceived risk of cancer recurrence assessed on day 1 was associated with increased cortisol reactivity, and baseline PA was associated with decreased cortisol reactivity.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONNOTESACKNOWLEDGMENTSREFERENCES |
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Contrary to what was predicted, at baseline (1 month before the mammogram), breast cancer survivors had higher levels of cortisol than controls. Although this result contradicts findings of basal hypoactivity in other individuals undergoing chronic stress (18,19), it is consistent with the finding of elevated basal levels of cortisol in women with metastatic breast cancer (25). Among women with metastatic breast cancer, elevated cortisol levels have also been associated with lower quality of social support (41). Although in the present study there were no significant associations between psychological variables and cortisol levels among breast cancer survivors, a shorter time since the cancer diagnosis and having not had chemotherapy were both associated with elevated baseline cortisol.
There was no evidence that breast cancer survivors had altered diurnal cortisol slopes compared with controls. At baseline, there were no group differences in diurnal slopes or in morning responses to wakening. This may have been due, in part, to the presence of high levels of intergroup variability in diurnal cycles. Previous studies of healthy adults have shown that individuals vary considerably in their diurnal patterns, and that diurnal patterns are not consistently associated with demographic or psychosocial factors (42, 43, 45). However, in women with metastatic breast cancer, flatter diurnal cycles have been associated with repressed emotion (26) as well as with shortened survival time (27). In this study, several medical variables including a higher cancer stage, having had a mastectomy, and not having had chemotherapy were associated with flatter diurnal slopes in breast cancer survivors. Thus, it is possible that the flattened diurnal cortisol slope, as well as elevated cortisol levels, may be markers of disease activity. Given the potential prognostic importance of diurnal patterns, this variable should be explored further in cancer survivors with larger sample sizes.
The findings regarding cortisol reactivity to the mammogram were consistent with the hypocortisolism hypothesis. Cortisol reactivity was conceptualized as changes in cortisol levels from the 3-day baseline period to the 3-day period surrounding the mammogram in order to incorporate anticipatory and recovery phases as well as the acute response to the event. While control subjects showed the expected increases in cortisol from Phase 1 (1 month before the mammogram) to Phase 2 (the day before, day of, and day after the mammogram), breast cancer survivors’ cortisol levels decreased from baseline to stress phases.2 These group differences in cortisol reactivity are consistent with the finding that women with metastatic breast cancer demonstrated a blunted cortisol response to a laboratory stressor (25). They are also consistent with results from a number of studies indicating that chronic stress leads to suppressed cardiovascular and neuroendocrine responses to acute stress (46, 47). One explanation for this suppressed response is that repeated efforts to cope may result in fatigue and an inability to mount new acute responses (18–19, 47) . Among the breast cancer survivors in this study, cortisol reactivity was not associated with any psychological variables indicative of higher stress levels or higher risk perception. However, a higher cancer stage and greater time since diagnosis were associated with decreased cortisol reactivity, whereas current hormone therapy was associated with increased cortisol reactivity.
Interestingly, among both breast cancer survivors and controls, cortisol levels decreased over the first 3 days of the study. This may be because of habituation to the study procedures and underscores the importance of sampling cortisol over multiple days rather than relying on a single day to represent the baseline period. Among breast cancer survivors, cortisol levels then continued to decrease during the second 3-day period. Although it is possible that this reflects a continued habituation process, this is unlikely because the habituation effect would likely have dissipated in the month-long interval before the second phase of the study. In contrast, the control group demonstrated a significant increase in cortisol during the second phase, consistent with what is typically seen in response to acute stress (22, 23).
It is notable that there were very few associations between psychological variables and cortisol levels, diurnal slopes, or reactivity in the breast cancer survivors. Responses on the Psychological Consequences Questionnaire were the only psychological variables to show significant correlations with cortisol indices. Women who reported more negative social responses the week before the mammogram (eg, withdrawing from others) had steeper diurnal cortisol slopes at baseline, while those who reported more positive emotional reactions after the mammogram (eg, feelings of relief) showed greater decreases in cortisol from baseline period to the 3-day period surrounding the mammogram. Perhaps the other psychological measures included in this study, which were measures of transient mood states and stress perceptions, were not sensitive enough to detect meaningful differences among subgroups of patients. Future studies should consider including more global measures of stress and distress, as well as measures of positive growth (eg, an enhanced sense of purpose, increased spirituality, closer relationships with others (44). These measures were not included in the present study because of the primary focus on differences between breast cancer survivors and controls, who tend to be similar in terms of their overall psychological well-being (48, 49) .
It is not clear whether the elevations in cortisol levels and the blunted cortisol reactivity to acute stress found in this study are a result of physiologic stress associated with cancer treatment or the disease process, psychological stress associated with fear of recurrence, or a combination of both. There were no group differences in baseline levels of daily stress or mood, suggesting that any stress posed by cancer survivorship is not an ongoing, unrelenting burden and that the elevation in cortisol seen in the breast cancer survivors at baseline was not due to anticipatory anxiety regarding the upcoming mammogram. However, the cancer survivors’ elevated baseline cortisol levels do suggest the possibility of chronic stress in this population. Although group differences in stress ratings associated with the mammogram were not statistically significant, they were suggestive that the breast cancer survivors felt more threatened by the experience than women without a history of cancer. Further research is needed to determine whether cancer survivors demonstrate patterns of cortisol reactivity that generalize across various cancer-related and non-cancer-related stressors and what significant this may have on their health. Studies using laboratory stressors may be useful in this regard, as well as in determining the temporal dynamics (eg, reactions in anticipation of the stressor, and poststressor recovery) of cortisol responses.
There are several limitations of this study that must be considered when interpreting these results. First, this was a pilot study conducted with a small sample of breast cancer survivors who were predominantly white and well educated. Future studies need to be conducted with larger, more heterogeneous samples—including survivors of other types of cancers—in order to replicate these findings. In addition, the current study did not include a comprehensive assessment of health behaviors such as sleep, diet, exercise, and alcohol consumption. However, of these variables, the only ones that have been consistently linked to cortisol secretion are smoking (which was measured in this study) and recent intense physical exercise (which participants were instructed to restrain from before saliva samples) (23). Thus, it is unlikely that controlling for other health behaviors would have significantly altered the pattern of findings. However, additional variables such as body size and central fat distribution may play a role in cortisol response (50) and should be assessed in future studies.
This study also has a number of notable strengths, including a prospective design and multiple days of sampling at baseline, which improves the reliability of the findings. The use of salivary cortisol assessed in the course of the participants’ daily lives as well as the use of a naturally occurring stressor enhances the ecological validity of the study. Finally, this is the first study to examine HPA-axis functioning in a group of cancer survivors. Stress associated with fear of recurrence is a major burden for at least some cancer survivors and may have physiological as well as psychological consequences.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONNOTESACKNOWLEDGMENTSREFERENCES |
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NOTES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONNOTESACKNOWLEDGMENTSREFERENCES |
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2 In order to examine whether the data for single time points showed any clear signs of an acute response on the day of the mammogram, individual time points for both groups were plotted over the baseline period (days 1–3) and day 5 (the day of the mammogram). Inspection of the plots revealed that, in comparison to the baseline period, on day 5 the breast cancer survivors had lower cortisol levels at each of the 6 time points. Women in the control group had higher cortisol levels at each of the 6 time points on day 5 in comparison to the baseline period. They also showed a more flattened diurnal pattern on day 5 with less of a decline in cortisol levels at the end of the day. Thus, there was no clear evidence of an acute cortisol response on the day of the mammogram, supporting the conceptualization of the acute response as occurring over multiple days rather than at a single time point.
Received for publication June 18, 2002.
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