This exploratory study describes cross-sectional associations between selected indicators of psychosocial adaptation and immunologic parameters in women who recently completed surgery for early-to-mid-stage breast cancer, a group that is under considerable stress from the physical and psychological effects of surgery and the anticipation of adjuvant therapy. We previously documented that this group of women reports many concerns at this point in time including fear of recurrence and concerns about the physical effects of adjuvant therapy (41
), and significant disruptions in quality of life (42
). Importantly, better psychosocial adaptation during breast cancer treatment predicts greater well-being up to 13 years after treatment (16
While much is known about the psychosocial aspects of dealing with the stress of diagnosis and treatment for breast cancer, less is known about how individual differences in these psychosocial experiences relate to biological parameters that may contribute to disease outcomes. Th1 cytokine regulation may vary as a function of psychosocial stress factors, which may account in part for the associations previously noted between psychosocial factors and cancer outcomes (for review see 22
). Animal studies have confirmed that experimental stressors are associated with lower NK cell cytotoxicity on the one hand and increased tumor progression on the other (43
). After surgical treatment of tumors, immune function may be important in eliminating residual disease and micrometastases and some have suggested that intact perioperative immune function is involved in tumor control (44
). This has led some to suggest the value of identifying stressed surgical cancer patients who might benefit from stress reduction interventions as a means to improve longer-term outcomes (45
In one prior clinical study greater levels of cancer-specific anxiety were associated with lower levels of NK cell cytotoxicity in women recently treated for Stage II-III breast cancer (18
). No prior work in humans has examined associations between other psychosocial variables such as mood and QOL and more specific indicators of immune functions that relate to cytokine signaling in women undergoing treatment for breast cancer. The purpose of this study was to report associations between mood and QOL on the one hand, and Th1 cytokine production on the other, in a sample of women who had received surgery for early-to-mid-stage disease within the past several weeks but who had not yet begun adjuvant therapy. Other work in the field has established associations between psychosocial factors and lymphocyte proliferation in breast cancer patients (46
) though less is known about how psychosocial factors relate to the production of important signaling molecules that are produced following lymphocyte stimulation.
Results of the analyses of psychosocial adaptation factors suggest that mood states and QOL indicators generally reflecting better adaptation were associated with several of the immune parameters measured in this cohort of breast cancer patients. In general, lower levels of negative mood state of anxiety was associated with greater production of the Th1 cytokine IL-2 while greater levels of positive mood states such as affection were associated with greater production of the Th1 cytokines IL-12 and IFN-γ. To our knowledge this is the first study to show associations between greater positive mood states and Th1 cytokine production in women being treated for breast cancer. The fact that greater levels of affection were associated with greater Th1 cytokine production suggests the importance of both positive mood states and the quality of personal relationships in this population. Since prior work from our group has shown that stress management can increase reports of positive affect and positive social interactions in women being treated for breast cancer (15
) future studies should examine how changes in positive affect and social relationships during stress management relate to alterations in cytokine production in these women as they move through treatment.
Interestingly, the pattern of results suggests that association observed between negative mood and Th1 cytokine production involved activated mood states (anxiety), which may be more likely to associate with elevated sympathetic nervous system hormones like norepinephrine (NE), which has been associated with immune alterations and other tumor-promoting changes (22
). Specifically, NE has been shown to inhibit Th1 cytokine secretion, target binding and apoptotic programming (52
). We plan to collect information on NE output in the future. Regardless of the biobehavioral pathways implicated, the present work is among the first to show a specific association between lower negative mood and greater positive mood and the ability of PBMCs of breast cancer patients to produce Th1 cytokines upon stimulation. Studies in ovarian cancer patients have shown associations between depressed and anxious mood, and lower ratios of IFN- γ vs. IL-4 production in T-helper and T-cytotoxic lymphocytes from peripheral blood and the tumor microenvironment (tumor-infiltrating lymphocytes and ascites), among ovarian cancer patients on the day of surgery (53
). Other studies have shown increased perceived stress, anxiety, and mood disturbance in women undergoing breast biopsy, accompanied by a persistent reduction in natural killer cell activity and IFN- γ production, as well as an increased production of IL-4, IL-6 and IL-10 (54
). We also found that greater breast cancer - specific quality of life was associated with greater production of the Th1 cytokine TNF-α. In women with advanced-stage ovarian cancer, Costanzo et al. found associations between psychosocial factors such as social attachment and quality of life, and plasma levels of IL-6 before surgery (55
). We are unaware of prior studies demonstrating associations between specific quality of life indicators and cytokine production in early-stage breast cancer patients after surgery. These findings converge on a pattern of better mood status and quality of life—indicators of psychosocial adaptation—being associated with greater Th1 production in these women undergoing treatment for breast cancer. Future work examining the effects of psychosocial interventions that modulate quality of life and indicators of psychosocial adaptation in women with breast cancer (46
) in the peri-surgical period may show parallel effects on Th1 cytokine regulation that could have implications for disease outcomes and well-being over time (44
The present findings should be considered in view of a few caveats. The women recruited for this study were a conveniencesample that is not necessarily reflective of all women undergoing treatment for breast cancer. In the present study women were required to provide blood samples for assays. Analyses of this subsample of women versus those who participated in the parent study examining the effects of psychosocial intervention (15
) revealed that the present sample represented a group with less advanced disease than those women from the parent sample who did not provide blood samples. This difference may be due to the fact that women with more advanced disease were likely to have received neo-adjuvant (pre-surgery) treatments, which excluded them from the present substudy of biological outcomes. These advanced cases are also more likely to have been unemployed due to health reasons. These factors singly or in combination may have made them less willing or able to provide blood samples for the study. Thus caution is in order in generalizing the present results to all women being treated for non-metastic breast cancer. Generally, the present sample tended to be largely White, middle-class and well-educated women who were receiving surgery at private practices in the study area. Future studies will need to recruit women across different ethnic groups and a broader range of socioeconomic status who may be receiving their treatments at public hospitals and community clinics. Also there is the fact that almost 40 % of the blood samples were obtained outside the time frame of 4 to 8 weeks after surgery. Although this variable was controlled for in our analyses, the wide range of days since surgery might have lead us to underestimate our findings on associations between psychosocial and immunological variables. Future studies should attempt to minimize this range by restricting recruitment to a shorter time frame.
In summary, this work indicates that greater negative mood states (anxiety) correlate with lower Th1 cytokine (IL-2) production, while greater positive mood (affection) correlates with higher Th1 (IL-12, IFN-γ) cytokine production. Better quality of life was also associated with greater Th1 cytokine production. These findings support the hypothesis that achieving better psychosocial adaptation in women with breast cancer under treatment may contribute to their health status by affecting cell-signaling molecules that orchestrate immunologic responses. It is reasonable to hypothesize that psychosocial interventions that increase positive adaptation by changing individuals’ appraisals of stress (cognitive behavioral-based interventions) in order to decrease negative mood states and increase positive mood and perceived quality of life during the period of active treatment for breast cancer might preserve immune system functioning as they begin adjuvant therapy. Such interventions may promote physiological “recovery” after surgery in order to interrupt the “window of opportunity” for micro-metastases to progress into full-blown recurrence of disease (17
). Longitudinal studies tracking psychosocial adaptation and immune parameters acrossthe recovery period after surgery and during and after adjuvant therapy may provide insight into biobehavioral processes that can explain the influence of psychosocial functioning on health outcomes in women treated for breast cancer.