Abstract
<p>Both depression and inflammation are independently associated with breast cancer health outcomes, and multiple studies have shown that depression and inflammatory markers may be linked among women with breast cancer. Studies of cognitive-behavioral based psychosocial interventions have found beneficial intervention effects on time to survival and recurrence in breast cancer patients. However, the mechanisms through which interventions affect clinical health outcomes are less understood. It has been suggested that psychosocial interventions may affect long-term breast cancer clinical disease endpoints via effects on immune and inflammatory processes, but more research is necessary to explore these relationships. The current study examined the relationships between post-surgical and pre-adjuvant levels of depressive symptoms and pro-inflammatory cytokines with long-term clinical health outcomes, both individually and in combination, among a cohort of non-metastatic breast cancer patients. It also sought to replicate recent findings that a cognitive behavioral stress management (CBSM) psychosocial intervention predicts favorable breast cancer clinical disease endpoints, and examined possible mediators of these effects. The present sample included 90 women with non-metastatic breast cancer and available blood data for analyses of serum pro-inflammatory cytokines from a larger clinical trial. Women were initially recruited and assessed at 2-10 weeks post-surgery (T1). At that time, information was collected related to demographic characteristics, medical history, treatment plans, and psychosocial functioning. Women were randomized to either a 10-week group-based CBSM intervention or a 1-day psychoeducational group seminar control. Participants were re-assessed at 6 months (T2), 12 months (T3), and 5-years (T5) post-T1. Blood samples for cytokine analyses were collected at T1 and T3. At 8-15 year follow-up (11-year median; T6), a tumor registry linkage was performed and medical chart reviews were conducted to determine mortality status (including cause and date of death) and disease free status (i.e., recurrence status) of study participants. Cox Proportional Hazards Models were conducted to assess the direct effects of baseline depressive symptoms and serum concentrations of pro-inflammatory cytokines (i.e., IL-1β, IL-6, and TNF-α) on time to clinical disease endpoints (i.e., all-cause mortality, breast cancer-specific mortality, and breast cancer recurrence) assessed at 11-year median follow-up (Aim 1a). Bootstrapped linear regression analyses were used to test indirect relationships between baseline depressive symptoms and pro-inflammatory cytokines with time to clinical disease endpoints (Aim 1b). Cox Proportional Hazards Models were conducted to assess for group differences (i.e., CBSM vs. control) in time to clinical disease endpoints (Aim 2a). Finally, bootstrapped linear regression analyses were used to test indirect effects of CBSM on time to clinical disease endpoints through 12-month changes in depressive symptoms and pro-inflammatory cytokines (Aim 2b). Unadjusted and adjusted models were conducted, which accounted for age, stage of disease, surgical procedure, hormone therapy, and smoking status. All analyses were run in the 90 women for whom blood data were available, and in a subset of 73 women who initially had invasive disease (i.e., not stage 0). At median 11-year follow-up, 8 women (8.9%) were deceased and 6 of those deaths (75.0%) were related to breast cancer. A total of 17 women (18.9%) had experienced a breast cancer recurrence. In Aim 1a, results of Cox Proportional Hazards analyses revealed non-significant relationships between baseline variables and time to clinical disease endpoints in both the full and invasive subsamples in unadjusted and adjusted models (all ps > 0.10). In Aim 1b, unadjusted and adjusted linear regression analyses revealed significant associations between greater baseline depressive symptoms and concurrent greater serum concentrations of IL-1β (β = 0.29, p = 0.007) and TNF- α (β = 0.30, p = 0.004). A marginal association emerged between greater baseline depressive symptoms and concurrent greater IL-6 (β = 0.179 p = 0.077). These findings were retained in the invasive subsample. However, as in Aim 1a, baseline levels of depressive symptoms and pro-inflammatory cytokines did not predict time to clinical disease endpoints (all ps > 0.10), and thus mediation was not supported. In Aim 2a, results of Cox Proportional Hazards analyses revealed non-significant group differences in time to clinical disease endpoints in both the full and invasive subsamples in unadjusted and adjusted models (all ps > 0.10). In Aim 2b, results of linear regression analyses revealed non-significant group differences in 12-month changes in depressive symptoms and pro-inflammatory cytokines (all ps > 0.10), and mediation was therefore not supported. The observed associations between baseline depressive symptoms and pro-inflammatory cytokines have implications for the treatment of women with breast cancer who report comorbid elevated depressive symptoms. However, the long-term implications of these findings, including the role of psychosocial interventions, are inconclusive. More research is needed, including large well-controlled trials, to further investigate the associations between these variables to elucidate the mechanisms through which depressive symptoms, inflammation, and psychosocial interventions interact and ultimately affect long-term clinical health outcomes of breast cancer patients.</p>