Effects of brief stress management interventions on distress and leukocyte nuclear factor kappa B expression during primary treatment for breast cancer: A randomized trial

Background: A randomized controlled trial (RCT) of 5-week stress management interventions teaching cognitive behavioral therapy (CBT) or relaxation training (RT) techniques showed decreases in stress and serum inflammatory markers over 12 months in women undergoing treatment for breast cancer (BCa). To understand the molecular mechanisms involved, we examined the effects of these interventions on the transcription factor NF-0B DNA binding activity in leukocytes in parallel with circulating inflammatory markers, stress management skill efficacy and multiple distress indicators. Methods: This is a secondary analysis using blood samples of 51 BCa patients (Stage 0-III) with high cancer specific distress selected from a completed RCT (NCT02103387). Women were randomized to one of three conditions, CBT, RT or health education control (HE). Blood samples and self-reported distress measures (Affects Balance Scale-Negative Affect [ABS-NA], Impact of Events Scale-hyperarousal [IES-H] and intrusive thoughts [IES-I]) were collected at baseline (T0) and 12-month follow-up (T2). Self-reported distress measures and perceived stress management skills (PSMS) were also measured immediately post-intervention (baseline + 2 months: T1). Repeated measures analyses compared changes in distress and NF-kappa B expression among conditions, controlling for age, stage of cancer, days from surgery to baseline, and receipt of chemotherapy and radiation. Regression analyses related T0 to T2 change in NF-kappa B expression with T0 to T1 changes in self-reported PSMS and distress measures. Exploratory regression analyses also associated change in NF-kappa B expression with change in serum cytokines (IL-113, IL-6 and TNF-alpha); and s100A8/A9, a circulating inflammatory marker important in breast cancer progression. Results: There was a significant condition (CBT/RT, HE) x time (T0, T2) effect on NF-kappa B, F(1, 39) = 5.267, p = 0.036, wherein NF-kappa B expression significantly increased over time for HE but did not change for RT or CBT. Greater increases in PSMS from T0 to T1 were associated with less increase in NF-0B expression over 12 months (13 = 0.426, t(36) = 2.637, p = 0.048). We found that women assigned to active intervention (CBT/RT) had significant decreases in ABS-NA (F(1, 40) = 6.537, p = 0.028) and IES-I (F(1, 40) = 4.391, p = 0.043) from T0 to T1 compared to women assigned to HE, who showed no change over time (p's > 0.10). For women assigned to CBT or RT, lower NF-0B expression at T2 was related to less ABS-NA, IES-H, and IES-I, all p's < 0.05, although T0-T1 change in distress was not related to T0-T2 change in NF-0B expression for those in an active intervention. Conclusions: Brief CBT or RT stress management interventions can mitigate increases in pro-inflammatory leukocyte NF-kappa B binding over 12 months of primary treatment in highly distressed BCa patients. These effects are likely brought about by improved stress management skills.