Plasma levels of interleukin‐6 mediate neurocognitive performance in older breast cancer survivors: The Thinking and Living With Cancer study

Abstract

Background: Immune activation/inflammation markers (immune markers) were tested to explain differences in neurocognition among older breast cancer survivors versus noncancer controls. Methods: Women >60 years old with primary breast cancer (stages 0–III) (n = 400) were assessed before systemic therapy with frequency‐matched controls (n = 329) and followed annually to 60 months; blood was collected during annual assessments from 2016 to 2020. Neurocognition was measured by tests of attention, processing speed, and executive function (APE). Plasma levels of interleukin‐6 (IL‐6), IL‐8, IL‐10, tumor necrosis factor α (TNF‐α), and interferon γ were determined using multiplex testing. Mixed linear models were used to compare results of immune marker levels by survivor/control group by time and by controlling for age, racial/ethnic group, cognitive reserve, and study site. Covariate‐adjusted multilevel mediation analyses tested whether survivor/control group effects on cognition were explained by immune markers; secondary analyses examined the impact of additional covariates (e.g., comorbidity and obesity) on mediation effects. Results: Participants were aged 60–90 years (mean, 67.7 years). Most survivors had stage I (60.9%) estrogen receptor–positive tumors (87.6%). Survivors had significantly higher IL‐6 levels than controls before systemic therapy and at 12, 24, and 60 months (p ≤ .001–.014) but there were no differences for other markers. Survivors had lower adjusted APE scores than controls (p < .05). Levels of IL‐6, IL‐10, and TNF‐α were related to APE, with IL‐6 explaining part of the relationship between survivor/control group and APE (p = .01). The magnitude of this mediation effect decreased but remained significant (p = .047) after the consideration of additional covariates. Conclusions: Older breast cancer survivors had worse long‐term neurocognitive performance than controls, and this relationship was explained in part by elevated IL‐6.