Plasma levels of interleukin-6 mediate neurocognitive performance in older breast cancer survivors: The Thinking and Living With Cancer study
The last two authors contributed equally to this article.
An earlier version of this research was presented at the American Association of Cancer Research Special Conference on Aging and Cancer; November 17–20, 2022; San Diego, California.
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.
CONFLICT OF INTEREST STATEMENT
Jeanne S. Mandelblatt has received grants from the National Institutes of Health. Traci N. Bethea has received grants from the National Cancer Institute. Martine Extermann has been a consultant for Aileron and Alnylam and has received honoraria from OncLive. Claudine Isaacs has been a consultant for Genentech, AstraZeneca, McGraw-Hill Companies, Gilead Sciences, Wolters Kluwer, Novartis, Puma Biotechnology, Seagen, and Pfizer Canada; other disclosures are available at https://coi.asco.org/share/KZZ-5URC/Claudine%20Isaacs. Heather S. L. Jim has been a consultant for SBR Bioscience. Brenna C. McDonald has received grants from the National Institutes of Health. Kelly E. Rentscher has received grants from the National Institute on Aging. Andrew J. Saykin has received support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in-kind contribution of a positron emission tomography tracer precursor), Bayer Oncology (scientific advisory board), Eisai (scientific advisory board), Siemens Medical Solutions USA (dementia advisory board), and Springer–Nature Publishing (editorial office support as editor in chief, Brain Imaging and Behavior). Danielle B. Tometich has received grants from the National Cancer Institute. Kathleen Van Dyk has received grants from the National Cancer Institute. Elizabeth C. Breen has received grants from the National Institutes of Health and has been a consultant for Georgetown University. Judith E. Carroll has received grants from the American Cancer Society and National Institutes of Health. All other authors have declared no conflicts of interest.
Open Research
DATA AVAILABILITY STATEMENT
The Thinking and Living With Cancer (TLC) data are available for sharing following the National Institutes of Health requirements and FAIR principles (findability, accessibility, interoperability, and reproducibility) for data access. Data access is via requests to the first author. The SAS or Mplus code and data for the analyses included in the article are available upon request within the constraints of TLC institutional review board requirements.
