Differences in attention, processing speed, and executive function in older breast cancer survivors compared to controls is partially explained by plasma IL-6: The Thinking and Living with Cancer (TLC) Study

Abstract Purpose: Cancer-related cognitive problems may result from peripheral inflammation effects on the brain. We tested whether differences in cognitive performance between breast cancer survivors and non-cancer controls was explained by elevated inflammatory cytokines. Methods: We enrolled women >60 years, newly diagnosed with primary breast cancer (stage 0-III) (n=400) and frequency-matched non-cancer controls (n=329) from six national centers from 2010- 2020, with blood collection beginning in 2016. Baseline assessments occurred pre-systemic therapy (or enrollment for controls) with annual follow-up to 60-months. The primary outcome was the score on neurocognitive tests of the attention, processing speed and executive function (APE) domain. Plasma levels of IL-6, IL-10, and TNF-alpha were determined using multiplex testing and mixed linear models compared results for each marker across all timepoints by survivor/control group, adjusting for age, race, WRAT scores, recruitment site, comorbidities, and BMI. Multi-level mediation analyses tested the simultaneous direct effects of survivor/control group on cognition and indirect effects of group on each immune marker and the effect of the marker on cognition, controlling for covariates. Results: Participants had an average age of 67.7 years (range: 60-90). Most survivors had stage I (60.9%) estrogen-receptor positive (87.6%) tumors. Survivors had significantly higher adjusted IL-6 levels than controls at baseline, 12-, 24- and 60-months (p=< 0.001 to 0.014), but there were no differences for other markers. Survivors had lower adjusted APE scores than controls, and this effect was due to the indirect effects of being a survivor vs. control on IL-6 (p=0.047). Conclusion: Cancer and its treatments were related to poorer attention, processing speed, and executive function compared to non-cancer frequency matched controls, and this difference was partially explained by elevated IL-6. Citation Format: Jeanne S. Mandelblatt, Brent J. Small, Xingtao Zhou, Zev M. Nakamura, Harvey J. Cohen, Tim A. Ahles, Jaeil Ahn, Traci N. Bethea, Martine Extermann, Heather S.L. Jim, Brenna C. McDonald, Sunita K. Patel, Kelly Rentscher, James Root, Andrew J. Saykin, Kathleen Van Dyk, Wanting Zhai, Elizabeth C. Breen, Judith E. Carroll. Differences in attention, processing speed, and executive function in older breast cancer survivors compared to controls is partially explained by plasma IL-6: The Thinking and Living with Cancer (TLC) Study [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A012.