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

Jeanne S Mandelblatt; Brent J Small; Xingtao Zhou; Zev M Nakamura; Harvey J Cohen; Tim A Ahles; Jaeil Ahn; Traci N Bethea; Martine Extermann; Deena Graham; Claudine Isaacs; Paul B Jacobsen; Heather S L Jim; Brenna C McDonald; Sunita K Patel; Kelly E Rentscher; James C Root; Andrew J Saykin; Danielle B Tometich; Kathleen Van Dyk; Wanting Zhai; Elizabeth C Breen; Judith E Carroll

doi:10.1002/cncr.34784

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

Cancer. 2023 Aug 1;129(15):2409-2421. doi: 10.1002/cncr.34784. Epub 2023 Apr 25.

Authors

Jeanne S Mandelblatt^{1

2

3}, Brent J Small⁴, Xingtao Zhou⁵, Zev M Nakamura⁶, Harvey J Cohen^{7

8}, Tim A Ahles⁹, Jaeil Ahn⁵, Traci N Bethea^{1

2

3}, Martine Extermann¹⁰, Deena Graham¹¹, Claudine Isaacs¹², Paul B Jacobsen¹³, Heather S L Jim¹⁴, Brenna C McDonald^{15

16}, Sunita K Patel¹⁷, Kelly E Rentscher^{18

19

20}, James C Root⁹, Andrew J Saykin^{15

16}, Danielle B Tometich¹⁴, Kathleen Van Dyk^{19

21}, Wanting Zhai⁵, Elizabeth C Breen^{19

20}, Judith E Carroll^{19

20}

Affiliations

¹ Department of Oncology, Georgetown University Medical Center, Georgetown University, Washington, DC, USA.
² Georgetown Lombardi Institute for Cancer and Aging Research, Georgetown University's Lombardi Comprehensive Cancer Center, Washington, DC, USA.
³ Cancer Prevention and Control Program, Georgetown University's Lombardi Comprehensive Cancer Center, Washington, DC, USA.
⁴ School of Aging Studies, University of South Florida, Tampa, Florida, USA.
⁵ Department of Biostatistics, Bioinformatics, and Biomathematics, Department of Oncology and Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
⁶ Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
⁷ Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
⁸ Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, North Carolina, USA.
⁹ Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
¹⁰ Department of Oncology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, Florida, USA.
¹¹ John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey, USA.
¹² Georgetown Lombardi Comprehensive Cancer Center, Department of Oncology, Department of Medicine, Georgetown University, Washington, DC, USA.
¹³ Healthcare Delivery Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
¹⁴ Cancer Prevention and Control Program, H. Lee Moffitt Comprehensive Cancer Center, Tampa, Florida, USA.
¹⁵ Department of Radiology and Imaging Sciences, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis, Indiana, USA.
¹⁶ Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, Indiana, USA.
¹⁷ City of Hope National Medical Center, Los Angeles, California, USA.
¹⁸ Department of Psychiatry and Behavioral Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
¹⁹ Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
²⁰ Cousins Center for Psychoneuroimmunology, University of California, Los Angeles, Los Angeles, California, USA.
²¹ Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California, USA.

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.

Keywords: breast cancer; cancer-related cognitive decline; cognition; immune activation; inflammation; older survivors.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Aged
Biomarkers
Breast Neoplasms*
Cancer Survivors* / psychology
Cognition
Female
Hominidae*
Humans
Interleukin-10
Interleukin-6
Middle Aged
Tumor Necrosis Factor-alpha

Substances

Biomarkers
Interleukin-10
Interleukin-6
Tumor Necrosis Factor-alpha
IL6 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding