Browsing by Author "Breen, Elizabeth C."

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    Elevated C-Reactive Protein and Subsequent Patient-Reported Cognitive Problems in Older Breast Cancer Survivors: The Thinking and Living With Cancer Study
    (American Society of Clinical Oncology, 2023) Carroll, Judith E.; Nakamura, Zev M.; Small, Brent J.; Zhou, Xingtao; Cohen, Harvey J.; Ahles, Tim A.; Ahn, Jaeil; Bethea, Traci N.; Extermann, Martine; Graham, Deena; Isaacs, Claudine; Jim, Heather S. L.; Jacobsen, Paul B.; McDonald, Brenna C.; Patel, Sunita K.; Rentscher, Kelly; Root, James; Saykin, Andrew J.; Tometich, Danielle B.; Van Dyk, Kathleen; Zhai, Wanting; Breen, Elizabeth C.; Mandelblatt, Jeanne S.; Radiology and Imaging Sciences, School of Medicine
    Purpose: To examine longitudinal relationships between levels of C-reactive protein (CRP) and cognition in older breast cancer survivors and noncancer controls. Methods: English-speaking women age ≥ 60 years, newly diagnosed with primary breast cancer (stage 0-III), and frequency-matched controls were enrolled from September 2010 to March 2020; women with dementia, neurologic disorders, and other cancers were excluded. Assessments occurred presystemic therapy/enrollment and at annual visits up to 60 months. Cognition was measured using the Functional Assessment of Cancer Therapy-Cognitive Function and neuropsychological testing. Mixed linear effect models tested for survivor-control differences in natural log (ln)-transformed CRP at each visit. Random effect-lagged fluctuation models tested directional effects of ln-CRP on subsequent cognition. All models controlled for age, race, study site, cognitive reserve, obesity, and comorbidities; secondary analyses evaluated if depression or anxiety affected results. Results: There were 400 survivors and 329 controls with CRP specimens and follow-up data (average age of 67.7 years; range, 60-90 years). The majority of survivors had stage I (60.9%), estrogen receptor-positive (87.6%) tumors. Survivors had significantly higher adjusted mean ln-CRP than controls at baseline and 12-, 24-, and 60-month visits (all P < .05). Higher adjusted ln-CRP predicted lower participant-reported cognition on subsequent visits among survivors, but not controls (P interaction = .008); effects were unchanged by depression or anxiety. Overall, survivors had adjusted Functional Assessment of Cancer Therapy-Cognitive Function scores that were 9.5 and 14.2 points lower than controls at CRP levels of 3.0 and 10.0 mg/L. Survivors had poorer neuropsychological test performance (v controls), with significant interactions with CRP only for the Trails B test. Conclusion: Longitudinal relationships between CRP and cognition in older breast cancer survivors suggest that chronic inflammation may play a role in development of cognitive problems. CRP testing could be clinically useful in survivorship care.
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    Epigenetic Aging in Older Breast Cancer Survivors and Non-Cancer Controls: Preliminary Findings from the Thinking and Living with Cancer (TLC) Study
    (Wiley, 2023) Rentscher, Kelly E.; Bethea, Traci N.; Zhai, Wanting; Small, Brent J.; Zhou, Xingtao; Ahles, Tim A.; Ahn, Jaeil; Breen, Elizabeth C.; Cohen, Harvey Jay; Extermann, Martine; Graham, Deena M. A.; Jim, Heather S. L.; McDonald, Brenna C.; Nakamura, Zev M.; Patel, Sunita K.; Root, James C.; Saykin, Andrew J.; Van Dyk, Kathleen; Mandelblatt, Jeanne S.; Carroll, Judith E.; Radiology and Imaging Sciences, School of Medicine
    Background: Cancer and its treatments may accelerate aging in survivors; however, research has not examined epigenetic markers of aging in longer term breast cancer survivors. This study examined whether older breast cancer survivors showed greater epigenetic aging than noncancer controls and whether epigenetic aging related to functional outcomes. Methods: Nonmetastatic breast cancer survivors (n = 89) enrolled prior to systemic therapy and frequency-matched controls (n = 101) ages 62 to 84 years provided two blood samples to derive epigenetic aging measures (Horvath, Extrinsic Epigenetic Age [EEA], PhenoAge, GrimAge, Dunedin Pace of Aging) and completed cognitive (Functional Assessment of Cancer Therapy-Cognitive Function) and physical (Medical Outcomes Study Short Form-12) function assessments at approximately 24 to 36 and 60 months after enrollment. Mixed-effects models tested survivor-control differences in epigenetic aging, adjusting for age and comorbidities; models for functional outcomes also adjusted for racial group, site, and cognitive reserve. Results: Survivors were 1.04 to 2.22 years biologically older than controls on Horvath, EEA, GrimAge, and DunedinPACE measures (p = .001-.04) at approximately 24 to 36 months after enrollment. Survivors exposed to chemotherapy were 1.97 to 2.71 years older (p = .001-.04), and among this group, an older EEA related to worse self-reported cognition (p = .047) relative to controls. An older epigenetic age related to worse physical function in all women (p < .001-.01). Survivors and controls showed similar epigenetic aging over time, but Black survivors showed accelerated aging over time relative to non-Hispanic White survivors. Conclusion: Older breast cancer survivors, particularly those exposed to chemotherapy, showed greater epigenetic aging than controls that may relate to worse outcomes. If replicated, measurement of biological aging could complement geriatric assessments to guide cancer care for older women.
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    Genetic Variants Associated with Longitudinal Cognitive Performance in Older Breast Cancer Patients and Controls
    (MDPI, 2023-05-23) Nudelman, Kelly; Nho, Kwangsik; Zhang, Michael; McDonald, Brenna C.; Zhai, Wanting; Small, Brent J.; Wegel, Claire E.; Jacobsen, Paul B.; Jim, Heather S. L.; Patel, Sunita K.; Graham, Deena M. A.; Ahles, Tim A.; Root, James C.; Foroud, Tatiana; Breen, Elizabeth C.; Carroll, Judith E.; Mandelblatt, Jeanne S.; Saykin, Andrew J.; Medical and Molecular Genetics, School of Medicine
    Background: There have been no published genome-wide studies of the genetics of cancer- and treatment-related cognitive decline (CRCD); the purpose of this study is to identify genetic variants associated with CRCD in older female breast cancer survivors. Methods: Analyses included white non-Hispanic women with non-metastatic breast cancer aged 60+ (N = 325) and age-, racial/ethnic group-, and education-matched controls (N = 340) with pre-systemic treatment and one-year follow-up cognitive assessment. CRCD was evaluated using longitudinal domain scores on cognitive tests of attention, processing speed, and executive function (APE), and learning and memory (LM). Linear regression models of one-year cognition included an interaction term for SNP or gene SNP enrichment*cancer case/control status, controlling for demographic variables and baseline cognition. Results: Cancer patients carrying minor alleles for two SNPs, rs76859653 (chromosome 1) in the hemicentin 1 (HMCN1) gene (p = 1.624 × 10-8), and rs78786199 (chromosome 2, p = 1.925 × 10-8) in an intergenic region had lower one-year APE scores than non-carriers and controls. Gene-level analyses showed the POC5 centriolar protein gene was enriched for SNPs associated with differences in longitudinal LM performance between patients and controls. Conclusions: The SNPs associated with cognition in survivors, but not controls, were members of the cyclic nucleotide phosphodiesterase family, that play important roles in cell signaling, cancer risk, and neurodegeneration. These findings provide preliminary evidence that novel genetic loci may contribute to susceptibility to CRCD.
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    Plasma levels of interleukin-6 mediate neurocognitive performance in older breast cancer survivors: The Thinking and Living With Cancer study
    (Wiley, 2023) Mandelblatt, Jeanne S.; Small, Brent J.; Zhou, Xingtao; Nakamura, Zev M.; Cohen, Harvey J.; Ahles, Tim A.; Ahn, Jaeil; Bethea, Traci N.; Extermann, Martine; Graham, Deena; Isaacs, Claudine; Jim, Heather S. L.; Jacobsen, Paul B.; McDonald, Brenna C.; Patel, Sunita K.; Rentscher, Kelly E.; Root, James C.; Saykin, Andrew J.; Tometich, Danielle B.; Van Dyk, Kathleen; Zhai, Wanting; Breen, Elizabeth C.; Carroll, Judith E.; Radiology and Imaging Sciences, School of Medicine
    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.