Although advancements in breast cancer treatments have resulted in improved rates of survival, a majority of women with breast cancer (BC) experience distressing symptoms during treatment, which for some, persist into survivorship. The symptoms most frequently reported among women with BC include cognitive dysfunction (CD), depressive symptoms, anxiety, fatigue, sleep disturbances, and pain, which may be collectively called """"""""psychoneurological (PN) symptoms."""""""" Inflammatory activation and epigenetic alterations have been associated with the etiology of cancer and with various chronic neurocognitive disorders. However, to date, no investigators have considered these epigenetic processes as possible mechanisms associated with the etiology of PN symptoms in women with BC. Given that epigenetic patterns have been shown to have plasticity, the further elucidation of the relationship of epigenetic alterations to the development and persistence of PN symptoms could provide foundational knowledge for the future development of predictive markers and treatments to address the epigenetic changes associated with PN symptoms in women with BC. Therefore, the specific aims of this study are to examine: 1. The frequency and severity of PN symptoms and the interrelationships among PN symptoms at each time point. 2. Levels of inflammation and to quantify the frequency and genome-wide localization of changes in epigenetic patterns across time following chemotherapy. 3. The relationships among inflammation, epigenetic changes, and the development, severity, and persistence of PN symptoms across time. To meet these aims, the proposed study will prospectively characterize PN symptoms (cognitive dysfunction;depressive symptoms and anxiety;fatigue;sleep disturbances;pain), inflammatory activation [(levels of C- reactive protein (CRP), tumor necrosis factor alpha (TNF-a), interleukin 1 beta (IL-1B), and interleukin 6 (IL- 6)], and epigenetic alterations in 75 women diagnosed with early-stage BC across 5 timepoints: prior to their receipt of chemotherapy, at the time of their fourth chemotherapy treatment, and at 6, 12, and 24 months following the initiation of chemotherapy. Epigenetic alterations will be detected by quantifying the: (1) frequency and genome-wide location of methylation;(2) expression of a histone methyltransferease, EZH2, which is a Polycomb group protein that is thought to be important for the early steps in the epigenetic """"""""decision"""""""" process;and (3) telomere attrition, which can lead to alterations in chromatin compaction/gene expression. The study results may potentially deepen understanding regarding the biological processes underlying PN symptoms and lead to improved strategies for symptom management in women with BC.

Public Health Relevance

Distressing symptoms are frequently reported among women with BC over the treatment period, which may result in a significant decline in quality of life and health outcomes over the active treatment period and into survivorship. The proposed study may identify epigenetic alterations and biobehavioral mechanisms associated with distressing symptoms in women with BC that can be used to develop targeted interventions to reduce symptoms, enhance quality of life and possibly prevent or reverse the adverse health outcomes associated with BC and its treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Nursing Research (NINR)
Type
Research Project (R01)
Project #
5R01NR012667-04
Application #
8511845
Study Section
Special Emphasis Panel (ZNR1-REV-T (02))
Program Officer
Tully, Lois
Project Start
2010-09-29
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$605,216
Indirect Cost
$195,875
Name
Virginia Commonwealth University
Department
Other Health Professions
Type
Schools of Nursing
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Lyon, Debra E; Cohen, Ronald; Chen, Huaihou et al. (2016) Relationship of systemic cytokine concentrations to cognitive function over two years in women with early stage breast cancer. J Neuroimmunol 301:74-82
Chakradeo, Shweta; Elmore, Lynne W; Gewirtz, David A (2016) Is Senescence Reversible? Curr Drug Targets 17:460-6
Lyon, Debra E; Cohen, Ronald; Chen, Huaihou et al. (2016) The relationship of cognitive performance to concurrent symptoms, cancer- and cancer-treatment-related variables in women with early-stage breast cancer: a 2-year longitudinal study. J Cancer Res Clin Oncol 142:1461-74
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Starkweather, Angela R; Heineman, Amy; Storey, Shannon et al. (2016) Methods to measure peripheral and central sensitization using quantitative sensory testing: A focus on individuals with low back pain. Appl Nurs Res 29:237-41
Starkweather, Angela R; Ramesh, Divya; Lyon, Debra E et al. (2016) Acute Low Back Pain: Differential Somatosensory Function and Gene Expression Compared With Healthy No-Pain Controls. Clin J Pain 32:933-939
Wright, Michelle L; Starkweather, Angela R; York, Timothy P (2016) Mechanisms of the Maternal Exposome and Implications for Health Outcomes. ANS Adv Nurs Sci 39:E17-30
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Zhou, Qing; Jackson-Cook, Colleen; Lyon, Debra et al. (2015) Identifying molecular features associated with psychoneurological symptoms in women with breast cancer using multivariate mixed models. Cancer Inform 14:139-45
Aboalela, Noran; Lyon, Debra; Elswick Jr, R K et al. (2015) Perceived Stress Levels, Chemotherapy, Radiation Treatment and Tumor Characteristics Are Associated with a Persistent Increased Frequency of Somatic Chromosomal Instability in Women Diagnosed with Breast Cancer: A One Year Longitudinal Study. PLoS One 10:e0133380

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