Cancer: Biology and Behavior

TAI CHI EFFECTS ON CHRONIC INSOMNIA IN BREAST CANCER SURVIVORS: IMMUNE MECHANISMS
PI: Michael R. Irwin, MD
NCI
Immune Mechanisms Breast cancer is the most common cancer in women. After completion of successful therapy, many behavioral symptoms persist with over 20% of breast cancer survivors reporting chronic insomnia of greater than 6 months duration that fulfils clinical diagnostic criteria with associated functional limitations, decreased quality of life, and possible effects on long-term survival. Behavioral interventions are highly efficacious in the treatment of insomnia and preferred over hypnotic medications when insomnia is chronic. However, insomnia studies conducted in cancer are scarce. The proposed research builds upon a program of study that has examined the efficacy of a mind-body intervention, Tai Chi Chih (TCC), on health outcomes including sleep impairments. Preliminary studies show that TCC, a slow moving meditation, contributes to improvements in subjective sleep quality, sleep amounts and sleep efficiency. We have further found that sleep, fatigue, and proinflammatory cytokine activity are reciprocally related and that TCC decreases proinflammatory cytokine levels. Thus, we further hypothesize that cytokine network is one physiological mechanism through which TCC carries its effects on sleep outcomes. In this randomized, controlled trial, 100 breast cancer survivors will be randomly assigned to TCC or sleep hygiene/education control (EC) over 16 weeks and followed for one year. The aims of this project are to: 1) evaluate the effects of TCC vs. EC on objective and subjective measures of sleep continuity, fatigue, and health functioning in breast cancer survivors with chronic insomnia; 2) determine the effects of TCC vs. EC on measures of proinflammatory cytokine activity; 3) evaluate whether circulating levels of proinflammatory cytokines temporally correlate with measures of sleep continuity in breast cancer survivors with insomnia over the course of the treatment trial. This project will constitute the first, randomized controlled clinical trial of the effects of TCC on sleep outcomes in breast cancer survivors, and will advance psychobiological models of insomnia treatment mechanisms.

EMOTION REGULATION AND DEPRESSION IN BREAST CANCER SURVIVORSHIP
PI: Annette L. Stanton
NCI
Both in individuals living with cancer and in the general population, the experience of clinical depression exacts a profound psychological, physical, and economic toll. Little research has examined the unfolding risk for depressive symptoms and episodes after a breast cancer diagnosis with careful assessments repeated over time. Moreover, theory and research in depression and in emotion science have not been integrated and tested in sophisticated biopsychosocial models to advance understanding of risk and protective factors/processes for depression in cancer patients. Accordingly, this study has three specific aims. Aim 1 is to investigate how personal vulnerabilities, cancer-related (e.g., treatments/side effects) and noncancer-related stressors, and emotion regulation processes shape trajectories of depression in women following diagnosis of breast cancer. Personal vulnerabilities include general depressive diatheses (history of depression, neuroticism, harsh early environment) and emotion dysregulation diatheses (low emotional awareness and acceptance, high emotional suppression, no intimate confiding relationship). Aim 2 is to examine a diathesis- stress model, in which interactions of personal vulnerabilities, genetic factors (a functional polymorphism of the serotonin transporter gene), and stressors shape depressive response. Aim 3 is to examine a proximal model of how emotion regulation processes (approach and avoidance) mediate the effects of personal vulnerabilities on depressive symptoms and episodes. We will accomplish these aims in longitudinal research beginning within three months of diagnosis (Time 1) of 450 women (study completers) with new diagnoses of initial or recurrent invasive breast cancer and subsequent assessments every six weeks through six months (Time 2-5) and at 9 months (Time 6) and 12 months (Time 7). DNA extraction, validated questionnaires and interviews, and measures of expressive behavior will be administered. Primary dependent variables are depressive symptoms and depressive disorder. Effects of age, ethnicity, and mental health treatment receipt will be explored. Findings will influence public health by informing the next generation of targeted preventive and therapeutic interventions for depression in cancer patients, thereby reducing the disorder's health and economic burden. PUBLIC HEALTH RELEVANCE: Cancer patients are more likely than the general population to evidence depressive symptoms and clinical depression, but little is known about the factors that put individuals at risk for clinical depression when they have cancer. This project will provide information about who is at risk and factors contributing to high risk for depression, when they can be identified, and ingredients of interventions that are likely to be effective in reducing depression in women diagnosed with breast cancer. This research will help to target limited mental health resources to make the largest impact in preventing and treating depression in the face of cancer.

PREPARATORY INTERVENTIONS FOR LIFE AFTER BREAST CANCER
PI: Annette L. Stanton, PhD; UCLA PI
NCI
In this competitive renewal of the Cancer Information Service Consortium (CISRC) program project grant, two health communication interventions will be tested for efficacy across three groups of cancer patients who call the Cancer Information Service (1-800-4-CANCER): newly diagnosed prostate (Project 1) and breast (Project 2) cancer patients, and breast cancer patients at re-entry (Project 3). These two interventions include: 1) an innovative and highly interactive multimedia program, and 2) an equally innovative telephone callback intervention conducted by CIS Information Specialists. Both interventions share the common theme of helping these three target populations prepare for their on-going cancer experience (e.g. cancer-treatment decision-making and preparation for treatment, Projects 1 and 2; life after breast cancer, Project 3). Among enrolled participants who report access to a computer at baseline, all projects will share the same randomized three-group stepped design, where: Group 1 = usual service (+)standard print material; Group 2 = Group 1 (+) multimedia program; and Group 3 = Group 2 (+) a CIS telephone callback intervention interview at 7 days follow-up. Among enrolled participants who do not report access to a computer at baseline, all projects will share the same two-group design that will be conducted as a feasibility study pursuant to a future randomized trial, where Group 1A = same as Group 1above; Group 2A = Group 1A (+) a CIS callback intervention interview. Hypothesis-driven mediational and outcome analyses will be based on telephone interviews at 2-, 6-, and 12-months follow-up. Innovative cross-project exploratory analyses are also proposed for a core set of shared outcome resources, which will be the first of their kind across an extended segment of the cancer survivorship continuum. This is a resubmission of an earlier application that has benefited greatly from several revisions prompted by the concerns of the previous review committee. Supporting each project will be the following core resources: Administrative Core, Intervention Development and Measurement Core (IDMC), Survey Methods Core (SMC), and the Biostatistical Core (BC). By collaborating with all regional call centers of the CIS, the CISRC will mobilize the premiere cancer information program in the nation, with an unprecedented opportunity to conduct these three trials simultaneously with ample statistical power, and with significant potential for dissemination.

HEALTH RELATED QUALITY OF LIFE IN YOUNG MEN WITH TESTICULAR CANCER
PI: Annette L. Stanton, PhD; UCLA PI
Lance Armstrong Foundation
Late adolescence and early adulthood (ages 18-29) is a critical developmental period in which young men are negotiating greater independence and autonomy in social, professional, and physical domains. A diagnosis of cancer, especially cancer that threatens sexuality and reproductive health, can be particularly distressing in this formative period. The limited research with young cancer survivors has relied on questionnaire instruments developed for the general cancer population and has largely ignored the unique issues of young men, such as masculine identity, reproductive health concerns, and body image, which likely affect health-related quality of life. The objective of this project is to address the identified need for scientific measures of health-related quality of life in young men (ages 18-29) with cancer by developing a questionnaire measure of health-related quality of life in young testicular cancer survivors. Phase I of the project will include in-depth interviews with cancer survivors to gain a rich understanding of central domains of quality of life that are developmentally appropriate and span a variety of areas (i.e., physical, cognitive, emotional, relational, behavioral and spiritual). From this phase of the project, a pool of possible items to be included in the questionnaire will emerge. The second phase will involve testing the items in a larger sample of young men with testicular cancer and using state of the art statistical techniques to construct an assessment tool that demonstrates utility for clinicians and researchers. In addition, relationships between psychosocial factors, such as how an individual copes with the cancer experience and quality of life will be examined. This research will be among the first to characterize the unique experience of young men with cancer and will result in a sophisticated assessment device with broad utility for clinicians and researchers.

COMBINATORIAL GENOMICS IN CANCER
PI: Steven W. Cole, PhD
NCI
Targeted therapy of cancer requires a clear understanding of the genetic alterations that drive malignant cell growth. Identification of causal genetic alterations is complicated by three characteristics of cancer etiology: 1.) multiple interacting alterations are often required to cause cancer, 2.) several distinct alterations may be sufficient to generate a single cancer phenotype, and 3.) oncogenic alterations appear in a dense background of normal genetic activity and spurious consequences of malignant cell growth. We propose to apply a variant of the machine learning algorithm PRIM to the task of identifying disjunctive sets of conjunctive genetic alterations that cause specific cancers or provide prognostic information about clinical course and treatment efficacy. These analyses synthesize information from low-level bioinformatics resources we have already developed to map chromosomal alterations and monitor global patterns of transcription factor activity. Based on those foundations, the present studies develop high-level analytic tools to map combinatorial interactions among low-level genomic events. Specifically, these studies seek to: Aim 1: Develop graphical user interface (GUI) software to support combinatorial genomic analyses by biologists with limited computational background. Aim 2: Optimize combinatorial prediction of disease progression and treatment response. Aim 3: Develop PRIM-based statistical models to identify functional complementation groups of genetic alterations and transcriptional control signals. The bioinformatic tools produced in these studies will create a generalized analytic infrastructure for mapping complex etiologies in cancer and deploying patient-specific targeted therapies.

COGNITIVE FUNCTIONING AFTER BREAST CANCER TREATMENT
PI: Patricia Ganz,MD; Julienne Bower, PhD, Co-I
NCI
Cognitive complaints have been anecdotally reported among women receiving adjuvant chemotherapy for breast cancer, and recently this has been subjected to more rigorous study. Cerebral functioning can be assessed by self-report, standardized neuropsychological testing, and through examination of brain metabolism (all of which have been studied in our laboratory). The literature suggests a relationship between chemotherapy exposure and poorer performance on neurocognitive testing; however, patients with cognitive complaints do not necessarily test poorly and their complaints are often associated with symptoms of depression and anxiety. Preliminary work in our laboratory suggests that hormonal changes associated with menopause and adjuvant endocrine therapy for breast cancer also influence the effects of chemotherapy on cognitive functioning. Little is known about the potential mechanisms by which adjuvant endocrine therapy influences cerebral functioning after breast cancer treatment, and in this study we will address this question by studying women who have recently completed their primary breast cancer treatments (surgery, radiation, chemotherapy) and who are about to initiate adjuvant endocrine therapy (with tamoxifen or aromatase inhibitors). We will examine the potential mechanisms by which endocrine therapy affects cerebral functioning, by consideration of a comprehensive framework that includes the role of constitutional symptoms (fatigue, depression, anxiety), and immune alterations, in addition to specific cancer treatments (chemotherapy, hormonal treatments), and endogenous endocrine exposures (estrogen, cortisol). In this longitudinal, observational cohort study, we propose the following specific aims: 1)To evaluate the effects of adjuvant endocrine therapy on cognitive functioning through standardized questionnaires and neuropsychological assessments in 260 breast cancer patients at the end of primary treatment (baseline) when endocrine treatment is initiated, and one year later (follow-up). 2)To examine the association between cognitive functioning and measures of cerebral metabolism by obtaining positron emission tomography (PET) brain imaging, at rest and with a memory challenge, in close temporal proximity to the baseline assessment of cognitive functioning in a subset of 60 women, with a follow-up assessment one year later. 3)To explore the biopsychosocial mechanisms by which adjuvant endocrine therapy influences cerebral functioning by examining changes in cognitive functioning and brain metabolism, and their relationship to immune and endocrine function, mood and symptoms between the baseline and follow-up assessment one year later. Lay summary: Breast cancer is the most common cancer in women. After treatments for breast cancer, some women complain of difficulty in concentrating and thinking. This study will examine the effects of breast cancer treatments on cognitive, psychological, immune and endocrine function to try to understand the biological mechanisms of these complaints so that they may be better prevented or treated in the future.

BIOBEHAVIORAL INFLUENCES AND THE OVARIAN TUMOR MICROENVIRONMENT
PI: Susan Lutgendorf, PhD, Iowa PI / George Slavich, PhD, UCLA PI
NCI
Ovarian cancer is the second most common gynecologic cancer. Because of low rates of survival for the majority of ovarian cancer patients, identification of factors contributing to tumor progression is of paramount importance. Epidemiologic studies have suggested an association between biobehavioral factors such as life stress, depression, and social support and cancer progression. This study examines a novel pathway that may underlie these links in ovarian cancer, specifically, the relationship of biobehavioral factors with resident macrophages within the tumor microenvironment. It is now acknowledged that the tumor microenvironment is critical in supporting or inhibiting tumor progression. We have previously reported associations of depression and low social support with a poorer cellular immune response in ovarian cancer patients in the tumor microenvironment. We have also demonstrated direct links between biobehavioral factors and cytokines supporting angiogenesis, the formation of new blood vessels that enhance tumor growth and progression. Macrophages are major components of the tumor microenvironment where they are predominantly converted from an anti-tumor phenotype to a pro-tumor phenotype and play a key role in supporting inflammation and tumor progression. However, little is known regarding whether biobehavioral factors influence tumor associated macrophages (TAM) and interactions between TAM and tumor cells in a way that favors tumor growth. Based on compelling preliminary data, we propose that biobehavioral influences on both TAM and tumor cells in the tumor microenvironment have significant effects on production of factors supporting tumor growth and progression. We focus on TAM because of their key role in the tumor microenvironment, and because of indications of macrophage sensitivity to stress factors in the cardiovascular literature and in our preliminary data. Thus, the overarching goal of this proposal is to examine pathways by which biobehavioral factors contribute to a permissive local environment for interactions between resident cells (TAM) and tumor cells that favor tumor growth in ovarian cancer. The proposed project will prospectively examine the relationship of biobehavioral factors (life stress, depression, and social support) and TAM products (inflammatory cytokines and tumor growth factors) in the tumor microenvironment in 206 ovarian cancer patients. Association of biobehavioral factors with upregulation of gene transcripts related to inflammation and proliferation in tumor cells will also be examined. Based on preliminary data we will examine the role of adrenergic signaling as a mediator in these relationships. To determine the clinical significance of these biological alterations, the investigation will assess progression-free and overall survival during the 24 months following diagnosis. Findings will have implications for innovative behavioral and pharmacological intervention strategies for ovarian cancer patients. PUBLIC HEALTH RELEVANCE: There has been very little research examining systemic effects on the tumor microenvironment. This research examines a novel pathway by which biobehavioral factors may contribute to a permissive milieu for tumor growth and disease progression in the tumor microenvironment among ovarian cancer patients. A clearer understanding of biobehavioral risk factors and pathways by which they operate is critical for identifying targets for psychosocial and pharmacological intervention for ovarian cancer patients who may be at risk. 

PRO-INFLAMMATORY CYTOKINES & NEUROBEHAVIORAL SYMPTOMS IN BREAST CANCER PATIENTS
PI: Sunita Patel, PhD / Elizabeth Breen, PhD, Co-I
NCI
Pro-inflammatory cytokines and neurobehavioral symptoms in women with breast cancer. Abstract Survivors of breast cancer report debilitating behavioral symptoms, such as fatigue and neurocognitive dysfunction, which are evident in some individuals even at pre-treatment baseline. There is sufficient evidence from varied lines of research to propose that cancer-related neurobehavioral symptoms may be driven, at least in part, by activation of the pro-inflammatory cytokine network. Concentrations of specific pro-inflammatory cytokines (IL-6, TNF) and soluble receptors in serum obtained prior to treatment in breast cancer patients are significantly higher than levels found in healthy individuals and have prognostic value; however, these pre- treatment elevations have not yet been evaluated with respect to their association with either acute or chronic behavioral symptoms. Among survivors of breast cancer, elevated levels of circulating sIL-6R and IL-1ra have emerged as prominent biomarkers of persistent fatigue in cross-sectional studies of women several years post chemotherapy. No similar work has identified biomarkers of neurocognitive dysfunction in this patient population, and it is not known if the cytokine links with fatigue, or other behavioral symptoms, exist closer to the diagnosis period or evolve over time as "late effects". In this study, we will address this knowledge gap as we will evaluate this association prior to cancer treatment, and again following treatment completion. We will compare these associations in a minimum of 137 breast cancer patients relative to two comparison groups at pre-treatment, and longitudinally evaluate only the breast cancer group after treatment. Findings are expected to increase our knowledge about the possible biomarkers associated with neurobehavioral symptoms in breast cancer patients, for the purpose of better identifying and treating those at risk for such effects. PUBLIC HEALTH RELEVANCE: Findings are expected to increase knowledge about the possible biomarkers associated with neurobehavioral symptoms in breast cancer patients, for the purpose of better identifying and treating those at risk for such effects. 

Relevant Publications:

Inflammation and behavioral symptoms after breast cancer treatment: do fatigue, depression, and sleep disturbance share a common underlying mechanism? Bower JE, Ganz PA, Irwin MR, Kwan L, Breen EC, Cole SW. J Clin Oncol. 2011 Sep 10;29(26):3517-22. Epub 2011 Aug 8. PMID:21825266

Antagonistic pleiotropy at the human IL6 promoter confers genetic resilience to the pro-inflammatory effects of adverse social conditions in adolescence. Cole SW, Arevalo JM, Manu K, Telzer EH, Kiang L, Bower JE, Irwin MR, Fuligni AJ. Dev Psychol. 2011 Jul;47(4):1173-80. PMID: 21639625

Physical and psychosocial recovery in the year after primary treatment of breast cancer. Ganz PA, Kwan L, Stanton AL, Bower JE, Belin TR. J Clin Oncol. 2011 Mar 20;29(9):1101-9. Epub 2011 Feb 7. PMID:21300931 

Yoga for persistent fatigue in breast cancer survivors: results of a pilot study. Bower JE, Garet D, Sternlieb B. Evid Based Complement Alternat Med. 2011;2011:623168. Epub 2011 Jan 13. PMID:21274288 Free PMC Article

Fatigue and gene expression in human leukocytes: increased NF-κB and decreased glucocorticoid signaling in breast cancer survivors with persistent fatigue. Bower JE, Ganz PA, Irwin MR, Arevalo JM, Cole SW. Brain Behav Immun. 2011 Jan;25(1):147-50. Epub 2010 Sep 18. PMID:20854893 

A randomized controlled trial of emotionally expressive writing for women with metastatic breast cancer. Low CA, Stanton AL, Bower JE, Gyllenhammer L. Health Psychol. 2010 Jul;29(4):460-6. PMID: 20658835 Free PMC Article 

Disrupted sleep in breast and prostate cancer patients undergoing radiation therapy: the role of coping processes. Thomas KS, Bower J, Hoyt MA, Sepah S. Psychooncology. 2010 Jul;19(7):767-76. PMID: 19885853 Free PMC Article 

Inflammatory biomarkers and fatigue during radiation therapy for breast and prostate cancer. Bower JE, Ganz PA, Tao ML, Hu W, Belin TR, Sepah S, Cole S, Aziz N. Clin Cancer Res. 2009 Sep 1;15(17):5534-40. Epub 2009 Aug 25. PMID: 19706826 Free PMC Article

The sympathetic nervous system induces a metastatic switch in primary breast cancer. Sloan EK, Priceman SJ, Cox BF, Yu S, Pimentel MA, Tangkanangnukul V, Arevalo JM, Morizono K, Karanikolas BD, Wu L, Sood AK, Cole SW. Cancer Res. 2010 Sep 15;70(18):7042-52. Epub 2010 Sep 7. PMID: 20823155 Free PMC Article 

Dopamine blocks stress-mediated ovarian carcinoma growth. Moreno-Smith M, Lu C, Shahzad MM, Pena GN, Allen JK, Stone RL, Mangala LS, Han HD, Kim HS, Farley D, Berestein GL, Cole SW, Lutgendorf SK, Sood AK. Clin Cancer Res. 2011 Jun 1;17(11):3649-59. Epub 2011 Apr 29. PMID: 21531818 

Inflammatory biomarkers and fatigue during radiation therapy for breast and prostate cancer. Bower JE, Ganz PA, Tao ML, Hu W, Belin TR, Sepah S, Cole S, Aziz N. Clin Cancer Res. 2009 Sep 1;15(17):5534-40. Epub 2009 Aug 25. PMID: 19706826 Free PMC Article

Surgical stress promotes tumor growth in ovarian carcinoma. Lee JW, Shahzad MM, Lin YG, Armaiz-Pena G, Mangala LS, Han HD, Kim HS, Nam EJ, Jennings NB, Halder J, Nick AM, Stone RL, Lu C, Lutgendorf SK, Cole SW, Lokshin AE, Sood AK. Clin Cancer Res. 2009 Apr 15;15(8):2695-702. Epub 2009 Apr 7. PMID: 19351748 Free PMC Article

Physical and psychosocial recovery in the year after primary treatment of breast cancer. Ganz PA, Kwan L, Stanton AL, Bower JE, Belin TR. J Clin Oncol. 2011 Mar 20;29(9):1101-9. Epub 2011 Feb 7. PMID: 21300931

A randomized controlled trial of emotionally expressive writing for women with metastatic breast cancer. Low CA, Stanton AL, Bower JE, Gyllenhammer L. Health Psychol. 2010 Jul;29(4):460-6. PMID: 20658835 Free PMC Article 

Reciprocal regulation of the neural and innate immune systems. Irwin MR, Cole SW. Nat Rev Immunol. 2011 Aug 5;11(9):625-32. doi: 10.1038/nri3042. PMID: 21818124

Expanding our therapeutic options: Beta blockers for breast cancer? Ganz PA, Cole SW. J Clin Oncol. 2011 Jul 1;29(19):2612-6.  Epub 2011 May 31. No abstract available. PMID: 21632500 

Social isolation is associated with elevated tumor norepinephrine in ovarian carcinoma patients. Lutgendorf SK, DeGeest K, Dahmoush L, Farley D, Penedo F, Bender D, Goodheart M, Buekers TE, Mendez L, Krueger G, Clevenger L, Lubaroff DM, Sood AK, Cole SW. Brain Behav Immun. 2011 Feb;25(2):250-5. Epub 2010 Oct 16. PMID: 20955777 

A longitudinal examination of couples' coping strategies as predictors of adjustment to breast cancer. Kraemer LM, Stanton AL, Meyerowitz BE, Rowland JH, Ganz PA. J Fam Psychol. 2011 Sep 19. [Epub ahead of print]  PMID: 21928887 

Quality of life among Latina breast cancer patients: a systematic review of the literature. Yanez B, Thompson EH, Stanton AL. J Cancer Surviv. 2011 Jun;5(2):191-207. doi: 10.1007/s11764-011-0171-0. Epub 2011 Jan 28. Review. PMID: 21274649 Free PMC Article 

Facets of spirituality as predictors of adjustment to cancer: relative contributions of having faith and finding meaning. Yanez B, Edmondson D, Stanton AL, Park CL, Kwan L, Ganz PA, Blank TO. J Consult Clin Psychol. 2009 Aug;77(4):730-41. PMID: 19634965 Free PMC Article