Cancer: Biology and Behavior
SLEEP DISTURBANCE, INFLAMMATION, AND CELLULAR AGING IN BREAST CANCER SURVIVORS
PI: Michael R. Irwin, MD
Advances in cancer treatment have resulted in a growing number of cancer survivors in the United States. Despite the success of cancer treatments, survivors face long-term changes in health, with twice the likelihood of disability as those without a cancer history, greater risk for second primary cancers, more age-related comorbid disorders, and 28% reduction in life expectancy. This study hypothesizes that the increased risk of morbidity and mortality in cancer survivors is due to accelerated biological aging. Furthermore given that the risk for the late effects of cancer diagnosis and treatment show considerable variability, individual differences may either confer protection or promote vulnerability. Given our preliminary data that sleep disturbance leads to greater increases in inflammation and telomere erosion over a one year period, we further hypothesize that sleep disturbance and depression history serve as susceptibility factors to accelerate biological aging. To examine these questions, this study leverages an existing project (CA160245) of a Kaiser Permanente Southern California (KPSC) SEER-affiliated tumor registry-based sample of 300 (>55 years) breast cancer survivors, includes biological aging outcomes of cellular and transcriptional markers of inflammation and telomere erosion, and recruits a KPSC comparison cohort of 300 older women without a cancer history. Both KPSC groups will be examined at baseline and prospectively followed at 8, 16, 24, and 32 months to address three specific aims: 1) to examine differences at baseline and in prospective rate of change of cellular and transcriptional markers of inflammation and telomere length as a function of breast cancer survivorship; 2) to examine differences at baseline and in prospective rate of change of cellular and transcriptional markers of inflammation and telomere length as a function of sleep disturbance and breast cancer survivorship; 3) to examine differences at baseline and in prospective rate of change of cellular and transcriptional markers of inflammation and telomere length as a function of depression history and breast cancer survivorship This study will determine whether biological aging is driven by breast cancer status, by independent effects of sleep disturbance or depression history, or by the interaction of these behavioral factors with breast cancer status. Such information is necessary to define the risk population (i.e., breast cancer survivors, depression history) and/or risk factors (i.e., sleep disturbance) in the design, implementation, and delivery of treatments, which selectively target biological aging with greatest efficacy with the potential to reduce risk of age-related morbidities.
SLEEP, INFLAMMATION, AND DEPRESSION OCCURRENCE IN BREAST CANCER SURVIVORS
PI: Michael R. Irwin, MD
In 2006, there were over 11.4 million cancer survivors in the US. However for many individuals with cancer, improved survival is complicated by long-term behavioral effects including depression. Indeed, the prevalence of depression in breast cancer survivors is nearly three to five times greater than the general population. Yet, the unique clinical, behavioral, and biological factors that prospectively contribute to increased depression risk in breast cancer survivors is not known. In older adults, we have found that sleep disturbance independently contributes to depression occurrence, and this prospective risk is specific to those with a history of depression. Breast cancer status may add to that risk, as we have found that breast cancer survivors with insomnia have a prevalence of depression history that is nearly twice that in older women with insomnia; yet, other factors in the prior risk model do not generalize to breast cancer survivors. There are no published prospective data that have examined the independent contribution of sleep disturbance on depression occurrence in breast cancer survivors. Increasing evidence also implicates sleep disturbance in the activation of inflammatory signaling, which serves as a biological mechanism that contributes to depression. Hence, in this SEER-affiliated tumor registry-based study, we will evaluate 300 early stage-, older adult (>55 years) breast cancer survivors and 300 age-matched comparison women, stratified by a history of major depression. All participants will be community members of Kaiser Permanente Southern California (KPSC), a large nonprofit health plan that serves over 3 million members. In a prospective cohort study, older adult breast cancer survivors vs. comparisons, stratified by depression history will be evaluated at baseline (i.e., 1 year post- primary treatmen for breast cancer survivors) and at 6, 12, 18, and 24 months with the following aims: 1) to determine the prospective association between sleep disturbance and depression occurrence; 2) to evaluate the prospective association between sleep disturbance and cellular and genomic markers of inflammation; and 3) to examine the prospective relationships between sleep disturbance, cellular and genomic markers of inflammation, and depression occurrence. Understanding the cancer-specific clinical, behavioral, and biological factors that prospectively contribute to depression risk in breast cancer survivors vs. comparison older women will substantially alter clinical management by leading to the development of a targeted intervention for depression prevention, specific for breast cancer survivors.
BIOBEHAVIORAL PREDICTORS OF FATIGUE IN NEWLY-DIAGNOSED BREAST CANCER PATIENTS
PI: Julienne Bower, PhD
Fatigue is one of the most common and distressing side effects of breast cancer treatment and may persist for months or years after successful treatment completion. Approximately one-third of breast cancer survivors report moderate to severe symptoms of fatigue, which has a negative impact on all aspects of quality of life. Although the prevalence and impact of cancer-related fatigue has now been well established, very little is known about predictors and mechanisms for the development and persistence of fatigue post-treatment. Accordingly, the primary goal of this prospective, longitudinal study is to identify biological and psychological risk factors for post-treatment fatigue, with intensive evaluation of mechanisms, in women newly diagnosed with early stage breast cancer. In particular, this application focuses on vulnerability factors that increase risk for inflammatory processes given evidence suggesting an inflammatory basis for cancer-related fatigue. Specific aims are to: 1) determine whether inflammatory risk genes, hypothalamic-pituitary-adrenal axis dysregulation, and body mass index at treatment onset predict post-treatment fatigue in breast cancer patients assessed longitudinally for 18 months after treatment completion; 2) evaluate whether history of depression and early life stress at treatment onset predict post-treatment fatigue in breast cancer patients assessed longitudinally for 18 months after treatment onset; 3) investigate the contribution of measured proinflammatory cytokine activity to the association between biological and psychological risk factors and post-treatment fatigue. We will recruit 360 women with newly-diagnosed, early-stage breast cancer before initiation of treatment with radiation, chemotherapy, trastuzumab or endocrine therapy. At baseline, participants will complete self-report questionnaires, diagnostic interview for depression, blood draw for cytokine gene polymorphisms and markers of inflammation, and saliva samples for diurnal cortisol slope. Follow-up assessments conducted at treatment completion and at 6, 12, and 18 months post-treatment will determine the trajectory of post-treatment fatigue and associated changes in inflammatory processes. This research is a critical next step in the early identification of patients who are at risk for persistent fatigue as a long term side effect of cancer treatment and for the development and implementation of targeted interventions to prevent and treat this disabling symptom.
A PHASE III RANDOMIZED TRIAL TARGETING BEHAVIORAL SYMPTOMS IN YOUNGER BREAST CANCER SURVIVORS
PI: Julienne Bower, PhD
Breast cancer is the most common cancer in women younger than 50 years, accounting for up to 25% of new breast cancer cases. Improved survival after a breast cancer diagnosis has focused attention on the critical need to address the impact of the disease and its treatments on long-term outcomes in younger women. This has become an increasingly important cancer control priority, including federal legislation focusing on the unique needs of women <45 years old. Studies have consistently shown that younger women have greater psychological and physical morbidity after breast cancer than older women and age-matched women with no cancer history, including elevated levels of depression and other behavioral symptoms (i.e., fatigue, sleep disturbance, vasomotor symptoms) that cause significant impairment in quality of life. Increased behavioral symptoms have been documented up to 10 years after diagnosis in this population, suggesting that effects may not remediate without intervention. Younger breast cancer survivors are at risk for adverse long-term effects, making them a particularly vulnerable population, for whom only a few specific interventions have been tested. A major barrier to adoption of many behavioral interventions is the lack of a translational research implementation strategy, and thus these interventions fail to become a standard of care that is clinically provided and reimbursed. To meet this challenge, we will conduct a phase III, three-group, randomized clinical trial at three geographically separated NCI-designated comprehensive cancer centers, randomly assigning 360 younger post-treatment breast cancer survivors, to one of two promising interventions (survivorship education or mindful awareness practices), comparing each to a usual care/waitlist control group. We hypothesize that both of the intervention programs will be effective in reducing behavioral symptoms (depression - primary outcome; fatigue, sleep disturbance, vasomotor symptoms-secondary outcomes) over a 6 month post- intervention period, in comparison to the usual care/waitlist control group. Additionally, we will examine the efficacy of the interventions relative to the control group on circulating and genomic markers of inflammation, hypothesizing that the mindfulness intervention will significantly reduce markers of inflammation. Finally, we will explore potential moderators of intervention efficacy in the intervention groups.
ADRENERGIC REGULATION OF TUMOR INFLAMMATION AND METASTATIC DISSEMINATION
PI: Erica Sloan, PhD
The metastatic microenvironment is receiving increasing attention as a target for new breast cancer therapies. The sympathetic nervous system (SNS) is a component of this microenvironment, and our recent studies indicated that SNS activity may support metastasis through beta-adrenergic pathways that recruit macrophages and induce a switch to pro-metastatic gene expression. Development of novel adjunctive therapeutic strategies that target neural regulation of metastasis requires characterization of the relationships between the SNS, the immune system and tumor cells. To address this need, the proposed studies utilize multimodal in vivo imaging techniques to address the following specific aims: 1. characterize SNS regulation of tumor cells in breast cancer metastasis, 2. characterize SNS regulation of tumor-associated macrophages in breast cancer metastasis, 3. characterize SNS regulation of the tumor microenvironment in breast cancer metastasis. These studies will define interactions between SNS nerve fibers, tumor cells and macrophages in the context of the tumor microenvironment and elucidate their collective effects on metastasis. Given recent clinical studies that suggest beta-blockade reduces breast cancer recurrence, the proposed studies are urgently needed to establish a mechanistic foundation for rapid translation of existing compounds (beta-blockers) and development of novel biomarkers of early cancer progression and new anti-metastatic strategies that target SNS regulation of the tumor microenvironment.
TRANSLATIONAL RESEARCH OF BIOBEHAVIORAL MECHANISMS IN CANCER CONTROL
PI: Donald Lamkin, PhD
The K07 Career Development Award will enable Dr. Donald Lamkin to achieve his career goal of becoming an independent investigator and future leader in translational biobehavioral cancer research. This proposal builds upon Dr. Lamkin's previous training in basic laboratory science, utilizing animal models of cancer and behavior to address biobehavioral questions in the area of cancer control. Training: The award will facilitate training specifically in (1) learning the cancer treatment regimens and research protocols that characterize clinical investigation at a comprehensive cancer center, (2) mastering functional genomics strategies and related technologies to study global gene expression in distinct cell populations within tumors, and (3) learning fluorescence microscopy and laser capture microdissection to visualize and retrieve cells in tumor microenvironments. The proposed training will allow Dr. Lamkin to acquire new skills that are essential for a translational scientit who wants to work at the boundaries of basic laboratory discovery and clinical investigation. Mentors & Collaborators: Dr. Patricia Ganz, a medical oncologist and Director of Cancer Prevention and Control Research at the UCLA Jonsson Comprehensive Cancer Center; Dr. Julie Bower, a clinical psychologist with expertise in immune, endocrine, and psychological factors in breast cancer patients and survivors; Dr. Steve Cole, a translational scientist and Director of the Social Genomics Core Laboratory at UCLA; Dr. Shimon Weiss, Director of the Advanced Light Microscopy-Spectroscopy Core Laboratory at UCLA; and Dr. Erica Sloan, a cancer biologist with expertise in preclinical models of breast cancer and neural- mediated metastasis. Research Plan: The Research Plan for this project builds upon two emerging findings in breast cancer research: First, preclinical evidence indicates that chronic stress induces a high buildup of "alternatively activated" (M2) vs. "classically activated" (M1) macrophages in tumors. This is significant because macrophages with M2 properties are increasingly becoming associated with poor outcomes in breast cancer. Thus, Aim 1 will examine the relationship between stress-related psychosocial factors and M2-related gene expression by macrophages in tumors of breast cancer patients. Second, preclinical research suggests that M2 macrophage buildup does not derive from blood stream monocytes that infiltrate the tumor but instead results from enhanced proliferation of macrophages that are already residing in the tumor microenvironment. Establishing such a finding in humans would challenge current ideas about how to target macrophages in cancer and open up new therapeutic opportunities. Thus, Aim 2 will investigate the extent to which M2 macrophages in primary tumor of breast cancer patients are locally established proliferating tissue macrophages. Aim 3 will experimentally determine whether chronic stress increases M2 macrophage proliferation in mammary tumors of mice. This plan will facilitate Dr. Lamkin's career training objectives and position him for a future R01 submission.
BEHAVIORAL INFLUENCES ON OVARIAN CANCER PROGRESSION: ROLE OF CHEMORESISTANCE
PI: Susan Lutgendorf, PhD, Iowa PI / Steve Cole, PhD, UCLA PI
Epithelial ovarian cancer is the second most common gynecologic cancer. Because of poor survival for the majority of ovarian cancer patients, identification of factors contributing to disease progression is of utmost importance. Although a significant percentage of ovarian cancer patients respond well to initial chemotherapy, the success of treatment is limited by the development of chemo resistance, and the majority of patients relapse and die from recurrent disease. Our previous work has shown a variety of mechanisms by which biobehavioral factors (referring collectively to behavioral, social, and/or psychological factors and concomitant biologic processes) can directly affect key biological signaling mechanisms to enhance tumor growth and impair the immune response in ovarian cancer. Although the neuroendocrine stress hormones norepinephrine (NE) and cortisol have been shown to increase chemo resistance pre-clinically, little is known about the contribution of psychological and social processes to chemo resistance in the clinical setting of ovarian cancer. Based on compelling preliminary pre-clinical data in ovarian cancer, we propose that psychological and social processes and the neuroendocrine stress response will contribute to impairment of the chemotherapeutic response in ovarian cancer patients. Thus, this grant will focus on mapping psychological and social and neuroendocrine influences on disease progression in 178 women with high grade serous epithelial ovarian cancer, with particular attention to chemo resistance as a mechanism. This study is highly innovative as 1) contributions of biobehavioral processes to chemo resistance in human epithelial cell cancers in a clinical setting have not been examined, and 2) this is the first translational study using exosomes (tumor derived vesicles in peripheral circulation) to examine relationships between biobehavioral factors and tumor dynamics. Use of the exosome biomarker approach will provide a longitudinal window on tumor characteristics not otherwise available in the absence of repeated surgery. If initial response to chemotherapy could be enhanced or maintained for a longer duration, it could have substantial survival benefits. Thus findings that biobehavioral stress-related processes alter the response to chemotherapy would have significant implications for clinical management of ovarian patients, specifically the potential for adjunct use of behavioral or pharmacological interventions to delay the development of chemo resistance. Because chemotherapeutic response is closely linked to ovarian cancer survival, understanding biobehavioral impediments to maximum chemotherapeutic response is of great public health significance.
BIOBEHAVIORAL INFLUENCES AND THE OVARIAN TUMOR MICROENVIRONMENT
PI: Susan Lutgendorf, PhD, Iowa PI / George Slavich, PhD, UCLA PI
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.
OVARIAN CANCER: MECHANISMS OF NEUROENDOCRINE REGULATION
PI: Anil Sood, MD / Steve Cole, PhD, Co-I
Psychosocial stress can elicit complex effects on the immune and other systems in cancer patients through mechanisms including the sympathetic nervous system (SNS), the hypothalamic-pituitary-adrenal (HPA) axis, and by other hormones and peptides. These catecholamine changes in the tumor microenvironment trigger a cascade of signaling events that create a highly permissive environment for tumor growth and metastasis. We have demonstrated that elevation of SNS mediators (e.g., catecholamines) in the tumor microenvironment can increase angiogenesis and block anoikis. However, the mechanisms by which catecholamines are delivered to the tumor microenvironment are not well understood. On the basis of our preliminary data, we hypothesize that there is increased tumor innervation in response to chronic stress, which promotes epithelial-to-mesenchymal transition (EMT) and metastasis. In this renewal application, we will examine the mechanisms by which chronic stress contributes to increased innervation and, and examine the resultant biological consequences using well-characterized orthotropic mouse models of ovarian cancer. We will also examine relationships between psychosocial stress factors and nerve density in tumors from patients. Findings from this proposal could lead to identification of novel mechanisms underlying accelerated ovarian cancer growth and therefore may lead to new preventive and therapeutic strategies.
PRO-INFLAMMATORY CYTOKINES & NEUROBEHAVIORAL SYMPTOMS IN BREAST CANCER PATIENTS
PI: Sunita Patel, PhD / Elizabeth Breen, PhD, Co-I
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.