Research Projects: Cancer Prevention and Control Program

Rural Cancer Survivors/Health Disparities

Prevalence and Health Status of Cancer Survivors in the Rural (5R03CA156641-02; PI: Kathryn Weaver, PhD, Co-Is: Ann Geiger,PhD, L. Doug Case, PhD) is a study using data from the National Health Interview Survey to generate the first population-based estimate of the number of US cancer survivors who reside in rural areas and to describe their socio-demographic and cancer characteristics, health behaviors, health care utilization, and health status (self-reported health, psychological distress, non-cancer comorbidities, and unemployment due to health).

Cancer-related Follow-up Care Experiences of Rural Cancer Survivors (5R03CA157211-02; PI: Kathryn Weaver, PhD; Co-Is: Nancy Avis, PhD, Janet Tooze, PhD) This study surveyed breast, prostate, and colorectal cancer survivors (n=174) who were two to five years post-diagnosis and resided in rural areas. Key topics of interest included characteristics of post-treatment follow-up care received, barriers to follow-up care, health-related information needs, and adherence to screening and surveillance guidelines.

Survivorship Care Planning and Communication for Rural Breast Cancer Survivors (5R21CA155932-02; PI: Ann Geiger, PhD, Co-Is: Kathryn Weaver, PhD, Julia Lawrence, DO, L. Douglas Case, PhD) The purpose of this study is to gather information about rural-, suburban- and urban-residing breast cancer survivors' (n=207) needs and preferences for their survivorship care, in order to support design and evaluation of a survivorship care planning and communication intervention with particular accommodation for the needs and preferences of rural-residing survivors. As a study co-investigator, I played a key role in the development of the survey and the recruitment protocols. I will continue to collaborate on data interpretation and manuscript development and will lead a manuscript describing follow-up care experiences and preferences.

End of Treatment Transition to Follow-Up Care among Early Stage Lung Cancer Survivors (NCI, PI: Weaver, PhD, Co-Is: Janet Tooze, PhD, James Urbanic, MD, William J. Petty, MD, Jimmy Ruiz, MD) (Pending R01) The proposed mixed-methods study will focus on an understudied, but growing population, early stage lung cancer survivors, and gather novel data on their follow-up care transition experiences and needs. This study will recruit patients diagnosed with localized lung cancer who have completed primary treatment within the past 3-24 months to explore lung cancer survivors' experiences in the two years after initial treatment, focusing on their health needs, communication with treatment team, and psychosocial concerns using both semi-structured interview and survey research strategies.

A Primary Care Multilevel mHealth Colorectal Cancer Screening (mCRC) (R01 CA178941; PI: D. Miller, MD, Co-I:Kathryn Weaver, PhD) This project is evaluating the efficacy of an innovative multilevel mHealth colorectal cancer (CRC) screening intervention (mCRC) designed for primary care practices that incorporates a tablet computer CRC screening decision aid and text messaging support. This randomized clinical trial will evaluate: 1) the ability of the mCRC system to increase receipt of CRC screening within 24 weeks of enrollment, 2) potential mechanisms of change by which the mCRC system facilitates screening, and 3) the additional cost of the mCRC system per patient screened.

Rural-Urban Disparities in Cancer Survivorship: Examining the Multilevel Context (NCI,PI: Geiger, Co-Is: Weaver, Case) In this pilot study, we are adding data on community level factors to our ongoing studies focused on rural cancer survivors. Specifically, we aim to: (1) explore the feasibility of snowball sampling to collect information about cancer organizations and support services available to survivors; (2) assess the availability of public use data about community characteristics and healthcare resources relevant to cancer survivorship outcomes; and (3) conduct preliminary analyses to ascertain which multilevel data sources are likely to be most useful in future survivorship studies.

Tobacco Control

Smokeless Tobacco Use in College Students (5R01CA141643-04; Co-PIs: Mark Wolfson, PhD; John Spangler, MD; Co-Is: Beth Reboussin, PhD, Erin Sutfin, PhD). The goal of this study is to better understand trajectories and correlates of SLT use among college students. To do this we will measure trajectories of SLT use among undergraduate college students over the course of their college careers; identify environmental and individual-level correlates of trajectories of SLT use; and examine patterns of use of different SLT products, including chewing tobacco, dry and moist snuff (including snus and other flavored products), and alternative products (including lozenges, strips, orbs, and sticks).

Dissolvable Tobacco Perceptions and Use among Young Adults in Test Markets (3R01CA141643-04S2, Co-PIs: Mark Wolfson, PhD, John Spangler, MD, Co-Is: Beth Reboussin, PhD, Erin Sutfin, PhD, Kim Wagoner, EdD) A new generation of dissolvable tobacco products has been introduced into test markets in the U.S. This study assesses perceptions and use of these products in three test markets where they are currently available (Denver, CO, Charlotte, NC and various cities in Kansas). This information will better enable the Food and Drug Administration to fulfill its responsibilities regarding regulation of these products under the Family Smoking Prevention and Tobacco Control Act of 2009.

Tobacco Use Trajectories and Surgical Outcomes in Newly Diagnosed Head and Neck Cancer Patients in North and South Carolina (Comprehensive Cancer Center of Wake Forest University / Hollins Cancer Center, Medical University of South Carolina Joint Pilot Grant; Co-PIs: Kathryn Weaver, PhD, Katherine Sterba,PhD, Christopher Sullivan, MD, Terry Day,MD; Co-Is: Janet Tooze) The goal of this observational pilot study was to understand the influence of smoking status on surgical outcomes in head and neck cancer patients (n=109) and to gather preliminary data that can be used to translate study findings into future clinic-based interventions for head and neck cancer patients.

End of Treatment Transition to Follow-Up Care among Early Stage Lung Cancer Survivors (NCI, PI: Weaver, Co-Is: Janet Tooze, James Urbanic, William J. Petty, Jimmy Ruiz) (pending) The proposed mixed-methods study will focus on an understudied, but growing population, early stage lung cancer survivors, and gather novel data on their follow-up care transition experiences and needs. This study will recruit patients diagnosed with localized lung cancer who have completed primary treatment within the past 3-24 months to explore lung cancer survivors' experiences in the two years after initial treatment, focusing on their health needs, communication with treatment team, and psychosocial concerns using both semi-structured interview and survey research strategies.

Effective Communication on Tobacco Product Risk and FDA Authority (NIDA, PI: Kurt Ribisl, PD: Erin Sutfin, Co-Is: Reboussin, Mark Wolfson, Wagoner) The goal of the center grant is to advance regulatory science by using communication science to improve messages about cigarette smoke constituents, emerging tobacco products, and FDA's regulatory authority over tobacco. The center aims to conduct three integrated research projects among vulnerable populations and across the lifespan to inform regulatory science.

Training Grant in Cancer Survivorship

Cancer survivorship is a major theme of our Program and we have a unique training grant in this area, "Postdoctoral Training in Cancer Control Research; Focus on Cancer Survivorship" (1R25 CA12206101A1; PI: Nancy Avis, PhD) Dr. Naughton of CPC and Dr. Blackstock, Director of the Clinical Research Program, serve as additional program faculty on the training grant and many of the CPC members serve as mentors. Our receipt of this Training Grant was facilitated by the resources afforded to us as a Comprehensive Cancer Center, and these same CCC resources greatly enrich the postdoctoral experience of our trainees.

Our two- to three-year postdoctoral program for physicians, social/behavioral scientists, and epidemiologists develops investigators with research skills focused on the design and implementation of cancer survivorship research. The program is multidisciplinary and collaborative with respect to faculty and training approach, the research projects of trainees, and the backgrounds of trainees. The training program provides a specialized curriculum in cancer survivorship and a tailored program for each trainee that combines formal course work and hands-on experience in survivorship research under the guidance of well-qualified mentors. The tailored program can also lead to an M.S. degree in Clinical and Population Translational Science. All trainees receive training in cancer survivorship and NIH grant preparation, and participate in interdisciplinary seminars and interest groups. The program provides practical training in research including interdisciplinary teamwork, research design selection, ethics in research, guidelines for the use of human subjects in research, grant preparation, patient recruitment, collection and analysis of data, presentations at scientific meetings, and preparation of manuscripts for publication. Trainees have opportunities to collaborate with our CCOP Research Base, the Maya Angelou Center for Health Equity, multi-site studies and cooperative groups, and the Center for Integrative Medicine. Study populations include underserved, elderly, and rural populations. Trainees have the opportunity to experience basic, clinical and population research environments, as well as take advantage of the interdisciplinary activities and full resources of the CCCWFU. This training grant ends in 2014, but a renewal is pending.

Large Epidemiologic Studies/Resources Covering Multiple Content Areas

Community Clinical Oncology Program (CCOP) Cancer Center Research Base (U10 CA 81851-09-13; PI: Edward Shaw, MD; Co-Is: Suzanne Danhauer, PhD, Glenn Lesser MD, Michelle Naughton, PhD, Steve Rapp, PhD, Mara Vitolins, PhD, Kathryn Weaver, PhD) This program is limited to NCI-designated Comprehensive Cancer Centers. Our Community Clinical Oncology Program (CCOP) Research Base is a unique resource for the WFSM. Interventions to improve QOL of cancer patients and survivors are often conducted within major cancer centers. One of the aims of our CPC Program is to translate such interventions into community cancer centers. The CCOP Research Base mechanism provides one avenue for accomplishing this.

The CCCWFU CCOP Research Base ("Research Base") (U10 CA081851; PI: Dr. Shaw (CR)) is one of four Cancer Center Research Bases in the United States. Today, 25 CCOPs throughout the U.S. participate in Research Base studies, as well as five non-CCOP institutions, which together represent a network of over 160 community cancer centers (plus Wake Forest) throughout the Midwest, Northeast, and Southeast U.S. The Research Base is a multidisciplinary, inter-programmatic effort of the Clinical Research and CPC Programs that provides a mechanism for Cancer Center investigator-initiated symptom management clinical trials to be conducted by a large number of community cancer centers located across the midwestern and eastern United States. The Research Base is led by Dr. Shaw, a radiation oncologist who has been PI since its inception in 1998. The executive steering committee includes Drs. Naughton, Vitolins, Weaver, Danhauer, Lesser (co-PI), and Rapp. Research Base funding provides the infrastructure to conduct investigator initiated trials within the CCOP system. The focus of the Wake Forest Research Base has been on symptom management interventions and more recently has expanded its focus to include observational research and behavioral interventions, opening up new opportunities for CPC members. The Research Base provides a ready population in which to conduct cancer control research. Support for concept and protocol development, staff training, data entry and analysis are available to faculty.

Women's Health Initiative and WHIMS (N01-WH-4-4221; PI: Sally Shumaker, PhD).The Women's Health Initiative (WHI) was initiated in the early 1990s, and was comprised of an observational cohort study of approximately 93,000 healthy women ages 50-79 at study entry. There were also three clinical trials in WHI: 1) low fat dietary modification (intervention vs. placebo group) of approximately 46,000 women; 2) post-menopausal hormone therapy study (n=26,000 women) comparing estrogen only (CEE) vs. placebo for those women with a uterus, or estrogen plus progesterone (CEE/MPA) vs. estrogen for those women who had not had a hysterectomy, and 3) a study of Calcium and vitamin D supplements vs. placebo, which was open to women in either the dietary modification and/or the hormone trials. In all, approximately 162,000 women were enrolled in either the observational or clinical trial components of WHI. Women were recruited into WHI from 1993 - 1999. The study was extended from 2005-2010, and then received a second extension from 2010-2015, enrolling approximately 93,000 of the original WHI participants. During the second extension, regional coordinating centers for WHI were created. Wake Forest University houses the center for the Southeastern Region of the United States, overseeing medical outcomes data collection and the production of papers and ancillary study proposals from WHI data. Dr. Shumaker is the PI of our Southeastern Region Coordinating Center.

Symptom Management and Quality of Life

Acupuncture for the Treatment of Hot Flashes (1 R01 AT005854; PI:Avis, PhD) We have studied two alternative treatments for hot flashes in women: acupuncture and yoga. A recently completed trial, "Acupuncture Treatment for Menopausal Hot Flashes" (R21 CA104427; PI: Avis) randomized women to one of three groups: true acupuncture, sham acupuncture, or usual care. We found a significant decrease in mean frequency of hot flashes, but no difference between the two acupuncture groups, but both showing a significantly greater decrease in hot flashes compared to the usual care group (Avis et al. Menopause, 2008). These results suggest either a strong placebo effect or that both traditional and sham acupuncture significantly reduce hot flash frequency. A subsequent study is currently underway to provide greater insight into the effectiveness of acupuncture for hot flashes (R01 AT005854-01 "Acupuncture for Hot Flashes" PI: Avis). This study is randomizing 200 women to examine real world effectiveness of acupuncture for hot flashes among cancer survivors and menopausal women.

Symptom Management for Leukemia Inpatients: Exercise and Yoga (SMILE) (PI:Suzanne Danhauer, PhD). (pending) Acute leukemia (AL) patients are an important group given substantial emotional and physical symptom burden in the midst of intensive induction chemotherapy regimens requiring lengthy inpatient stays. This study is a randomized, controlled trial that will compare the efficacy of two 4-week cancer-adapted individualized interventions [gentle yoga or physical activity (PA)] versus usual care in newly diagnosed adults with AL on the following outcomes: depressive symptoms, fatigue, sleep quality, physical function, and range of motion. The study will also examine several potential biological (inflammatory cytokines) and psychosocial (perceived stress, spirituality) mechanisms of action for the interventions. We will recruit a sample of 246 adult (≥21 years) patients with acute myelogenous leukemia (AML) or acute lymphocytic leukemia (ALL) undergoing induction chemotherapy who report clinically meaningful levels of depressive symptoms or emotional distress and randomly assign them to one of three groups: gentle yoga, physical activity or usual care. If validated, this study will yield 2 well-developed interventions for use with AL inpatients and elucidate potential mechanisms of action for future studies. These interventions could improve cancer-related symptoms for the nearly 20,000 AL patients who are treated each year, and may be extended to inpatients with other cancers and other diseases.

Reducing Lung Cancer Survivor Anxiety (RELAX) with Brief Device-Guided Breathing (PIs: Danhauer, PhD; Kathryn Weaver, PhD) (pending). Lung cancer is the second-most common cancer diagnosed in the US, yet little "survivorship" research has focused on this population. As the number of early stage lung cancer (ESLC) survivors increases because of uptake in low dose computerized tomography lung cancer screening, it will be increasingly important to develop interventions to improve their well-being. The goal of study is to determine feasibility of a device-guided breathing intervention versus a music control group and to obtain preliminary data on effects on anxiety, dyspnea, pulmonary function, and functional fitness in ESLC survivors. This study will enroll 60 post-treatment ESLC survivors with clinically meaningful anxiety symptoms through two sites of the Wake Forest Community Clinical Oncology Program Research Base (WF CCOP RB). Participants will be randomly assigned to one of three groups: low-dose (15 minutes, once per day) RESPeRATE device-guided breathing (n=20), high-dose (15 minutes, twice per day) RESPeRATE (n=20), and music control (15 minutes, once per day) (n=20). The results of this study will provide outstanding preliminary data for our planned R01 application for a larger randomized controlled trial that will be run through the WF CCOP RB that can better elucidate the impact of the proposed simple intervention for anxious, post-treatment ESLC survivors, that can be easily disseminated.

Investigating Mechanisms to Explain Age Associated Differences in Quality of Life among Breast Cancer Patients (PI: Nancy Avis, PhD, Co-I: Michelle Naughton, PhD). The purpose of this study is to better understand why younger women have greater psychological morbidity following a breast cancer diagnosis than older women and to examine age-related differences in treatment. This prospective observational cohort study has enrolled over 650 women and followed them for 2 years post diagnosis and provides a rich resource for manuscripts related to cancer survivorship.

Lifestyle Interventions

Prosocial Behavior and Volunteerism to Promote Physical Activity in Older Adults (5R01 HL109429; PI:Capri Foy, PhD, Mara Vitolins, PhD, Janet Tooze, PhD) is a 5-year randomized controlled trial that compares the effect of a "healthy aging" control intervention (n=150) vs. that of a physical activity intervention (N=150) which embeds prosocial behavior and volunteerism upon physical activity at 12 months. Three hundred men and women aged 55 to 80 years are being randomized into the two interventions. This study involves administration of questionnaires, direct measures of blood pressure, body weight and size, and direct measures of physical performance. In addition, survivors of cancer are eligible for this study, which may provide opportunities for qualitative interviews and assessments which address cancer survivorship.

Taking Health Realization into Valued Eating and Exercise (THRIVE): A Feasibility Study of an Intervention to Prevent Weight Gain for Breast Cancer Survivors during Chemotherapy. (PI: Shannon Mihalko, PhD, Suzanne Danhauer, PhD). The goal of the THRIVE pilot study is to demonstrate the feasibility of conducting a randomized clinical trial to test the effectiveness of an intervention to prevent weight gain for breast cancer survivors during chemotherapy. This study tests the efficacy of the intervention as a springboard to a short-term healthy lifestyle program.

A Feasibility Study of a Physical Activity Intervention in Older Adult Inpatients with Acute Leukemia (Intramural grant; PI: Shannon Mihalko; Co-Is: Suzanne Danhauer, Heidi Klepin). Acute myelogenous leukemia (AML) is a disease of older adults characterized by disproportionately worse survival associated with increasing age. Adults undergoing intensive treatment for AML frequently experience substantial physical deconditioning, treatment-related symptoms and emotional distress. Development of evidence based treatment guidelines for older adults will depend upon targeted interventions designed to minimize the impact of therapy in this population on physical function and quality of life. The goal of this pilot study is to demonstrate the feasibility of conducting a randomized clinical trial to test the effectiveness of a physical activity intervention for older adult patients with acute leukemia who are undergoing induction or reinduction chemotherapy on physical and psychological health.

Loss of fat tissue and functional responses to exercise in older, obese adults (R01 AG020583; PI: Barbara Nicklas, PhD) The primary goal of this randomized, clinical trial is to determine whether addition of caloric restriction to a standardized, progressive resistance training (RT) program enhances improvements in skeletal muscle and overall physical function in 120 older (65-79 yrs), overweight/obese adults. We will also examine the effects of the two interventions on in vitro characteristics of skeletal muscle and on systemic inflammation.

Effect of fat loss on functional and cardiovascular benefits of aerobic exercise (R01 HL093713; PI: Barbara Nicklas, PhD). This randomized, clinical trial will determine whether older, obese men and women who lose more fat during an exercise training program will experience greater improvements in aerobic function as a result of the exercise training. The study is designed to assess the effects of adding moderate (-250 kcal/d deficit) or intensive (-600 kcal/d deficit) caloric restriction to a standardized aerobic exercise training intervention on maximal aerobic capacity (VO2max), functional endurance (400-m walk time), CVD risk factors (inflammatory markers, blood lipids, blood pressure, glucose tolerance and endothelial function), and inter-muscular, abdominal visceral and pericardial fat volumes.

Omega-3 PUFA-Gene Interaction in Prostate Cancer (5R01CA163273-02; PI-Yong Chen). The goal of this research is to study the interaction between dietary PUFA and their metabolic enzymes in prostate cancer. We have previously shown that I3 PUFA reduced prostate cancer (PCa) growth, slowed histopathological progression and increased survival, whereas I6 PUFA had the opposite effects. We hypothesize that I3 PUFA is primarily metabolized by Cox1 in vivo and that the anti-proliferative effect of I3 PUFA is, in part, mediated by Cox1 metabolite(s). Furthermore, I6 PUFA is metabolized by Cox1, Cox2 and Lox5, and the corresponding metabolites play important roles in stimulating PCa growth. To test our hypothesis, three specific aims are proposed: (1) Study the cellular mechanism(s) of PUFA-gene interaction on PCa growth, (2) Identify metabolite(s) of I3 and I6 PUFA important in PCa and (3) Examine metabolite signaling in PCa cell proliferation and apoptosis.

Late Effects of Cancer Treatment

Resonance Imaging Trial for Heart bioMarkers (RITHM) in AYA Cancer Survivors (1R21CA159557-01A1; PI: Sharon Castellino, MD; Greg Hundley, MD)This study is an observational clinical trial with a cross-sectional and longitudinal design to evaluate the cardiac MRI in detecting subclinical markers of cardiac injury after anthracycline therapy. Treatment of childhood cancer has been one of the resounding successes of medicine in the last half of the 20th century, as 1 in 640 young adults in the US is a survivor of childhood cancer. With increased person-years of life impacted, cardiovascular (CV) disease is now the leading cause of non-cancer death in childhood cancer survivors. Anthracycline chemotherapy is a major risk for this CV morbidity and mortality. A lack of functional markers of CV risk has limited cardioprotection and secondary prevention strategies. Cardiac magnetic resonance imaging (CMR) provides precise measures of aortic and cardiac function, making it ideal for establishing surrogate markers of subclinical disease in smaller populations. Our project is an observational clinical trial with a cross-sectional and longitudinal design to evaluate the application of CMR in detecting subclinical markers of cardiac injury after anthracycline therapy. We plan to use CMR to measure aortic stiffness and myocardial wall strain in adolescent/young adult survivors of childhood cancer off therapy in comparison to a control group without cancer. In addition we will evaluate the ability of CMR to detect and follow changes in aortic function in newly diagnosed adolescent patients receiving anthracycline chemotherapy. The trial at two childhood cancer programs will lead to: novel CMR biomarkers of subclinical anthracycline cardiotoxicity~ an understanding of previously unexplored concepts of aortic stiffness and myocardial strain in the pathophysiology~ and the establishment of a young anthracycline exposed cohort who can be followed with CMR for future studies of the technology and targeted interventions. This Quick Trial of CMR will facilitate development of needed surrogate endpoints for timely, targeted pharmacologic or behavioral interventions to alleviate the burden of CV disease in this cancer population

Early Imaging Detection of CV Injury after Cancer (5R01CA167821-02; PI: Greg Hundley, Sharon Castellino, MD) In collaboration with Siemens Medical Solutions, this project develops a new magnetic resonance imaging (MRI) scanner for detecting early subclinical vascular toxicity secondary to cancer chemotherapy. This technical and methodological solution for cancer investigations establishes an innovative methodology to detect the risk for early cardiovascular disease, and thereby enable timely new preclinical therapy guidelines designed to reduce potential cardiovascular events and thus improve the overall survival of those treated for cancer.

CV injury, Exercise Intolerance and Fatigue after Chemotherapy for Breast Cancer (PI: Greg Hundley, Co-Is: Nancy Avis, Shannon Mihalko, Ed Shaw, Doris Brown) (Pending) This multi-center prospective longitudinal cohort study combines a National Cancer Institute (NCI)-supported patient recruitment infrastructure with National Heart, Lung, and Blood Institute (NHLBI) expertise in cardiovascular (CV) disease to determine the influence of adjuvant chemotherapy (Adj-C) on CV function, exercise capacity, and fatigue among women treated for Stage I-III breast cancer. We will use innovative magnetic resonance imaging (MRI)-which identifies early evidence of LV and vascular injury-cardiopulmonary exercise testing, and standardized questionnaires to obtain objective data regarding the development of CV injury, exercise intolerance and fatigue. Our longitudinal design will allow us to account for pre-existing risk factors and dynamic changes during receipt of Adj-C. The study will be conducted at 11 referral sites nationwide through the network of the NCI-supported Wake Forest Community Clinical Oncology Program Research Base. Under this unique arrangement, the NCI has committed existing infrastructure and funding for participant enrollment and site per case reimbursement. Longitudinal within-person and between-group comparisons will be accomplished with a group of 500 age-matched women without cancer. Our project is the first epidemiologic cohort study, with methods adopted from large population-based studies of CV disease and heart failure, designed to define and fully characterize using CV MRI the time course and associative factors that influence the development of subclinical CV dysfunction, exercise intolerance, and fatigue in women treated with Adj-C for breast cancer. The knowledge from this study will characterize the risk of developing subclinical CV disease and exercise intolerance in asymptomatic women treated with adjuvant therapy for breast cancer, and thereby will inform the development of future screening and intervention studies to reduce CV disease and prolong overall survival in women with breast cancer.

Cognition

Cognitive functioning is an important area of cancer survivorship as researchers are increasingly finding cognitive deficits following cancer treatment. More research needs to be done on the exact nature of these deficits, identification of risk factors for cognitive deficits, and possible interventions to prevent or slow these deficits. Cognition is a strong area at WFUSM in population sciences, basic sciences, and radiation oncology and several multidisciplinary groups are already addressing these issues.

Women's Health Initiative Memory Study (PI: Sally Shumaker, Co-Is: Michelle Naughton, Steve Rapp). A long standing ancillary to WHI is the Women's Health Initiative Memory (WHIMS) suite of studies. These studies were developed by Dr. Shumaker and colleagues and the WHIMS coordinating center is also located at WFSM. Beginning in 1996, the WHI included a unique and detailed assessment of global cognitive functioning, mild cognitive impairment, and dementia on a subset of women (aged 65 and older) who were enrolled in the WHI hormone trials (N=7,450). Follow-up of about 3,700 of these women still continues. The Women's Health Initiative Study of Cognitive Aging (WHISCA) and the Women's Health Initiative Magnetic Resonance Imaging (WHIMS-MRI) study were conducted on subsets of WHIMS participants. In addition, the Women's Health Initiative Memory Study of Younger Women (WHIMS-Y) began in 2008.

This study is designed to assess the long-term impact of random assignment to postmenopausal hormone therapy among women who were 50-54 years of age at the time they were initially enrolled into the WHI hormone trials. Hormone therapy continues to be widely prescribed for the treatment of menopausal symptoms. There remains a strong belief among basic and clinical scientists that hormone therapy begun during the peri- or immediate post-menopausal periods may bestow cognitive benefits and that the cognitive harm associated with hormone therapy in the post-menopausal woman occurs only when there is some pre-existing, sub-clinical disease and/or the aging brain is more vulnerable to the possible negative effects of hormones. This specific issue was not addressed within the original WHIMS cohort, and WHIMS-Y takes advantage of the rich WHI cohort by adding critical information on the clinical treatment of peri-menopausal and early post-menopausal women and on potential mechanisms of action for how HT may affect cognition.

Both WHI and WHIMS provide a wealth of opportunities to study factors related to cancer prevention and control, as well as survivorship, due to rich data on dietary habits, exercise, social support, comorbidities, quality of life and health disparities. Both Drs. Shumaker and Naughton have been involved in WHI since its inception, and will assist the post-docs in working with WHI and WHIMS data.

Phase III Study of Donepezil in the Irradiated Brain (R01 NR009675-01A2; PI: Steve Rapp; Co-I: Michelle Naughton) This recently completed Phase III randomized, placebo-controlled, double blind clinical trial tested the efficacy of donepezil (5mg x 6 wks, 10 mg x 18 weeks) to improve cognitive functioning in brain tumor survivors > 6 months following brain radiation treatment. Data analyses are currently underway and post-docs will be encouraged to use them for papers and ancillary study proposals.

PPARs and Radiation-Induced Brain Injury (5R01CA112593-10; Co-PIs Linda Metheny-Barlow and William Blackstock). This study examines the mechanisms by which radiation of the brain leads to brain injury, including cognitive impairment, and evaluates the ability of PPAR agonists to ameliorate the damage and protect cognition in rodent models. Dr. Metheny-Barlow is also working on the development and characterization of models to study breast cancer brain metastasis development and treatment. As part of a recently completed DoD pilot grant, she has developed a unique brain metastasis-bearing rat model to study effects of therapeutic fractionated whole brain irradiation on tumor response and cognition; this model better represents the human condition where damage results from a combination of tumor and therapy.

Gene-Hormone Interaction and Risk of Breast Cancer (5R01CA149135-03; Co-PI: Mara Vitolins). The overall hypothesis of this study is that common genetic variants can be used to classify women into low or neutral risk groups for developing breast cancer due to HT use (gene-hormone interaction). We specially hypothesize that 1) a subset of genetic variants account for individual differences in risk of developing breast cancer upon HT use (E+P or E only) on breast cancer risk, 2) those SNPs may or may not alter the risk of developing CVD upon HT use. We will identify the genetic variants using data and samples from the Hormone Therapy Trial (HT) of the Women's Health Initiative (WHI) study, a large randomized, double-blind, placebo-controlled clinical trial, and perform a replication study in the WHI Observational Study (OS). To test these hypotheses, we have four specific aims. Aim 1 is to identify SNPs that account for individual differences in risk of developing breast cancer upon HT use (SNP-HT interactions). Aim 2 is to confirm the top significant SNPs identified in Aim 1 among women in the OS arm. Aim 3 is to evaluate the SNP-HT interaction with other phenotypes (primarily CVD) among women in the OS arm. Aim 4 is to estimate the individual absolute risk of developing breast cancer upon HT use among women in the OS arm. The identified genetic variants will be used to create a risk-benefit profile for HT treatment and may potentially improve clinical decision making for HT use.

The Study of Women's Health Across the Nation (SWAN) (3U01 AG12546; Wake Forest PI: Nancy Avis) is a large multi-site, multi-ethnic 15-year study of mid-aged women as they transition through menopause. The dataset includes psychosocial factors, health risks and health behaviors, physiological measures, and disease outcomes. The data provide the opportunity to prospectively examine cancer survivorship among those women who develop cancer over the course of the study and to compare health status to healthy controls. An ancillary study focused on cancer survivors is planned for the Fall.

Paricalcitol for Palliation in Advanced Prostate Cancer: A Phase II Trial; PI: Schwartz) This ongoing Phase II clinical trial is being conducted in men with androgen-insensitive prostate cancer who have bony metastases and who have significantly elevated serum parathyroid hormone (PTH). 19-nor-1,25-Dihydroxyvitamin D₂ (Zemplar, a paricalcitol capsule), is an FDA-approved oral vitamin D analogue, being used to suppress serum PTH. We have previously shown that this drug in intravenous form inhibits the proliferation of prostate cancer cells in vitro. , this research represents a translation of our laboratory and clinical trial work to an investigator-initiated extramurally-funded, clinical trial. The current trial is in the process of enrolling 30 men with advanced prostate cancer for 16 weeks to suppress serum PTH levels to ≥50% of their baseline values. The Specific Aims are to: 1) test the hypothesis that medical suppression of serum PTH in men with metastatic prostate cancer will result in a decrease in bone pain, a reduction in use of analgesic medications, and improved QOL; 2) test the hypothesis that subjective changes in bone pain and improved QOL will be associated with objective changes in bony remodeling, as assessed by biochemical markers of bone resorption and bone formation; and 3) use these data to plan a blinded, placebo-controlled Phase III trial of paricalcitol in pain reduction and QOL in metastatic prostate cancer.