Rebecca A. Silliman - US grants

An estimated 178,700 women were diagnosed with breast cancer in 1998, more than half of whom were 65 years of age or older. This proportion is likely to grow, not only because older age is the most important risk factor for breast cancer, but because gains in life expectancy and decreases in deaths due to cardiovascular disease will result in more women at risk for longer periods of time. Older women are at risk for receiving less than definitive care for their breast cancer and emerging evidence suggests that this translates into poorer health outcomes. We are studying 900 breast cancer patients at least 65 years of age who are at intermediate or high risk of breast cancer recurrence to identify physician and patient predictors of tamoxifen prescription and one year treatment adherence. We propose to follow this cohort, enrolled at four different geographic sites (Los Angeles, Minnesota, Rhode Island, and North Carolina) for five years to answer critical questions about the relationships between breast cancer treatments and disease-specific and health-related quality of life outcomes. Specifically, we propose to: (l) compare the effectiveness of adjuvant tamoxifen therapy, versus no adjuvant tamoxifen therapy, in reducing breast cancer recurrence and breast cancer mortality rates among older women receiving recommended definitive primary tumor therapies and those not receiving such therapies; (2) quantify the prevalence of tamoxifen discontinuance and identify patient and physician characteristics associated with it during the recommended five years of therapy; and (3) identify risk factors associated with a decline in health-related quality of life outcomes, particularly upper body function, during five years after breast cancer diagnosis. In the parent project, patients are interviewed 3, 6, and 15 months after their definitive surgery; medical record abstractions are performed; and breast cancer physicians provide information about treatments recommended. In the proposed project we will interview the same patients at months 27, 39, and 51 after their definitive surgery; obtain additional physician recommendation information at 30 months; and obtain semi-annual medical record-documented breast cancer recurrence information as well as National Death Index cause-specific mortality information. Findings from this study will characterize the effectiveness of adjuvant tamoxifen therapy in reducing rates of breast cancer recurrence and breast cancer-specific mortality among older women at high risk for recurrence who are cared for in community practice settings. The findings will also allow us to identify women most likely to discontinue tamoxifen therapy and those most likely to experience a significant decline in health-related quality of life during the first five years following the diagnosis of breast cancer.

DESCRIPTION (provided by applicant): There is a demonstrated need to increase the number of outstanding investigators trained in clinical research, clinical epidemiology and health services research to address the health issues of women. The Boston University (BU) Interdisciplinary Women's Health Research Scholars Program will build upon the existing programs in women's health research to provide a model program to recruit, select, train and evaluate a group of junior faculty prepared to develop their own research careers and complete for independent extramural support. The BIRCWH builds upon the BU Program in Research in Women's Health, an interdisciplinary program that has promoted basic, translation, clinical, public health and health services research in women's health. The Boston University Center of Excellence in Women's Health has developed a novel junior faculty mentoring program, systems to support expanded clinical research on women's health and an intramural junior faculty outreach award. The BU BIRCWH Program is a structured and individualized program, building upon the research training strengths of the Master's programs in epidemiology and health services research at the Boston University School of Public Health, and the Boston University Clinical Research Training Program (CREST). The BU BIRCWH Program will recruit internal and external candidates who have completed their clinical training, with an emphasis on recruitment of minority candidates. The Program will address the needs of Basic Scholars, who have not had formal research training, and Advanced Scholars, who have completed a formal research-training program. All Scholars will have a primary mentor, who with the Program Director will guide the process of the training experience. Basic Scholars will spend part of the first two years completed a Masters in Epidemiology or Health Services Research. All Scholars will participate in a curriculum of research seminars including the BIRCWH seminar series, the CREST seminar series, and the Course for the Responsible Conduct of Research, as well as an individualized program of other seminars and training opportunities. All Scholars will work with a mentor on a research project. All Scholars will develop and submit a research proposal, in anticipation that all Scholars will complete the program with independent funding. A Core Database Research Laboratory Facility will provide resources to all Scholars for conducting their research. An external annual evaluation will assess the program, and result in continued improvements to strengthen the curriculum and Scholar experience.

DESCRIPTION (provided by investigator): An estimated 192,200 women were diagnosed with breast cancer in 2001, more than half of whom were 60 years of age or older. Of concern is that while breast cancer-specific mortality rates have declined among women less than 70 years old, they are either stable (70-79 year olds) or are increasing (80+ year olds) among those 70 years or older. One explanation for this is that older women receive less than standard therapy more frequently than younger women. Neither efficacy nor effectiveness data to date justify this pattern of care. Taking advantage of the Health Maintenance Organization (HMO) Cancer Research Network, we propose to conduct a historical cohort study of an unselected group of older women (>65 years of age) newly diagnosed with early stage breast cancer (stages I-II) between 1990 and 1994. Specifically, we will (1) Compare the effectiveness of standard primary tumor therapy (breast conserving surgery, axillary dissection, and radiation therapy or modified radical mastectomy) versus other than standard therapy in preventing breast cancer recurrences and mortality, adjusting for co-morbidity, tumor characteristics, geographic site, and demographic characteristics; (2) Determine the extent to which the addition of systemic adjuvant therapy (chemotherapy, hormonal therapy, or the combination of chemotherapy and hormonal therapy) modifies the effectiveness of standard and other than standard primary tumor therapy in preventing breast cancer recurrences and mortality; (3) Describe patterns of surveillance testing for breast cancer recurrence and determine the extent to which surveillance testing is associated with a reduction in breast cancer-specific mortality; and (4) Identify provider, tumor, and patient characteristics associated with the receipt of standard primary tumor therapy and systemic adjuvant therapy in older women with newly diagnosed early stage disease in the HMO setting. Six sites from throughout the United States will together identify and follow 2180 women for ten years. Both electronic and medical record data sources will be used to collect information that will allow us to characterize the separate and joint effects of treatment, tumor, and patient characteristics on breast cancer recurrence and mortality. Findings from this study will inform clinical practice, particularly the care of older women with co-morbidities who are unlikely to participate in clinical trials.

DESCRIPTION (provided by applicant): Recent and anticipated demographic changes in the United States have magnified the concentration of cancer survivors among persons >=65 years of age. At present 60% of the estimated 8.9 million cancer survivors are >=65 years of age and the number of incident cases in this age group is expected to double over the next 30 years. These overall trends are reflected in the specific case of breast cancer. An estimated 203,500 women were diagnosed with breast cancer in 2002, with almost half of the cases occurring in women >=65 years of age. This proportion and the corresponding absolute numbers are likely to grow, because older age is the most important risk factor for breast cancer and because gains in life expectancy will result in more women being at risk for longer periods of time. For these older women, the consequences of breast cancer and its treatment are likely to be complex, due to the interaction of breast cancer treatment sequelae, non-breast cancer comorbidities, and age-related disabilities. We are conducting a multi-site study of over 900 women 65 years of age and older at intermediate and high risk of breast cancer recurrence. We propose to follow this cohort for an average of 10 years following diagnosis to examine the relationships among breast cancer and its treatment, age-related comorbidities and functional impairments, and health outcomes in long-term older breast cancer survivors. Taking advantage of this carefully and comprehensively studied cohort of women whom we have followed since diagnosis, and complemented by Medicare claims data, we will: (1) describe patterns of breast cancer recurrence surveillance and assess the impact of guideline surveillance on breast cancer mortality, all-cause mortality, and health-related quality of life (HRQOL); (2) identify demographic, treatment, and tumor characteristics associated with successful and unsuccessful survivorship with respect to HRQOL, specifically psychosocial and physical function; and (3) determine the impact of a breast cancer diagnosis on total comorbidity burden and quality of non-breast cancer care. Results from the proposed project will provide new information about the large and growing number of older women who are long-term survivors of breast cancer. Understanding their physical, psychological, and medical and oncological care needs will inform the future care of older women with this disease.

DESCRIPTION (provided by applicant): More than one-third of U.S. adults over 65 years of age have inadequate or marginal functional health literacy, and among indigent and minority patients in urban areas this number rises to over 80 percent. Face-to- face conversation with health providers remains one of the best methods for communicating health information to patients with low health literacy. The investigators have developed and successfully pilot tested a new computer agent technology for simulating face-to-face conversation with older adult patients in order to effect health education and behavior change in the area of physical activity promotion. In this research project the investigators will translate this pilot work into a computer system and protocol that can be readily deployed to ambulatory care settings, and will evaluate the efficacy of the resulting system as a mechanism to promote behavioral change among older adult patients with low health literacy in a two-arm randomized clinical trial. The intervention will be tailored for use primarily by an urban, African American, older adult population and evaluated in a similar study population. The computer agent intervention for walking promotion among older adults will occur in two-phases: (1) an intensive in-home, two-month, daily contact intervention deployed on a portable, touch-screen computer that patients carry home from the clinic, followed by (2) an occasional contact intervention via a kiosk-based computer that patients use when they come to their primary care clinic for an additional 10 months, to promote maintenance of walking behavior. The resulting intervention will be evaluated in a randomized study to assess its impact on walking behavior, fitness and mobility, and well-being in patients stratified by health literacy level, compared to a standard-of- care control condition. Older adults who begin an exercise program can reduce their risk of several chronic diseases (e.g., cardiovascular disease, type 2 diabetes, osteoporosis, etc.) as well as depression, disability, falls and overall mortality. Low health literacy has been associated with limitations in instrumental activities of daily living, activities of daily living, and limitations in activity because of physical health. The proposed study will determine whether a low-cost automated system that can be easily deployed from ambulatory clinics will be effective in motivating older adults with low literacy to obtain more physical activity.

DESCRIPTION (provided by applicant): Women 65 and older ("older women") account for nearly half of all new cases of breast cancer. With the "graying of America" the absolute number of older women diagnosed and undergoing breast cancer treatment will almost double by the year 2030. Treatment guidelines for these older patients include systemic therapy and older women are interested in chemotherapy for even small returns in survival extension. But systemic therapy is not without side effects, and numerous studies have documented cognitive decline after receipt of these agents. Imaging and animal studies confirm that cancer chemotherapy affects brain structure and function. However, very little is actually known about cognitive decline in older patients, because virtually all of the existing research has been conducted in younger patients. Since aging itself is associated with cognitive decline, older patients are likely to be particularly vulnerable to the adverse cognitive effects of systemic therapy. Our preliminary work suggests that this is the case, but this has never been empirically tested. This study will be the first large scale, prospective, controlled investigation to evaluate cognitive changes in older cancer patients. We use the vulnerability model of cancer survivorship to describe systemic therapy effects on cognition over a 12 month period, test associations between cognition and quality of life and to evaluate whether APOE polymorphisms moderate cognitive outcomes. We have assembled a team of oncologists, geriatricians, neurologists, neuro-, cognitive and behavioral psychologists and consumers from Lombardi Comprehensive Cancer Center, Memorial Sloan-Kettering Cancer Center, Boston University and Y- Me (a national consumer advocacy organization). We will enroll 325 newly diagnosed older breast cancer patients and an equal number of non-cancer friend controls. Participants will undergo baseline (pre-systemic therapy) neuropsychological testing and telephone interviews;clinical data will be abstracted from records. Participants will repeat cognitive testing and QOL measures 12 months after baseline. The primary outcome is change in the summary score on tests in the Attention, Working Memory, and Psychomotor Speed Domain. Four additional domains are included as secondary outcomes to assess broader cognitive function and examine differential impact: Language;Executive Functioning;Learning and Memory;Visuospatial. The results of this study will contribute to designing appropriate regimens for older women, developing preventive interventions, informing clinical decision-making about treatment, and guiding second generation studies. Overall, this topic has high research, clinical and public health importance, given the projected growth in the older population, rising incidence with advancing age, trends towards increasing use of systemic therapy in older patients, use of more aggressive dosing regimens, high survival rates, and increasing life expectancy. PUBLIC HEALTH RELEVANCE: Cancer is the leading cause of death in the US and breast cancer is the second most common cancer among women in our country. Older women (women 65 and older) presently account for nearly half of all new cases of breast cancer. With the "graying of America" and advances in treatment for breast cancer, the absolute number of older women undergoing breast cancer treatment and surviving their disease will almost double by the year 2030. Systemic hormonal and non-hormonal chemotherapy is credited with improvements in survival, and rates of use of these modalities have increased substantially over the past two decades. In our preliminary work, we have found that older women are interested in chemotherapy even for small returns in survival extension. However, cognitive impairment has been demonstrated in most studies of breast cancer systemic treatments, but virtually all of this research has been conducted in younger populations. Since aging itself is associated with cognitive declines, it seems very likely that older women are particularly vulnerable to the adverse cognitive effects of systemic therapy;our preliminary work strongly suggests that this is the case, but this has never been empirically tested. This study will be the first large scale, prospective, controlled investigation to evaluate cognitive changes in older cancer patients and it will provide the basis for the next generation of mechanistic, treatment and intervention studies. These will be important since data from younger patients cannot be directly translated into the older population. We will use the vulnerability model of cancer survivorship to prospectively describe systemic therapy effects on cognition in older breast cancer patients over a 12 month period, test associations between cognition and quality of life (QOL) and to evaluate whether polymorphisms in the APOE gene moderate cognitive outcomes. To achieve our objectives, we have assembled a multi-disciplinary team of oncologists, geriatricians, neurologists, neuro- and cognitive psychologists, behavioral scientists and consumers from Lombardi Comprehensive Cancer Center (LCCC), Memorial Sloan-Kettering Cancer Center (MSKCC), Boston University (BU) and Y-Me (a national consumer advocacy organization). This team will work together to prospectively enroll 325 newly diagnosed older breast cancer cases from LCCC and MSKCC, tertiary referral centers with high volumes. BU will coordinate cognitive testing protocols. We will recruit an equal number of non-cancer friend controls. We have chosen friend controls since they will be similar to patients in most ways except for exposure to cancer and its treatments and they should be motivated to participate. If friends are not available, we will recruit controls matched to cases on age, education, race, and area (DC/NY). We will administer baseline neuropsychological testing prior to any systemic treatment (or at enrollment for controls), survey women about subjective cognitive function, psychosocial factors, QOL and activities of daily living (IADLS). We will abstract clinical data from medical records. We will obtain blood to test for APOE polymorphisms at enrollment;these results will not be provided to participants since this is considered a research test). We conduct follow-up interviews and repeat the neuropsychological testing 12 months after baseline assessment;this time point corresponds to 3-6 months post-treatment among women who receive chemotherapy. Our primary cognitive outcome will be change in summary score on tests in the Attention, Working Memory, and Psychomotor Speed Domain. In secondary analyses we examine changes in scores on 4 additional domains to assess broader cognitive function and examine questions of differential impact: Language;Executive Functioning;Learning and Memory;Visual-spatial. Data from this study will guide future interventions to better select older women for whom the benefits of systemic therapy outweigh the harms and to develop approaches to mitigate negative consequences of systemic treatment when it is indicated, improving the quality of care for the growing population of older breast cancer patients.