The primary focus of the AMBER Study will be to identify the independent and interactive associations of PA and HRF with disease outcomes (e.g., recurrence, breast cancer-specific mortality, overall survival). Other important health outcomes will include treatment completion rates, symptoms and side effects (e.g., pain, lymphedema, fatigue, cognitive dysfunction), and PROs (e.g., QoL, anxiety, depression, self-esteem, happiness). We will also be able to examine the mediators and moderators of any observed associations between PA, HRF, and health outcomes. Finally, we will be able to identify the key determinants of PA and HRF including demographic, medical, and social cognitive variables, at various time points across the survivorship trajectory. Taken together, these data will provide a detailed understanding of the unique benefits, risks, and determinants of PA and HRF at multiple time points of survivorship so that intervention strategies can be developed to help breast cancer survivors achieve and maintain healthy levels of PA and HRF. The AMBER Study is designed initially to address the following five major research themes.
Physical activity, health-related fitness, and disease outcomes
The primary aim of this project is to examine the associations between self-reported and objective PA (including sedentary behavior), HRF (including body composition), and disease outcomes in breast cancer survivors (including recurrence-free interval, breast cancer mortality, and overall survival). These data will provide critical information on the optimal type, volume, and pattern (i.e., how the volume is achieved over a given week) of PA that may be most strongly associated with disease outcomes in breast cancer survivors. Moreover, while previous studies have used self-report PA assessments, the use of accelerometers to measure PA will provide an accurate (and gold-standard) estimate of PA at multiple time points across the survivorship trajectory. Further, no studies have examined associations between objectively-determined PA and disease endpoints. Multivariable analyses will be able to determine any independent associations of the PA and HRF variables with disease outcomes that may identify one or more PA-related exposures of primary importance. For example, two research questions will be to determine whether: (a) cardiorespiratory fitness and muscular strength or other HRF assessments are independently associated with disease outcomes among breast cancer survivors, and (b) vigorous PA and sedentary behavior are independently associated with disease outcomes. A secondary aim is to examine potential moderators (effect modifiers) of the associations between PA, HRF, and disease outcomes. These data will provide critical information on which subgroups of survivors may benefit the most from engaging in PA and may also even identify different optimal PA prescriptions for different survivor subgroups. The ultimate goal of this project is to provide insights regarding the relative importance of various aspects of the PA prescription and the various HRF components for breast cancer outcomes that will be directly relevant for PA and sedentary behavior recommendations for breast cancer survivors.
Physical activity, health-related fitness, and biologic mechanisms
The primary aim of this project is to examine the mechanisms that may explain any associations between self-reported and objective PA (including sedentary behavior), HRF (including body composition), and disease outcomes in breast cancer survivors (including recurrence-free interval, breast cancer mortality, and overall survival). The exact biologic mechanisms whereby PA and HRF may influence breast cancer recurrence and survival have not yet been delineated. More research has focused on the role of PA in breast cancer incidence. One hypothesized biologic model for postmenopausal breast cancer risk implicates adiposity, sex hormones, insulin resistance and chronic inflammation as mediators of PA
. This model is further supported by recent results from exercise intervention trials that demonstrated a direct impact of PA on sex hormones
[48, 49] and adiposity levels
, which are both convincingly associated with postmenopausal breast cancer risk in the epidemiologic literature
. The same model and biologic rationale relating PA to postmenopausal breast cancer risk
 can be adapted to breast cancer recurrence and survival since many of the same biomarkers have been associated with PA in breast cancer survivors, and breast cancer recurrence/survival, respectively. Adaptations to the model include the addition of breast cancer therapies and their potential influence on biomarkers
[51, 52] as well as the addition of insulin-like growth factor 1 (IGF-1) and IGF binding protein 3 (IGFBP-3). HRF (i.e., body composition, muscular strength, muscular endurance, cardiorespiratory fitness) can also be added to the model since body composition is influenced by PA, changes in muscle mass may affect insulin resistance, and in one recent healthy cohort study, cardiorespiratory fitness was found to decrease risk of breast cancer death through an unknown mechanism
Clearly, there is a lack of consistent information relating PA and breast cancer outcomes to our hypothesized biomarkers. A better understanding of the underlying biologic pathways involved in the association between PA and breast cancer outcomes could be gained with a sufficiently powered study using more accurate measures of body fat, valid measures of PA, and careful control for patient and tumor-related moderators of the effects of PA on breast cancer outcome. Serial measurements of our proposed biomarkers over time will be a novel attribute of this study and will enable us to identify significant time points for influencing breast cancer outcome and the effect of biomarker level changes over time. This understanding will add biologic plausibility to the association between PA and breast cancer outcome, guide future epidemiologic research, identify new targets for interventions, and inform clinical recommendations for improving survival after breast cancer diagnosis.
Physical activity, health-related fitness, and patient-reported outcomes
The primary aim of this project is to examine the associations between PA, HRF, and PROs across the breast cancer continuum. Breast cancer survivors have an elevated risk for poor QoL, anxiety, depression, fatigue, and cognitive impairment both during treatment
 and throughout survivorship
[55, 56]. Some evidence suggests that women surviving cancer may continue to demonstrate poor function on various PROs for up to 10 years after their initial diagnosis
[57–59]. While preventing declines in PROs after a breast cancer diagnosis is important, new research is suggesting that less decline in QoL during adjuvant therapy for breast cancer may also be associated with a reduced risk of breast cancer recurrence
 (Sarenmalm et al., 2009).
Systematic reviews support the role of PA as a safe and effective intervention to improve HRF and selected PROs in breast cancer survivors, particularly during survivorship
[61, 62]. The most commonly studied PROs in PA research are fatigue, QoL, physical functioning, depression, and anxiety
. Systematic reviews provide evidence that PA can improve patient-reported physical functioning and anxiety during treatment, and QoL, fatigue, depression, and anxiety during survivorship. In particular, these studies suggest that particular QoL domains, especially physical well-being, functional well-being, and fatigue appear to be domains that are most likely affected by PA. Indeed, some data suggest that improvements in several PROs are dependent on changes in HRF such as cardiorespiratory fitness
Although over 50 randomized controlled trials (RCTs) have examined the effects of PA on PROs in breast cancer survivors
, few of these trials have had adequate power for subgroup analysis, few have examined the optimal type of PA (e.g., aerobic, resistance) or intensity of PA (e.g., light, moderate, vigorous activities), few have examined the HRF components most relevant to PROs, and few have examined the effects of PA or HRF on PROs across the continuum of breast cancer survivorship (e.g., treatment, early survivorship, later survivorship). Little is known about other relevant PROs such as cognitive function, taxane symptoms, hormonal symptoms, and psychological well-being (e.g., happiness and satisfaction with life). Further, to date there are no studies examining sedentary behavior (time spent sitting) and associations with PROs among breast cancer survivors. Information of this nature may facilitate further understanding of how PA and sedentary behavior is related to PROs during breast cancer survivorship. This project will also examine important mediators and moderators of the associations between PA, HRF, and PROs.
Physical activity, health-related fitness, and physical functioning
This project will examine the relationship between PA, HRF and the incidence, severity and natural progression of lymphedema and upper limb morbidity (e.g., pain, numbness, weakness and shoulder dysfunction) from diagnosis through treatment and recovery from breast cancer. Lymphedema is a chronic swelling of the limb on the surgical side that may present immediately or many years after treatment
[65, 66]. More recent estimates suggest an incidence rate of around 20%, with higher rates found in studies with longer follow-up
[67, 68]. Lymphedema is a known consequence of surgical and radiotherapeutic techniques and is known to have deleterious effects on QoL
. Among systemic factors, obesity has been associated with increased lymphedema risk
. While PA has been traditionally viewed as a possible risk factor, PA has not been associated with lymphedema in prospective research and more recent evidence suggests a possible protective effect of PA
Upper limb morbidity occurs frequently following treatment for breast cancer
[71, 72] and recent evidence suggests symptoms such as pain and shoulder dysfunction are more prevalent than lymphedema
. Although upper limb morbidity is reduced with newer techniques such as Sentinel Lymph Node Biopsy, studies have shown that a majority of breast cancer survivors have at least one upper limb symptom (e.g., numbness, pain, weakness, swelling, stiffness) in the long term
Peripheral neuropathy is a condition that results from damage to or dysfunction of the peripheral nerves
. In breast cancer survivors this damage may occur from administration of a neurotoxic chemotherapeutic agent
. Sensory symptoms associated with chemotherapy induced peripheral neuropathy include numbness, tingling and pain that presents in the distal aspects of the upper and lower extremities, often described as a stocking/glove distribution
. Motor symptoms associated with the condition may include upper and lower limb weakness, impaired proprioception and balance. Functional impairments may result in difficulty performing fine motor tasks, walking and increase the risk falling
. Thus, breast cancer survivors experiencing treatment related effects such as lymphedema, upper limb morbidity and peripheral neuropathy, may have unique challenges that impact their PA, HRF, and PROs.
Determinants of physical activity and health-related fitness
The aim of this study is to develop a comprehensive understanding of the determinants of PA in breast cancer survivors across the survivorship continuum. A social ecological approach and a theoretical framework [i.e., Theory of Planned Behavior (TPB)] will be used to identify key determinants of both the adoption and maintenance of PA across the continuum of breast cancer survivorship including social cognitive, demographic, personal, biological, medical, and environmental factors. The social ecological approach provides a broad framework to examine the multiple effects and interrelatedness of these factors at all levels of influence (i.e., individual, interpersonal, organizational, community, and society). Moreover, the TPB is one of the most widely tested theoretical frameworks within the PA and cancer literature.
More research is necessary to determine the specific relationship between these demographic variables and aspects of PA, including specifically the type, frequency, duration and intensity, as well as the timing of PA across the breast cancer continuum. Less is known about the role of medical factors as determinants, although PA participation consistently decreases with advanced breast cancer and during treatments. No research to date has specifically examined the role of biological factors as determinants of PA behavior during and after treatment. Therefore, examining biomarkers as PA determinants may provide a unique insight into the role of cancer-related biology as a determinant of PA.
Given the scarcity of literature on the myriad of determinants of PA for breast cancer survivors, the proposed prospective cohort study will generate new knowledge and be instrumental in formulating eventual clinical and community-based programming for breast cancer survivors. We will more clearly elucidate the complex interplay between a range of determinants and PA adoption and maintenance. Ultimately, the determinants project will enable us to achieve more effectively targeted interventions that help breast cancer survivors achieve healthy levels of PA and HRF.
In summary, the AMBER Study will establish a cohort in which we will conduct five initial studies that address the outcomes, determinants, mechanisms, and moderators of PA and HRF in breast cancer survivors. The AMBER Study will answer wide-ranging questions related to PA and HRF in breast cancer survivors. The result will be a unique data source containing data from objective and gold-standard measures that has not previously been created. This study will provide insight into a multitude of future research questions. Other important questions will arise for which the AMBER Study could provide timely answers. The ultimate goal of this research is to identify how PA and HRF can be used to inform clinical and public health recommendations for improving outcomes after breast cancer.