Exercise to Improve Neurovascular Function in Breast Cancer Survivors

Study Rationale: Breast cancer survivors are more likely to develop cardiovascular disease (CVD) or neurocognitive disease than age-matched counterparts without a history of cancer diagnosis. Some anti-cancer treatments cause damage to the cells of heart and the walls of blood vessels, which may exacerbate neurovascular dysfunction and cancer-related cognitive impairment (symptoms such as 'chemo-brain'), as well as accelerating the onset of neurocognitive disease. Therefore, effective policies and therapeutic strategies are needed to minimize neurovascular dysfunction and neurocognitive disease in at-risk populations like breast cancer survivors. Regular exercise training is effective in slowing or preventing the development of CVD. Furthermore, higher fitness levels are associated with lower dementia risk in older adults, which may be due to better neurovascular function. However, whether exercise training incorporated into a Cardio-Oncology Rehabilitation and Exercise (CORE) programme can improve neurovascular function in breast cancer survivors is currently unknown. Therefore, the primary aim of this study will be to determine the effect of a CORE programme on neurovascular function in long-term breast cancer survivors. Study Description: This study will be a randomised controlled trial to investigate the effect of a CORE programme on neurovascular function in long-term breast cancer survivors. Participants will complete a series of baseline assessments, including lifestyle questionnaires, a cognitive function assessment, dual-energy x-ray absorptiometry (DXA), a cardiopulmonary exercise test (CPET), ultrasound assessments of arterial stiffness and vascular function, and brain magnetic resonance imaging (MRI). Furthermore, participants will wear a blood pressure monitor at home for 24 hours, and a physical activity monitor for seven days. Following completion of baseline assessments, participants will be randomised to either the CORE program or a 'usual care' group. The CORE program will include a 6-month exercise training program supervised by an Exercise Physiologist at the Baker Heart and Diabetes Institute. The usual care group will carry on with healthcare from their usual healthcare provider(s) for 6 months. Participants will then complete two follow-up study visits following completion of the 6-month intervention period, with identical procedures to the baseline study visits. Study Duration: This study involves two baseline study visits in month 1, followed by two study visits in month 7. Participants randomised to the CORE program will be asked to attend the Baker Heart and Diabetes Institute on a weekly basis for supervised exercise training sessions. However, the supervised exercise training sessions will be provided by a mix of in-person, video-conferencing and tele-health modes depending on each participants availability and needs.

Study Rationale: Breast cancer (BC) is the most common diagnosed cancer in Australian females (BreastScreen Australia Monitoring Report 2024, Summary, 2024). Although the 5-year relative survival from a stage 1 - 3 BC diagnosis is improving due to earlier screening and more targeted treatment plans (Breast Cancer in Australia, 2012), females with a previous BC diagnosis are more likely to develop cardiovascular disease (CVD) or neurocognitive disease than age-matched counterparts without a previous BC diagnosis (Lange et al., 2019). Aging is a major risk factor for CVD (Deaths in Australia, Leading Causes of Death, 2024) and neurocognitive disease (Dementia in Australia, Summary, 2024). Australians over the age of 65 years old currently account for 16% of the population, but this is expected to increase to 23% by 2066 (Older Australians, Demographic Profile - Australian Institute of Health and Welfare, 2024). Furthermore, the majority (69%) of BC cases are diagnosed in females aged 40-69 (Breast Cancer in Australia, 2012). As such, the number of females diagnosed with BC is expected to increase given the ageing population, and a as result, so too will the number of long-term BC survivors diagnosed with either CVD, neurocognitive disease, or both. Therefore, effective policies and therapeutic strategies are needed to minimize the growing societal and economic burden of CVD and neurocognitive disease, with particular focus on high-risk populations like BC survivors. The clustering of CVD risk factors and the cardiotoxic effects of anti-cancer treatments (e.g. anthracycline-based chemotherapy and radiotherapy to the left side of the chest) contribute to the higher prevalence of CVD in BC survivors (Yeh \& Bickford, 2009). While the exact mechanisms are currently unclear, the increasing burden of neurocognitive disease and cancer-related cognitive impairment (CCRI) in BC survivors may be related to the 'vascular'-toxic effects of anti-cancer therapies (Cameron et al., 2016). Indeed, both arterial stiffness and vascular function are impaired in BC patients within 15 months of initiating anti-cancer therapies (Anastasiou et al., 2023), which may be followed by neurovascular dysfunction, brain hypo- or hyper-perfusion and impaired glymphatic clearance, leading to the onset of cerebral small vessel disease and brain atrophy (Andjelkovic et al., 2023; Reeve et al., 2024). Neurovascular units tightly regulate cerebral blood flow (CBF) to match the metabolic demands of the brain and maintain normal cognitive function (Iadecola, 2017), but damage to the neurovascular unit is associated with a reduction in CBF and the progression of and vascular-related cognitive impairment (Santisteban et al., 2023; van Dinther et al., 2024). Accordingly, resting CBF may be a clinically useful biomarker to identify patients at risk of vascular-related cognitive impairment (van Dinther et al., 2024). However, little is known about the long-term trajectory of CBF and neuro Покажи пълното описание...

Inclusion Criteria: * Female * Aged 45 - 75 years old at study enrolment * Diagnosed with stage 1 - 3 breast cancer 5 - 10 years prior to study enrolment * Have received potentially toxic chemotherapy, including: * Anthracycline (any dose) * Trastuzumab (Herceptin) in breast-cancer with the HER2 mutation OR * Tyrosine kinase inhibitors (e.g. sunitinib) OR * Left chest radiotherapy * ≥ 1 'traditional' CVD risk factor (I.e., Hypertension, dyslipidaemia, diabetes, obesity, smoking or family history of CVD) (Mehta et al., 2023) * 'Physically inactive', not meeting Australian physical activity guidelines for adults or regularly participating in structured exercise training (Care, 2024). * Eligible for Medicare * Willing to provide written informed consent to participate in the study Exclusion Criteria: * Diagnosed CVD or stage B heart failure * Diagnosed neurocognitive or cerebrovascular disease * Diagnosed atrial fibrillation or cardiac arrythmia * BMI ≤ 18.4 kg∙m2 * Any other contraindications to exercise testing and training that make participation in this study unsafe, determined through medical screening * Unable to speak and understand the English language * Contraindication to brain MRI * Participating in another clinical research trial where randomized treatment would be unacceptable * Oncologic (or other) life expectancy ≤ 12 months or any other medical condition (including pregnancy) that results in the belief (deemed by the Principal Investigator) that it is not appropriate for the patient to participate in this trial.