Mechanical suppression of osteolytic bone metastases in advanced breast cancer patients: a randomised controlled study protocol evaluating safety, feasibility and preliminary efficacy of exercise as a targeted medicine

Bone metastases are generally incurable and clinically problematic, yet are present in over 80% of patients with advanced breast cancer [1, 2], representing a debilitating stage of disease with very poor patient prognoses during palliation, and one of the leading causes of breast cancer mortality among women worldwide [3‐5]. Osteolytic (lytic) bone metastases, in particular, present a considerable challenge to patients and clinicians due to rapid microarchitectural deterioration of affected skeletal sites through tumour-driven dysregulation of bone metabolic activity in favour of excess resorption [1, 6, 7]. Metastatic breast carcinomas commonly deposit in trabecular (cancellous) regions of bone [6, 8‐10], such as the skull, ribs, spine, pelvis and proximal and distal segments of long bones, owing to their strong affinity to red bone marrow [2, 7, 9, 11]. Of direct relevance, the majority of these skeletal structures are characteristically load-bearing [12‐14], thus any accelerated bone loss and heightened fragility following tumoural infiltration [8, 10, 15‐17] has immediate consequences for patients with cancer if left untreated or unmanaged. Consequently, this destructive skeletal process leads to increased patient morbidity and mortality, with heightened fragility, increased risk of spinal compression, potential development of hypercalcaemia, increased bone pain and increased fracture risk [7, 17‐19]; whilst simultaneously creating a localised microenvironment conducive to tumoural growth and invasion within affected bone sites [20‐23].

Chemotherapy, hormone therapy, radiotherapy and anti-resorptive medications are the primary therapeutic agents used in breast cancer palliation to delay disease progression, alleviate bone pain and associated symptoms, preserve skeletal integrity and extend survival [24‐32]. Whilst effective, these treatments produce well-documented side effects to varying degrees, which can lead to dose limitation or cessation, subsequently restricting their full clinical utility. For example, patients with advanced breast cancer with bone metastases are provided with bone strengthening (anti-resorptive) medications such as bisphosphonates or denosumab to fortify bone through induced sclerosis leading to increments in bone density [33, 34]. While efficacious in the mid-term; long-term use of these medications themselves eventually generate skeletal fragility in the absence of a discontinuation period [35‐37], which is not a clinically viable option for patients with advanced cancer and osteolytic bone metastases.

Bone is highly adaptive and osteogenically sensitive to its mechanical environment, principally through muscular contraction of neighbouring muscle, but also from impact and gravitational forces acting upon the skeleton during human movement and from external loads [12, 38, 39]. Up-regulation of osteoblastic activity through exercise may therefore allow mechanically driven regulation of bone metabolism (i.e. osteocyte-mediated coupling of osteoblast and osteoclast activity) to counteract tumour-driven dysregulation which could have two key benefits: (1) to preserve bone strength through anabolic morphological (material and structural) adaptations; and (2) to interfere with tumoural processes that blunt osteoblastic formation and promote osteoclastic resorption, thus potentially suppressing tumour growth in affected skeletal sites. Preclinical studies [8, 13, 40, 41] have explored this potential relationship in rodent orthotopic models, implanting human breast cancer cells into trabecular skeletal tissue in order to induce osteolysis in the load-bearing tibia. Impressively, when comparing loaded and non-loaded tumour-affected tibiae within host rodents, repeated bouts of externally controlled mechanical compression preserved skeletal integrity (0% versus 71% degradation for loaded and unloaded conditions), blunted tumour-mediated osteolysis, and significantly suppressed tumour growth by approximately 80% [8, 13] in the absence of muscular influence. In addition to osteocyte-driven osteogenic signalling, the inextricable anatomical, mechanical, metabolic and pleiotropic link between muscle and bone [12, 38, 42, 43] provides another avenue of therapeutic osteogenic and anti-tumour potential not yet explored [14, 44‐47]. The voluntary activation of muscle surrounding skeletal lesions may deliver anabolic cytokines and myokines (secretome cross-talk) to lesion sites [14, 44, 45, 48] to countenance catabolic tumour-mediated processes [46, 47, 49, 50]. Accordingly, mechanical signals propagated by muscle contraction may concurrently stimulate osteocyte-mediated metabolic activity and myokine-cytokine secretome cross-talk to promote osteogenesis while modulating tumoural behaviour and biology in order to slow tumour growth [14, 45, 48‐51].

Human clinical trials have yet to be implemented in this space, owing to a historical and misplaced belief that patients with advanced cancer and bone metastases should be excluded from exercise programmes and synonymous research due to increased risk of skeletal complications or other potential adverse events [52‐54]. Formative work by Galvão and colleagues [51, 55‐58] demonstrated the safety and feasibility of delivering supervised exercise to patients with advanced prostate cancer and bone metastases, avoiding exercises that placed direct or targeted stress on bones with identified lesions. Separate work by Rief and colleagues [59, 60] demonstrated the safety and feasibility of physiotherapy-instructed spinal isometric training in isolation for patients undergoing palliative radiation therapy for spinal bone metastases, though in a small cohort of heterogeneous patients with cancer and disparate lesion types. Taken together, these studies illustrate the potential for preclinical studies to be translated to human patients; specifically models of advanced breast cancer with osteolytic bone metastatic disease. This is particularly important as animal studies do not always translate to the human condition, particularly in exercise-mediated bone adaptation studies, often due to poorly designed human trials for equivalency [12, 61‐63].

Given that bone metastases remain one of the leading causes of breast-cancer-related deaths worldwide, additional and novel interventions to target osteolytic lesions in skeletal tissue are highly clinically relevant. Expanding on our prior work, the aim of this study is to (1) assess the safety and feasibility of a supervised and individually tailored resistance, aerobic and flexibility exercise programme that includes targeted spinal isometric training in patients with advanced breast cancer and osteolytic bone metastases; (2) explore the preliminary efficacy of the exercise programme to slow tumour growth and tumour biomarker activity in target osteolytic spinal lesions and (3) examine the broader efficacy of the exercise programme to preserve muscle and bone mass, improve physical fitness, enhance physical function, reduce cancer-related fatigue and increase quality of life. It is the working hypothesis of this study that the exercise programme will be safe and feasible; will show signs of tumoural suppression and/or favourable alterations in tumour biomarkers; and will lead to positive physical and psychosocial outcomes for patients. If successful, the outcomes of this trial will be used to improve clinical knowledge pertaining to exercise prescriptions for patients with advanced cancer who have metastatic carcinomas and high disease burden, and will be used as a foundation for future phase II and phase III efficacy-focused human clinical trials to establish the anti-cancer effects of exercise. It is anticipated that this new information will aid in the establishment and/or renewal of clinical exercise guidelines for the management of cancer across the disease spectrum.

Complications arising from bone metastases present a major clinical issue for patients and clinicians alike [18], with bone metastases evident in over 80% of metastatic breast carcinoma (advanced breast cancer) cases. Currently, it is a treatable, yet incurable stage of disease, thus strategies that delay disease progression and extend survival without an adverse impact on quality of life or excessive clinical risk are highly sought after. Exercise medicine is an emerging field in oncology (i.e. exercise oncology), known for its neo-adjuvant and adjuvant role for symptom control, reduction of treatment toxicity and ability to improve the tolerance of and recovery from intensive cancer treatment regimens [48, 52, 65, 94‐103]. Recent insights are beginning to illustrate the synergistic (assistive) and targeted (independent) role of exercise medicine in patients with cancer throughout the disease trajectory to assist with delaying disease progression and plausibly extending overall survival, largely through preclinical studies ([13, 14, 47‐51, 70‐74, 83, 104‐118]) or epidemiological associations [119‐134]. Most promisingly, exercise seems to be able to favourably modulate tumour biology towards improving cancer control, including skeletal orthotopic models, highlighting a key candidate intervention for human, patient-focused studies to target and pursue [14, 51, 135].

Exercise medicine may positively alter tumour biology through numerous mechanical and non-mechanical mechanisms targeting local, neighbouring and systemic pathways in response to various modes and dosages of activity [70‐74, 105, 110, 112, 113, 136]. Specifically, exercise regulates endocrine-paracrine activity, systemic immune function (pro-inflammatory and anti-inflammatory activity), blood glucose and blood cholesterol levels, insulin response and body composition [97‐101, 106, 116, 137, 138]. Exercise can also epigenetically modulate tumour vasculature (morphology and permeability), tumour cell proliferation (growth and distribution), telomeres (length and enzyme activity), platelet functions (cloaking and adhesion) and oxidative stress capacity [49, 50, 113, 139‐144]. Whilst exercise concurrently acts across many of these regulatory and modulatory pathways, the targeted suppression of tumour formation, growth and invasion through mechanically driven epigenetic alterations, and muscle driven endocrine-paracrine activity is of particular interest. Indeed, biological alterations from biomechanical stimuli and biochemical responses (an emerging field known as “mechanomics”, applied to exercise oncology) [8, 12, 118, 145, 146] presents clinicians and allied health practitioners (such as clinical exercise physiologists) with a unique opportunity to suppress the growth and spread of metastatic breast carcinoma in bone through targeted exercise interventions.

Compelling new insights from metastatic orthotopic animal models demonstrate the ability of mechanical stimulation (i.e. repeated bouts of external compression) to interfere with tumour-driven remodelling in skeletal tissue containing human breast cancer cells [13, 41]. Exercise is a dose-dependent mechanical stimulant (with evidence of dose-response) that can be safely prescribed to patients with advanced prostate cancer and sclerotic metastases [14, 48, 51, 55, 57, 58, 106]. It is of equal interest to explore whether this can also be achieved in patients with advanced breast cancer with osteolytic metastases, who experience skeletal fragility at much faster rates than their counterparts with sclerotic metastases. Furthermore, it is of interest to explore whether skeletal integrity and tumoural suppression are prevalent in humans, as preclinical studies do not always translate to the human condition [61‐63]. Indeed, it is not yet known whether disease-affected bone sites adapt to mechanical stimuli to the same order of magnitude or in the same morphological manner as unaffected healthy bone sites; nor is it clear how muscle surrounding lesions may adapt given the catabolic tumour microenvironment.

Accordingly, this study is our evaluation of the feasibility, safety and preliminary efficacy of a modular, multi-modal exercise programme, coupled with spinal isometric training, to provide a non-invasive, low-cost, innovative and scalable therapy in the management of advanced breast cancer. Examination of the modulatory potential of direct and targeted mechanical loading of osteolytic spinal bone metastases will also be conducted by quantifying tumour morphology and systemic activity of metastatic biomarkers (HIF-1α, local hypoxia; TGF-β, transformation growth-like factor), whilst also exploring whether targeted exercise can reduce bone pain, preserve neighbouring skeletal mass and structure (i.e. unaffected vertebrae above and below affected lesion sites) and reduce or avoid exacerbation of bone pain. Additionally, this study will also examine the multifaceted and broader effects of exercise participation by patients with advanced breast cancer on muscle and bone health (mass and strength), adiposity (subcutaneous and visceral), physical fitness and function and psychosocial health (focusing on quality of life).

Outcomes of this study will inform future research into sclerotic, osteolytic or mixed lesions across solid and haematological malignancies (such as multiple myeloma), particularly in patients with cancer and extensive or widespread bone metastases and high disease burdens who would otherwise be contraindicated for exercise. Optimistically, the generalisability of this exercise programme across models seems achievable, given it is supervised, individualised and tailored to each patient’s unique condition, and thus auto-regulated accordingly [48, 51]. The mechanistic insights of this study may also inform the development of effective pharmaceutical or medical treatments with avenues to target bone metastases. Given the preliminary efficacy (phase 1) nature of this pilot study, the results will be used to pursue larger phase II and III clinical trials to determine the efficacy of the programme in tumour suppression or regression in patients with osteolytic bone metastases secondary to breast cancer, and to develop an exercise program that can inevitably and immediately be delivered in clinical and community settings by accredited or certified clinical exercise physiologists.