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Consultant Clinical Oncologist
Velindre NHS Trust
The management of the patient with metastatic breast cancer is a challenging process. There are now numerous treatment options that have to be carefully tailored to the individual according to various factors such as age, performance status, symptoms, site of metastases, hormone and HER2 (human epidermal growth factor receptor 2) receptor status. As a consequence of this, the prognosis of metastatic breast cancer continues to improve, and, in particular, patients with disease confined to bone may live for several years, with a median survival of 2.5 years.(1)
Bone metastases represent the commonest site of metastatic spread from breast cancer. Up to 80% of patients with metastatic breast cancer will develop bone metastases during the clinical course of their illness.(2) Bone metastases may cause significant morbidity and disability, with clinical manifestations such as bone pain, pathological fracture, hypercalcaemia and spinal cord compression.
The radiological appearance of bone metastases from breast cancer may be osteoblastic, osteolytic or mixed in appearance. The sites most often affected are within the axial skeleton – the spine, sacrum, pelvis and skull. In general, a bone scan (see Figure 1) is a more sensitive method for detection than plain films. In patients clinically suspected to have bone metastases who have negative bone scans, an MRI (magnetic resonance imaging) or CT (computerised tomography) scan of the symptomatic region should be performed.
Pathophysiology of bone metastases
The fundamental process of disruption of bone architecture occurs as a result of an imbalance of the amount of bone laid down (ie, bone resorption).(3) Tumour cells secrete growth factors and cytokines that stimulate osteoclast activity, which increases bone resorption. The activity of osteoblasts (new bone formation) and osteoclasts, which is normally closely linked, becomes uncoupled. Ultimately this leads to a reduction in skeletal integrity and an increase in skeletal complications.
Treatment of bone metastases
The treatment of bone metastases in breast cancer may be local or systemic. Radiotherapy remains an important and effective local treatment with minimal morbidity and rapid pain relief. The management of spinal cord compression, an oncological emergency, is usually treated with radiotherapy – a palliative dose of 20Gy in five fractions prescribed at the depth of the cord, as measured on the MRI scan. High-dose steroids are also indicated (eg, dexamethasone 16mg/24h). A neurosurgical opinion should be sought when there is a single level of cord compression. In early presentations of cord compression, complete neurological recovery may occur (see Figure 2).
The other indication for which to consider local surgery is in patients at high risk of pathological fracture, defined as bone metastases in long bones with cortical destruction of >50%.
Systemic treatments include analgesics and disease-specific therapies such as chemotherapy, hormone therapy and antibody therapy.(4) Biphosphonates have become part of the standard of care in the management of bone metastases in breast cancer and will be discussed in greater depth.
Biphosphonates are analogues of pyrophosphate, characterised by a phosphorus–carbon–phosphorus (PCP) bond.(5) This stable bond binds to mineralised bone matrix and inhibits bone turnover by decreasing bone resorption. There are three generations of biphosphonates with differing molecular mechanisms of action determined by their structural appearances. They each have a different side-chain attached to the central carbon atom. First-generation biphosphonates, such as clodronate, are non-nitrogen-containing and are thought to be incorporated into adenosine triphosphate (ATP) analogues, which inhibit ATP-dependent intracellular enzymes.(6) The nitrogen- containing second- and third-generation aminobiphosphonates, such as zoledronate and ibandronate, inhibit farnesyl diphosphate synthase in the mevalonate pathway, disrupting the signalling functions of key regulatory proteins.(7,8) There is in-vitro evidence for the antitumour effects of biphosphonates, such as induction of apoptosis and inhibition of cell growth, invasive behaviour and angiogenic factors.(4,9)
Biphosphonates have been shown to be effective in preventing and treating skeletal-related events (SREs) from metastatic bone disease.(5) Clodronate was initially widely used because of its oral preparation and the evidence that it significantly reduced the incidence of skeletal events such as hypercalcaemia and the incidence of vertebral fracture.(10) However, gastrointestinal side-effects and large tablet size have limited patient tolerability of this drug.(11)
In a double-blind, placebo-controlled trial of intravenous (IV) pamidronate in breast cancer patients, it has been shown that the risk of any SRE (ie, pathological fracture, need for RT or surgery and hypercalcaemia) is significantly decreased with monthly infusions of pamidronate, and this effect is maintained for at least two years.(12) Recently, zoledronic acid (4mg) was found to be significantly more effective than pamidronate (90mg), reducing the risk of developing an SRE by an additional 20% (hazard ratio 0.799; 95% CI 0.68–0.98; p=0.025), as assessed by the Anderson and Gill multiple-event analysis.(13) Both treatments were tolerated equally well, common adverse events being bone pain, nausea and fatigue.
Ibandronate has been evaluated in both oral and IV preparations in the treatment of bone metastases in breast cancer in double-blind, placebo-controlled trials. Efficacy was measured by the skeletal morbidity period rate (SMPR), defined as the number of 12-week periods with new bone complications. Compared with placebo, IV ibandronate (6mg) significantly reduced the SMPR by 40% (p=0.004), as assessed by multivariate Poisson regression analysis.(14) It was also associated with decreased bone pain scores and analgesic usage. The oral form (50mg/day) reduced the relative risk of new bone events by 39% compared with placebo and was apparently well tolerated.(15)
The treatment of bone metastases requires a multimodality approach. The optimal timing, dosing and choice of biphosphonate remain controversial. Ultimately, it should depend on factors such as efficacy and tolerability as well as quality of life and health economics. Recent reports of renal toxicity(16) and rare events of osteonecrosis(17) with certain biphosphonates are concerning. Results of comparative trials are needed to clarify these issues.(18) The role of adjuvant treatments in preventing bone metastases is currently being explored and is likely to make the greatest impact so far in the management of bone metastases from breast cancer.