Bone-targeted agents and skeletal-related events in breast cancer patients with bone metastases

Introduction

One of the first to observe the propensity of breast cancers to form bone metastases was the surgeon, Stephen Paget, who described the site distribution of metastases in 735 cases of breast cancer proposing that the association of metastases in bone from primary breast cancers could not be by chance alone. He wrote in the Lancet (1889): “The evidence seems to be irresistible that in cancer of the breast, the bones suffer in a special way, which cannot be explained by any theory of embolism alone” [ ].

Paget popularized the “seed and soil” hypothesis, writing: “the best work in pathology of cancer is done by those who … are studying the nature of the seed … observations of the properties of the soil may also be useful.” This notion that there might be a local reason for metastases to develop at specific sites beyond a chance colonization following embolism was given a mechanistic anatomical twist by Batson [ ] who described the connection between the vertebral venous plexus and the bone marrow spaces, hypothesizing a retrograde spread that would allow metastases from a primary prostate cancer to lodge preferentially in the lower vertebrae. Once within the marrow space, metastases had a blood supply for further growth.

Mundy took the “seed and soil” idea one step further by adding the concept of a “vicious cycle,” with products from tumor-induced breakdown of bone leading to stimulation and further growth of malignant cells [ , ].

Incidence

Prevalence and survival

Coleman and Rubens [ ] reported (1987) that in 587 patients dying of breast cancer, 69% had radiological evidence of bone metastases before death compared to lung and liver metastases (27% each). In this report of 2240 patients who presented with breast cancer and were followed for a median of 5 years, 47% of those relapsing at distant sites relapsed in bone.

National Surgical Adjuvant Breast and Bowel Project (NSABP) data are similar and showed that bone metastases account for the highest proportion of first sites of distant relapse in breast cancer patients recurring after adjuvant therapy. Nearly half of the patients who developed distant metastases did so in bone either as the sole site of recurrence or simultaneously with other sites of disease. The annual rate of bone metastasis development was higher in node-positive patients (approximately 2% per annum) than in node-negative (approximately 1% per annum) and higher in ER-positive patients than in ER-negative [ ]. Recurrence rates in bone in later and current NSABP trials are lower than at the time of the above NSABP report, possibly due to a reduced rate of recurrence at all sites (except the central nervous system) because of more effective therapies.

The survival of patients with bone metastases also appears to be improving at a rate that cannot be explained by diagnostic lead time alone. Over 30 years ago we assessed the median survival of patients diagnosed with bone metastases to be around 16 months. Survival was greater for patients originally presenting with a Stage 1 primary than those presenting with a Stage 2 primary which in turn was greater than for those presenting with a Stage 3 primary [ ]. This phenomenon was originally termed “biological predeterminism” and described the generally slower growth of metastases from smaller primary tumors with the idea that small tumors were not necessarily small because they were “early” but because they were growing slowly. The phenomenon is likely to be explained by differing intrinsic genetics of smaller presenting tumors compared to larger ones.

In the NSABP series of patients diagnosed in the 1990s the median survival from diagnosis of bone metastases was between 18 and 20 months [ ]. During a similar observation period, Coleman and Rubens reported a median survival in the order of 24 months [ ].

However, these patients had also had metastatic sites other than bone. Patients with bone-only recurrence can survive much longer. Ahn et al. in a South Korean series of patients with bone-only recurrence reported a median survival of 55.2 months with a 10-year survival rate of 34.9% [ ]. They also point out that patients having solitary bone metastases and a positive estrogen receptor and who receive bisphosphonate therapy survived longer than the median.

It has recently been shown that the number of circulating tumor cells detected in patients with metastatic breast cancer before they receive treatment is an independent predictor of progression-free survival and overall survival [ ].

Diagnosis and types of bone metastases

The clinical diagnosis of bone metastases can vary from the obvious to the uncertain. Patients who have had a primary breast cancer and who develop bone pain, evidence of multiple osteolytic, osteosclerotic, or mixed lesions on X-ray with typical bone scan changes showing multiple areas of asymmetric uptake, and elevation of bone markers usually require no biopsy or further testing for diagnostic certainty although biopsy for an update of biomarkers may be worthwhile (vide infra).

Much harder to diagnose is the patient who may be asymptomatic but has bone scan findings suspicious of metastases but who has no confirmatory X-ray changes. Osteoporosis with vertebral fractures can present this way and indeed the two diagnoses may be concurrent. If bone biopsy is impractical or unsuccessful, sometimes serial scanning will clarify the diagnosis. The patient can usually start hormone therapy while the diagnosis is being made. Patients with rarer bone diseases such as Paget's disease of bone or bone histiocytosis usually have typical X-ray changes. The patient with a solitary area of increased uptake on bone scintigraphy will require an attempt at bone biopsy under CT guidance for diagnosis.

Some of the hardest cases to diagnose are women who have several areas of uptake on a bone scan but who are asymptomatic with either no changes or minimal radiological changes. In these instances, biopsy under CT or MRI guidance can be helpful, although inconclusive biopsies are a frequent irritant to patient and oncologist alike. Sometimes a second malignancy such as myeloma, bladder, renal, lung, or colonic cancer will metastasize to bone in a patient who has had a previous primary breast cancer.

Generally these days, biopsy should be seriously considered in all patients with bone metastases as demonstrated by Simmons et al. [ ] who have shown a 10% incidence of benign disease, a 40% change in ER status, and an 8% change in HER status resulting in 20% of patients having a change in management.

Clinical consequences of bone metastases

Bone metastases in the absence of fracture can be asymptomatic but often lead to a low to moderate aching pain. This pain may fluctuate between anatomical sites, sometimes over a few days. In the humerus and femur the pain is exacerbated by weight bearing and can be a sign of impending fracture. Severe localized back pain can herald a vertebral fracture and spinal cord compression. Vertebral fracture is particularly common and may occur in the absence of metastases. We have shown that patients presenting with breast cancer have a four to five times higher rate of vertebral fracture on follow-up than an age-matched group of well women [ ]. This is most likely related to chemotherapy-induced premature menopause with accelerated bone resorption. With the increased use of aromatase inhibitors, this increased vertebral fracture rate will continue.

Trials of adjuvant aromatase inhibitors versus tamoxifen in early breast cancer show that even without specifically looking for fractures by performing regular thoracic vertebral X-rays, after 5 years of follow-up some 3%–4% of patients on aromatase inhibitors sustain a fracture—a figure closely approximating the absolute benefit over tamoxifen in disease-free survival at 5 years. The fracture rate appears to stabilize after aromatase inhibitors are stopped [ ].

The majority of patients with bone metastases will suffer a fracture or fractures at some point during the course of their illness and an absence of bone pain prior to the fracture event is not an indicator of less likelihood of this happening. Patients who have one fracture are more likely to fracture again. Prior to the routine use of bisphosphonates, hypercalcemia would occur in about 25% of patients. With the widespread use of bisphosphonates, hypercalcemia now occurs more commonly as a terminal event. From time to time, a patient on additive hormone therapy will develop hypercalcemia as a “flare phenomenon.” Cord compression due to vertebral fracture or a paravertebral mass occurs in 1%–3% of patients with bone metastases from breast cancer.

Response to treatment in bone metastases

Assessing response to treatment in patients with bone metastases can be difficult since observation of diminution of a tumor mass within bone cannot be assessed within 2 or 3 months as it often can at other sites. Hybrid PET/CT imaging may turn out to be useful here but more studies are needed [ ].

On occasions, lytic bone metastases will heal over and the bone will normalize over a period of 12–18 months. More frequently, in a responding patient the area of the lytic metastasis will show a rim of sclerosis on X-ray indicating new bone formation. Responding sclerotic bone metastases may show little change over many years of observation.

Bone scanning can be deceptive for disease monitoring and is best used for identification of anatomical sites of disease (for example, for radiation field planning for bone pain) rather than assessment of response since sites where new bone formation is occurring will display on the gamma camera as areas of increased uptake. Even the diagnosis and reporting of “new sites of disease” on a bone scintigraphy report does not necessarily mean progressive disease since these new sites of uptake may have been undetectable on initial scanning but with increased bone turnover associated with healing they may become visible on follow-up scanning due to enhanced tumor: background radionuclide uptake ratios.

Elevations of serum alkaline phosphatase and bone markers such as serum or urine N- or C-telopeptides are suggestive of progression of disease in the presence of increasing pain. A bone scan showing new areas of uptake in the absence of symptoms can occur with a flare reaction to additive hormone therapies.

Sclerotic bone metastases can be very difficult to assess since extension of sclerotic areas is suggestive of disease progression but in the absence of new symptoms can be compatible with slow healing and clinically stable disease. In these circumstances it is wise to avoid changing therapy until some additional evidence occurs. The clinical diagnosis of response in bone metastases is an old problem, and again, more studies are required [ ].

Predicting bone metastases

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