Management of Bone Metastases in Breast Cancer

Introduction

Bone is the most common site of first recurrence in patients with breast cancer, affecting up to 70% of patients with metastatic disease. Patients with bone metastases are at high risk for developing clinically significant complications, often referred to as skeletal-related events (SREs), including radiation therapy or surgery to prevent or treat a bone fracture and palliate pain, pathologic fracture, spinal cord compression, and hypercalcemia, with pathologic fractures and the need for radiation therapy being the most commonly observed SREs. In studies conducted in the 1990s, before the introduction of bone-targeted agents such as the bisphosphonates, the proportion of patients with bone metastases who experienced at least one SRE after a median follow-up of 21 to 24 months was 64% in those with breast cancer, with an SRE rate of 3 to 4 per year. Data collected from routine clinical practice in the 2010s continue to support the relevance of SREs as an important clinical issue in patients with bone metastases, with a high proportion of patients still experiencing SREs despite the advancements in treatment of the underlying cancer that have emerged since the 1990s. Cancer registry data suggest that the lives of patients with metastatic breast cancer who develop SREs are significantly shorter than those of similar metastatic patients who do not develop skeletal complications. Complications stemming from bone metastases can be life-threatening and are a major source of morbidity for patients, making their prevention and treatment a vital component of comprehensive oncologic care.

The development of bone metastases is common to all breast cancer subtypes but is especially prevalent in estrogen receptor–positive disease, in which bone metastases are found in more than 80% of patients with distant relapse compared with 50% in patients with breast cancer that is negative for hormone receptor and HER2 expression (triple negative). Up to 30% of patients with metastatic breast cancer relapse exclusively in the bone without visceral involvement (bone-only disease). Breast cancer predominantly metastasizes to the axial skeleton, particularly the spine (87%), pelvis (63%), skull (35%), and ribs (77%), as well as the proximal humeri and femora (53%), rather than to the distal appendicular skeleton (1%). The lumbar spine is the single most commonly involved site, accounting for up to 20% of osseous metastases. This pattern of metastatic spread to bone reflects the distribution of the red bone marrow, a highly vascular tissue containing hematopoietic stem cells and an active microenvironment that promotes cellular growth.

This chapter addresses the pathophysiology, clinical presentation, diagnosis, and treatment of bone metastases with surgery, radiotherapy (RT), and systemic osteoclast inhibitors. Chapters 61 to 63 discuss chemotherapy, endocrine therapy, and targeted treatment options for patients with bone metastases, which are not discussed here. However, poor systemic disease control remains the greatest risk factor for progression of bone metastases and for the development of SREs. Effective cytotoxic and targeted antitumor therapies are thus essential in the management of all patients with bone metastases.

Pathophysiology

Bone is a highly specialized, vascularized, and innervated connective tissue containing an unmineralized matrix, known as osteoid, composed predominantly of type I collagen and a mineralized matrix of hydroxyapatite crystals. The mineralized compartment encompasses the marrow space containing multiple cell types including osteoblasts, osteoclasts, bone marrow stromal cells, immune cells, mesenchymal stem cells, adipocytes, fibroblasts, endothelial cells and hematopoietic cells, all interspersed within a fibrous stroma containing fat and interstitial fluid.

Under physiologic conditions, bone is in a state of constant remodeling, maintaining a dynamic balance between osteoclastic (resorptive) and osteoblastic (bone-forming) activity. Bone resorption is mediated by osteoclasts, which are multinucleated giant cells derived from granulocyte-macrophage precursors, while bone formation is carried out by osteoblasts, derived from mesenchymal fibroblast-like cells. The receptor activator of NF-κB ligand (RANKL) and RANK pathway mediates osteoclast activity and is a key regulator of bone metabolism. RANKL is produced by osteoblasts, bone marrow stromal cells, and other cells under the control of various growth factors, hormones, and cytokines including parathyroid hormone (PTH), parathyroid hormone–related peptide (PTHrP), progesterone, prostaglandins, and interleukins. By binding to the RANK receptor expressed on osteoclasts and preosteoclasts, RANKL controls the development, formation, activation, and survival of osteoclasts and plays a primary role in stimulating osteoclast-mediated bone resorption. As the only known ligand for the RANK receptor, RANKL is indispensable for normal osteoclast activity. Osteoblasts and stromal cells also produce osteoprotegerin (OPG), a soluble decoy receptor that binds to and inactivates RANKL preventing osteoclast activation. The RANKL/OPG ratio is the primary determinant of osteoclast activity in physiologic as well as several pathologic conditions, including cancer.

In patients with metastatic bone disease, bone formation and resorption are uncoupled, leading to both osteoblastic and osteolytic lesions. Bone resorption largely occurs through tumor-mediated osteolysis induced by the secretion of RANKL as well as other osteoclast-stimulating factors; direct resorption of bone by cancer cells is less common and probably only occurs very late in the evolution of the disease. The process of bone resorption leads in turn to the release of growth factors from the bone matrix including type I collagen, osteocalcin, insulin-like growth factors, transforming growth factor (TGF)-β, as well as calcium, which may stimulate cancer cells directly, leading to the hypothesized vicious cycle of bone destruction and progressive tumor growth.

PTHrP is often the primary culprit responsible for RANKL release and bone destruction in breast cancer patients. This protein was originally identified as a hypercalcemic factor in several cancer types, including from the breast. PTHrP has 70% homology to the first 13 amino acids of PTH, the major hormone responsible for calcium homeostasis, and binds to the common PTH/PTHrP receptor. The binding of PTHrP to receptors on osteoblasts and marrow stromal cells results in the production of RANKL, causing increased osteoclast differentiation and activation and the initiation of the vicious cycle. Approximately 80% of hypercalcemic patients with solid tumors have detectable plasma PTHrP concentrations.

The pathogenesis of osteoblastic metastases is less well understood than that of osteolytic lesions. As with osteolytic lesions, osteoblastic bone metastases are the result of dysregulated bone metabolism. Preclinical data suggest that, in osteoblastic lesions, an initial phase of bone destruction occurs, as evidenced by the presence of elevated bone turnover markers in patients with prostate cancer metastatic to the bone, which is then followed by extensive bone formation. Endothelin-1, a vasoconstrictor peptide produced by prostate and breast cancer cells, is thought to be a key stimulator of the osteoblast proliferation that drives the development and progression of osteoblastic metastases.

Clinical Presentation

Pain is the most common presenting symptom of bone metastases and is seen in up to 75% of patients. Bone pain is also the most common cause of cancer-related pain in advanced breast cancer patients, rendering pain control an essential goal of therapy. The mechanisms of pain production are varied and depend on the location of the metastatic foci as well as the type of lesion causing the pain. Nociceptive pain is caused by the local release of cytokines and chemical mediators by tumor cells, periosteal irritation, and stimulation of intraosseous nerves. Neuropathic pain is produced by the direct destruction of nerve tissue by tumors, whereas mechanical pain is caused by pressure or mass effect of the tumor within the bone, leading to loss of bone strength. The use of pharmacologic therapies including nonsteroidal antiinflammatory drugs, opioid analgesics, gamma-aminobutyric acid (GABA) analogs, and corticosteroids are often an important and necessary adjuvant to nonpharmacologic therapies for pain control.

Other common presenting signs and symptoms in untreated patients include pathologic fractures, spinal cord compression, and hypercalcemia. Because bone metastases from breast cancer most frequently include a lytic component, pathologic fracture is the most commonly observed SRE, occurring in up to 60% of patients with metastatic breast cancer to bone in historical series.

Spinal cord compression is a relatively infrequent complication, occurring in only 3% to 5% of patients, and is becoming increasingly uncommon as patients receive bone-targeted treatments to minimize structural damage. Cord compression most commonly occurs through direct extension of a vertebral body metastasis into the epidural space with resultant compression of the spinal cord. Symptoms of spinal cord compression include pain, weakness, and sensory changes, with bowel or bladder dysfunction a late finding. Sixty percent of patients with back pain and an abnormal two-dimensional plain radiograph of the spine will have evidence of epidural disease on magnetic resonance imaging (MRI).

Before effective treatment with bone-targeted and antitumor therapies was introduced, hypercalcemia was observed in up 20% of patients with metastatic breast cancer to bone. More recent studies suggest that hypercalcemia of malignancy is now a much rarer condition, affecting less than 5% of patients with breast cancer. Hypercalcemia of malignancy is thought to occur through several mechanisms, including direct skeletal destruction by tumor and the release of humoral factors secreted by tumor cells, particularly PTHrP. Hypercalcemia can also rarely occur as a complication of hormonal therapies, especially tamoxifen, as part of the flare response. Symptoms and signs of hypercalcemia reflect a variety of gastrointestinal, renal, neurologic, and cardiovascular complications, including constipation, nausea, fatigue, lethargy, coma, and, ultimately, death. The marked decrease in the incidence of malignant hypercalcemia is thought to be due to both more effective systemic treatments for the underlying cancer and the increased use of systemic osteoclast inhibitors including bisphosphonates and denosumab in patients with metastatic breast cancer.

Diagnosis

The diagnosis of bone metastases is suggested by the presence of symptoms, abnormal laboratory values (alkaline phosphatase and calcium), and imaging studies. Imaging studies may include plain radiographs, ^99m Tc bone scintigraphy (bone scan), MRI, computed tomography (CT), and positron emission tomography (PET) with or without CT or MRI. Plain radiographs are often the first test in the evaluation of bone pain because they are inexpensive and specific when abnormal, albeit relatively insensitive (50%) for the detection of bone metastasis. Bone scans are more sensitive than plain radiographs, particularly for lesions with an osteoblastic component as the radiolabeled methylene diphosphonate preferentially accumulates at areas of increased osteoblastic activity. However, limitation in the diagnostic specificity of bone scans requires confirmation of abnormal findings with plain radiographs, CT, MRI, and/or biopsy with a tissue diagnosis being particularly important for patients with a single bone abnormality on imaging. CT imaging provides additional information such as the presence of soft tissue masses and cortical integrity. MRI is superior for identifying spinal metastases, diagnosing radiologic spinal cord compression, and assessing bone marrow involvement.

Fluorodeoxyglucose ( ¹⁸ F-FDG) PET/CT has shown higher sensitivity and specificity than bone scans for detecting osteolytic bone metastases because FDG uptake occurs predominantly in cancer cells providing for a more specific tumor tracer. Recent studies suggest ¹⁸ F-FDG PET has improved sensitivity over bone scans in detecting early bone lesions, as FDG uptake in metastatic tumor cells in the bone marrow may predate the osteoblastic activity required for detection by bone scan. However, PET scans may not be as sensitive as bone scans for detecting osteoblastic metastases, and in particular lesions originating from invasive lobular breast cancers. ¹⁸ F-FDG PET scans have limitations in certain parts of the body, such as the skull, where uptake from the brain may prevent visualization of skull metastases. PET offers an additional advantage for monitoring response to therapy as decreases in PET uptake (SUV _max ) correlate with tumor responses and time to progression. ¹⁸ F-FDG PET/MRI has similar sensitivity as ¹⁸ F-FDG PET/CT but provides better anatomic delineation.

Fluorine-18–labeled sodium fluoride (F-fluoride) PET provides particularly high contrast and spatial resolution as ¹⁸ F-NaF is rapidly absorbed into areas of osteoblastic activity with subsequent incorporation into the bone mineral as a fluorapatite. F-fluoride PET has been shown to be more sensitive than the bone scan as well as ¹⁸ F-FDG PET for detecting bone metastases; however, changes in SUV _max have not been consistently reported to correspond to tumor responses. In addition, F-fluoride PET is useful only for the detection of bone metastases, whereas ¹⁸ F-FDG PET can be useful for detecting metastases in other organs and sites outside the bone.

Treatment

Treatment of bone metastases is aimed at preventing disease progression and symptom palliation, with cure not realistic for patients with metastatic breast cancer. Treatments vary depending on the underlying disease. External beam RT, endocrine treatments, chemotherapy, targeted, and immunologic therapies are all potentially important. Treatment decisions depend on whether the bone disease is localized or widespread, on the presence or absence of extra-skeletal metastases, and on the biologic subtype of the underlying breast cancer. Resistance to systemic treatments can be expected to develop, necessitating periodic changes of therapy in an effort to regain control of the disease. In addition, surgical intervention may be necessary for the structural complications of bone destruction or nerve compression. Bone-targeted agents are included to reduce morbidity and complement all these treatment modalities ( Fig. 60.1 ).