Tis (carcinoma in situ)
T1 (≤20 mm)
T0 or T1 (≤20 mm)
N1mi (nodal micrometastasis, >0.2 mm but ≤2 mm in lymph node)
T0 or T1 (≤20 mm)
N1 (1–3 nodes)
T2 (>20 mm but ≤50 mm)
T2 (>20 mm but ≤50 mm)
N1 (1–3 nodes)
T3 (>50 mm)
T0, T1,T2, T3 (any tumor not invading skin or chest wall)
N2 (4–9 nodes)
T3 (>50 mm)
N1 (1–3 nodes)
T4 (tumor invading chest wall or skin)
N0, N1, N2 (0–9 nodes)
N3 (≥10 nodes)
M1 (distant metastasis)
At the time of diagnosis, about 5 % of all breast cancers are metastatic, with bone being the most common location of distant spread. Thirty percent of women with early-stage breast cancer will eventually experience a recurrence of their breast cancer and subsequently develop metastatic disease . Compared to bone metastases from other malignancies, breast cancer is most likely to become metastatic to the bone years after the initial cancer diagnosis. This is a result of recurrence of a localized breast cancer that spreads to the bone as opposed to having bony metastases at initial presentation.
Breast cancer demonstrates a particular predilection for spread to the bone, with 35 % of women whose only burden of metastatic disease is bony metastases. During the clinical course of metastatic breast cancer, the majority of women, estimated at 71 %, will eventually develop bone metastases . Importantly, women with bone-only metastatic breast cancer have a significantly better prognosis compared to women with visceral metastases. Studies demonstrate a median overall survival of 71 months for women with metastatic bone disease only from breast cancer compared to women who have concomitant bone and liver metastases, whose median survival is 5.5 months [3, 4]. Furthermore, a significant portion of women with bone metastases from breast cancer, estimated at 41 %, have a solitary metastatic lesion, which is associated with increased survival compared to women with multiple bone metastases .
Breast Cancer Subtypes
Historically, breast tumors were defined according to the histologic subtypes of invasive ductal carcinoma, which are most common at 80 %, invasive lobular carcinoma at 15 %, or other less frequent subtypes . Mixed ductal and lobular carcinoma is an infrequent pathologic subtype of breast tumor though it is more likely to become metastatic to the bone compared to either ductal or lobular breast cancer . Breast tumors that recur in the skeletal system only are more likely to be clinically less aggressive, as determined by the pathologist as these tumors tend to be of low or intermediate grade (grade I or II, respectively) and thus have a slower rate of cell turnover .
The subclassification of breast cancer has become much more complicated though prognostically more meaningful due to the discovery of specific receptors on tumor cells. Breast cancer is increasingly being recognized as a very heterogeneous disease, with several different subtypes of cancer that are located within the same organ of the breast. These different subtypes are biologically and behaviorally distinct and microarray analyses have defined discrete patterns of gene expression . Clinically, pathologists utilize three proteins on the surface of breast cancer tumor cells to categorize breast cancer into separate categories that carry both prognostic and predictive importance. These include estrogen receptor (ER ), progesterone receptor (PR) , and human epidermal growth factor 2 (HER2 or HER2/neu).
ER, PR, and HER2 receptor status are initially pathologically defined by immunohistochemistry (IHC) with ER and PR receptors defined by percent of cells expressing the receptor from 0 to 100 %. Tumors with a higher percentage of ER or PR positivity carry a better prognosis that correlates to the higher likelihood of tumor response to endocrine-based therapy. If either the ER or PR receptor status of a breast tumor is negative (or 0 % positivity) this portends a worse prognosis compared to cases where ER and PR status are both positive. However, ER and PR receptor status is typically concurrently either both positive or both negative.
ER negative tumors represent a more biologically aggressive subtype of breast cancer with a higher risk of recurrent disease, and typically with rapid relapse of local disease. Unfortunately there are limited effective treatment options available for patients with recurrent metastatic ER-negative breast cancer.
About 20 % of breast cancers over-express the HER2 protein and are classified as HER2-positive (HER2+) breast cancer. These tumors also represent a biologically aggressive subtype of breast cancer with higher risk of recurrent metastatic disease. Common sites of metastases of HER2+ disease include the brain, liver, and lung . In the past decade, specific targeted therapies, such as trastuzumab, have been designed to target HER2+ breast cancer and have dramatically improved the outcomes of women with this type of breast cancer .
Breast cancers that are both ER+ and HER2− comprise the majority of breast cancer diagnoses at 75 % of cases. These tumors occur more commonly among older postmenopausal women and have a lower risk of relapse following initial therapy when compared to ER− breast tumors .
There are two distinct groups of ER+ and HER2− breast cancer based on their tumor genomic profiles, termed luminal A and luminal B subtypes. These subtypes express genes associated with luminal epithelial cells of normal breast tissue and ER+ breast cancers, including ER, PR, and other genes associated with ER activation. Luminal A tumors, which make up about 40 % of all breast cancers, are the most common subtype and carry the best prognosis as they tend to have high expression of ER-related genes and low expression of proliferation-related genes. Luminal B tumors, which comprise about 20 % of all breast cancers, carry a worse prognosis compared to luminal A tumors due to lower expression of ER-related genes and higher expression of proliferation-related genes [11, 12] (Table 4.2).
Clinical features of breast cancer subtypes, 1986–1992
Luminal A (ER+/HER2−)
Luminal B (ER+/HER2−)
Her2 positive (HER2+/either ER)
Triple negative (ER−/PR−/HER2−)
Age at diagnosis (median)
Overall survival from diagnosis at 10 years
If metastatic, % of women with bone metastases
Time from metastases to death
Available medical treatment options
Hormone therapy (tamoxifen, aromatase inhibitor, fulvestrant)
Trastuzumab (HER2-directed therapy)
ER+ breast cancers harbor the unusual proclivity to recur up to 20 or more years after a woman’s initial breast cancer diagnosis. Notably, in cases of ER+ breast cancer that recur decades after initial presentation, nearly all of these women experience bone metastases . There is a special symbiotic relationship between ER+ breast cancers and the milieu of the bone, with one review demonstrating that up to 90 % of women who have bone-only metastatic breast cancer had ER+ breast cancer .
When ER+ breast cancers recur and metastasize, they typically follow a more indolent course. Women with ER+ breast cancer also have more treatment options available as we are able to take advantage of the dependence of these tumors on estrogen. In these cases we utilize targeted biologic therapies, specifically estrogen blockade with oral agents such as selective estrogen receptor modulators (SERMs) or aromatase inhibitors (AIs) . These are oral therapies that are well tolerated with low side effect profiles. Unfortunately most metastatic ER+ breast cancer will become resistant to endocrine therapy over time, and women eventually require cytotoxic chemotherapy agents, which have more side effects (Table 4.2).
Bone metastases are disproportionately common among ER+ breast tumors and it is important to note that women with ER+ bone-only metastatic breast cancer can live many years with good quality of life, typically treated for years with only oral endocrine therapy. Thus, aggressive management of bony metastases and attention to the prevention of skeletal complications within this group of women are imperative.
Biology and Pathophysiology of Breast Cancer Metastases
The most common type of metastatic bone disease from breast cancer is generally classified as osteolytic , estimated at 80–90 %, which causes bone destruction. Osteoblastic lesions which cause bone formation can occur, although less commonly . Breast cancer cells are thought to activate mature osteoclast formation and to influence the differentiation of hematopoietic cells into osteoclasts that create the destructive osteolytic lesions . Importantly, osteoblastic and osteolytic categories are determined by crude radiologic criteria, and in reality, most breast cancer metastases to the bone are both osteoblastic and osteolytic, and the term “mixed lesion” is sometimes used to describe this phenomenon .
Clinical Presentation of Breast Cancer Bone Metastases
Bone metastases among women diagnosed with breast cancer are very common and present the greatest morbidity for women with breast cancer. The most common sites of bone metastases from breast cancer are vertebrae and pelvis followed by ribs, skull, and femur. The lymph and venous drainage from breast tumors proceed not only into the vena cavae but also through the epidural and perivertebral veins, which may partially explain why breast cancer tends to spread to the axial skeleton and limb girdles predominantly .
Bone pain is experienced by the majority of women, about 80 %, with bone metastases from breast cancer and is one of the key features that determine a patient’s ability to retain good quality of life. Many women describe the pain from bony metastases as deep and aching, with occasional episodes of more acute or sharp pain, and pain that is often worse at night. Narcotic and other analgesic use for pain control from bony metastasis is a significant psychological burden on patients and presents increased costs to the overall healthcare system. Additionally, 37 % of women with bone metastases ultimately require palliative radiation for pain relief alone . While the intensity of pain does not clearly dictate which women are at highest risk of fracture, pain that is worsened by movement can be a sign of an impending pathologic fracture . Pain reduction should be a primary endpoint for any intervention for bone metastases.
Nearly two-thirds of women diagnosed with bone metastases from breast cancer will undergo a skeletal-related event (SRE ), which are defined as a pathologic fracture, spinal cord compression, hypercalcemia, or pain requiring hospitalization or a procedure [20, 21]. SREs occur every 3–4 months among women with bony metastases from breast cancer . For 22 % of women, an SRE is the clinical event that uncovers the diagnosis of metastatic breast cancer . There is evidence that SREs occur disproportionately more commonly during the year immediately following a woman’s diagnosis with metastatic breast cancer than during the subsequent years .
A compilation of two placebo-controlled multicenter randomized trials evaluating pamidronate, an intravenous bisphosphonate, published in 2000, offers the following insights into the frequency of particular SREs among women with metastatic breast cancer to the bone: within the placebo group, hypercalcemia was diagnosed among 13 % of women, 43 % of women received radiation to the bone for various indications, pathologic fracture occurred in 52 % of women, overall 11 % of women required surgery for a pathologic fracture, and lastly 3 % of women incurred spinal cord compression from bony metastases. These statistics underscore the clinical burden of bone metastases upon women with breast cancer . The risk of pathologic fracture can increase with the duration of metastatic involvement. Thus, women with metastatic ER+ breast cancer, who overall have a better prognosis and potentially live longer, have a relatively increased risk of pathologic fracture.
Sternal metastases from breast cancer represent a unique site of spread in terms of prognosis and treatment. This is a relatively frequent site of local metastases because breast cancer can directly spread from intra-mammary nodes of the breast, and sternal metastases may remain isolated due to lack of communication with the paravertebral venous plexus. Therefore, women with isolated sternal metastases from breast cancer should be considered for surgical resection, particularly since cancer in the sternum can be very painful and psychologically distressing .
Treatment of bone metastases among women with breast cancer represents a very important part of their overall oncologic care and represents an expensive challenge to the overall healthcare system. Women with bone metastases from breast cancer, who proceed to have an SRE, incur an increased $50,000 in healthcare costs compared to women of a similar health profile who do not have an SRE [25, 26, 27].
Imaging of Breast Cancer Bone Metastases
Since breast cancer frequently metastasizes to the bone, nuclear medicine bone scan or positron emission tomography (PET ) is routinely performed for staging purposes among women who are at high risk of metastatic disease. The National Comprehensive Cancer Network (NCCN) recommends consideration of staging imaging for bone metastases among women who are diagnosed with either a locally advanced primary tumor (T3 or T4 lesion) or positive lymph nodes (N1 or N2 disease) (Table 4.1) . If a woman is diagnosed with recurrent breast cancer, either locally or distally, women are typically restaged with imaging to evaluate specifically for bony metastases . For this reason, many bone metastases are not detected from symptoms but from discovery from staging imaging.
Bone scans utilize radionuclides to measure increased osteoblastic activity and skeletal vascularity. It is the favored screening test for bony metastases in women with breast cancer since it is widely available and affordable. Additionally, bone scan has good sensitivity and specificity, at 62–100 % and 78–100 %, respectively, for detecting breast cancer in the bones. False positives do occur and can be caused by trauma, inflammation, or other hypermetabolic processes within the bones. In contrast, false negatives can occur when bone metastases are very indolent or when blood flow is absent from the metastatic site .
Typically, tumor response to therapy is visualized as decreased tracer uptake and progressive cancer demonstrate increased tracer uptake. “Tumor flare ” is an important and confusing phenomenon that frequently occurs when interpreting bone scans. Patients with known bony metastases who have recently initiated medical therapy can appear to have progressive disease on bone scan due to increased radionuclide uptake in the metastatic lesion as the bone is actually healing. Therefore, it is key to implement caution when interpreting a bone scan soon after the onset of a new therapy. After about 6 months of therapy, the bone scan may again become an accurate tool to assess the status of the cancer in the bones . A less common but equally confusing situation can occur when tumors are growing rapidly and do not demonstrate increased tracer uptake on bone scan because the large amount of bone destruction from cancer does not allow formation of new bone. If new bone formation is not occurring, no tracer uptake occurs and the bone scan does not demonstrate an abnormality despite the fact that a metastatic lesion does exist .