Frequency
Mammary carcinoma is the most frequent malignant tumor in women. It effects one out of ten women, is fatal in 30% of cases, and over 75% of patients will have osseous metastases with progression of the disease. The average survival after the appearance of osseous metastases is approximately 2 to 3 years. The prognosis is much worse (only a few months) when visceral metastases have occurred.
Circulating Tumor Cells
Cytologic examination of blood and bone marrow has shown that almost every woman with breast cancer has circulating tumor cells even before surgery. Con- sequently the apparently localised cancer at diagnosis must be considered a sys- temic disorder with potential for metastatic development at any time. Moreover, immunohistological studies of sections of iliac crest biopsies have confirmed an even higher frequency of bone marrow involvement by tumor cells and tumor cell emboli. This strongly confirms the assumption that every aggressive breast cancer (histologic grades G3 and G4), if not all cancers of the breast, have already spread by the time the diagnosis is established.
Complications
Destruction of bone and replacement of hematopoietic tissue by the tumor or by the cytotoxic effects of chemotherapy or both, lead to the following complica- tions:
▶ Bone pain 60–80%
▶ Osteoporosis 40–50%
▶ Pathologic fractures 10–30%
▶ Hypercalcemia 10–30%
▶ Bone marrow failure 20%
▶ Spinal cord compression 10%
210 Chapter 26 Skeletal Metastases of Breast Cancer
Treatment Strategies
Before beginning therapy for breast cancer, certain goals are set:
▶ Prevention of development of metastasis by tumor cells already dispersed in the body. Treatment of micrometastases and prevention of skeletal destruction once bone marrow involvement has been detected, for example, by MRI, bone scan or bone biopsy. The efficacy of bisphosphonates in this setting has already been established.
▶ Prevention and treatment of osteoporosis: It should be noted that bone loss may be due to the patient’s age, to the disease itself, and to therapy, any or all of which can cause osteoporosis resulting in pathologic fractures. Recent studies have indicated that this bone loss can be prevented by bisphosphonates, and skeletal integrity maintained.
▶ Treatment of pre-existing skeletal complications or those associated with radio- therapy or other procedures (palliative treatment). Administration of bisphos- phonates after radiotherapy can accelerate the re-calcification of osteolytic le- sions after radiation.
▶ Prophylaxis with bisphosphonates is becoming even more significant, also in view of the minimal side effects of these drugs.
The following treatment options are available:
▶ Chemotherapy (various protocols)
▶ Radiotherapy (local osteolyses)
▶ Surgical intervention
▶ Hormone therapy (tamoxifen now largely replaced by inhibitors of aromatase)
▶ Bone marrow transplantation (usually in clinical trials)
▶ Antibodies against HER2 (in HER2 positive tumors)
▶ Bisphosphonates (adjuvant and palliative)
Bisphosphonates for Prevention of Metastasis
Bisphosphonates form an integral part of the management of breast cancer. Clinical studies of patients treated with clodronate over a 3-year period have shown a 50%
reduction in skeletal metastases. The survival time of patients on long-term ther- apy with clodronate or ibandronate was significantly increased. However, these studies did not produce uniform results with respect to visceral metastases and survival. It is clear that patients who had circulating tumor cells or high levels of bone sialoprotein (BSP) benefit most from this type of adjuvant therapy. BSPs are produced by osteoclasts and tumor cells and play an important part in cell-matrix interactions in bone, e.g. adhesion of osteoclasts to collagen type I. The following bisphosphonate protocols were used in the studies described above:
▶ Clodronate (Ostac
®
, Bonefos®
) 1600 mg orally daily▶ Ibandronate (Bondronat
®
) 2–6 mg infusion (15 min) monthlyStudies have not yet demonstrated whether daily oral or intermittent parenteral therapy is more effective. Similarly, optimal doses and the possible advantages of a combination of bisphosphonates (e.g., clodronate orally and an aminobisphos- phonate intravenously) still require clarification.
Micrometastases: groups of tumor cells with their own stroma. Today, these can be detected by means of MRI, bone biopsies and presence of tumor markers. Tu- mor cells in bone biopsies should be checked for estrogen and progesterone recep- tors HER 2 (human epidermal growth factor receptor 2) in addition to routine immuno-histochemistry. There are now 2 specific options available for therapy of micrometastases:
▶ Antibodies against HER 2 (Herceptin
®
, Trastuzumab). Over-expression of HER 2 in tumor cells in the bone biopsy has a 3-fold significance: as a prognos- tic factor, as an indicator of the reaction to anthracycline, taxane and tamoxi- fen, and as an indication for therapy with trastuzumab.▶ Bisphosphonates. In this setting both their anti-proliferative and osteoprotec- tive effects are utilised. Osteoclastic resorption is inhibited and micro-meta- static spread is prevented, Moreover, results of large clinical trials designed to elucidate the short and long term effects of bisphosphonate therapy in patients with mammary cancer, with and without demonstrable metastases, are now beginning to appear in the literature. The reduction in incidence of skeletal meta- stases and improvement of survival have now been documented.
The following bisphosphonates are currently recommended for use in oncological centers:
▶ Clodronate (Ostac
®
) 1600 mg orally daily▶ Pamidronate (Aredia
®
) 90 mg i.v. monthly▶ Ibandronate (Bondronat
®
) 6 mg i.v. monthly▶ Zoledronate (Zometa
®
) 4 mg monthly/3monthlyIn the meantime other inhibitors of osseous resorption and of tumor cell growth are also being investigated:
▶ osteoprotegerin
▶ RANK-fc
▶ Antagonists of endothelin-A-receptor
▶ Antibodies to PTHrP
▶ Vitamin D analogs
212 Chapter 26 Skeletal Metastases of Breast Cancer
Bisphosphonates for Prevention of Skeletal Complications
Micrometastases – as well as larger established metastases – are demonstrable by MRI, tumor markers in blood and by bone biopsy. At this point, these metastases have not evoked any osseous reactions demonstrable by bone scan or X-ray, and administration of bisphosphonates can prevent their establishment and develop- ment on and in the bones.
Two additional therapeutic options are available:
▶ Herceptin
®
(trastuzumab), a specific antibody against HER2: Overexpression of HER 2 is demonstrable even in micrometastases in the bone marrow. This is significant for three reasons: for prognosis, for predicting response to tetra- cycline, taxane, tamoxifen and aromatase inhibitors, and as an indication for Herceptin®
therapy.▶ Bisphosphonates: in this context bisphosphonates are utilised for their antiprolif- erative and osteoprotective effects (Fig. 9.10). As outlined previously, inhibition of osteoclasts prevents the release of growth factors from bone, directly as well as through the action of cytokines. In addition, tumor cell adhesion to bone is prevented by inhibition of metalloproteinases secreted by tumor cells them- selves. Bisphosphonates have not yet been authorised specifically for preven- tion of skeletal metastases, and therefore informed consent must be obtained.
The following protocols are recommended for use in oncology:
▶ Clodronate (Ostac
®
, Bonefos®
) 1600 mg orally daily▶ Pamidronate (Aredia
®
) 90 mg infusion monthly▶ Ibandronate (Bondronat
®
) 2–6 mg infusion monthlyBisphosphonates for Treatment of Skeletal Complications
Bisphosphonates have strong antiresorptive effects and also some degree of osteo- reparative (recalcification) effect. They can prevent unwanted bone loss following radiotherapy. Administration of bisphosphonates leads to increased formation of callus which accelerates healing of bone defects. 1000 IU vitamin D daily (after exclusion of hypercalcemia!) promotes mineralisation of the newly formed bone.
However, since complete restoration of normal bone structure in large osteolytic lesions can take years, it is all the more important to prevent them. Previous stud- ies have shown that bisphosphonates can prevent skeletal related events (SREs): new osteolytic lesions, pathologic fractures, hypercalcemia, spinal cord compression, bone pain and thereby reduce the need for surgery and radiotherapy. Clinical studies on
the renal safety and on the efficacy of bisphosphonates in patients treated for over 10 years have now been published.
A modest increase in survival of premenopausal patients was also observed.
Administration of a bisphosphonate such as clodronate together with irradiation of an osteolytic lesion is thought to have an additive effect. The presence of vis- ceral metastases, though probably predictive of a shorter survival, is no justifi- cation for not giving bisphosphonates. In addition, numerous articles from many countries have now confirmed the efficacy of bisphosphonates for skeletal protection in patients with breast cancer.
Treatment of skeletal complications is best achieved by monthly intravenous or daily oral administration of bisphosphonates:
▶ Pamidronate (Aredia
®
) 90 mg infusion monthly▶ Ibandronate (Bondronat
®
) 6 mg infusion (15 min) monthly▶ Ibandronate (Bondronat
®
) 50 mg orally daily▶ Zoledronate (Zometa
®
) 4 mg infusion (15 min) monthlyThese protocols automatically include both treatment and prevention of osteopo- rosis; note that both oral and i.v. administration are now available. The optimal du- ration of bisphosphonate therapy in this clinical setting has not yet been established.
A diet rich in calcium and a vitamin D supplement should also be prescribed after exclusion of hypercalcemia.
