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Bone-Modifying Agents as Adjuvant Therapy for Early-Stage Breast Cancer

Bone-Modifying Agents as Adjuvant Therapy for Early-Stage Breast Cancer

The development of effective systemic therapies to reduce the risk of disease recurrence or metastases in early-stage breast cancer remains an important challenge. The use of bone-modifying agents (BMAs), including the bisphosphonates (BPs) and the monoclonal antibody denosumab (Xgeva), is well established for metastatic bone disease. In the adjuvant setting, some studies have shown provocative findings with some of these agents for the prevention of future breast cancer–related events, with improved survival in some subgroups. The most compelling results have been seen with clodronate and zoledronic acid. In this review we describe the current evidence for use of BPs as part of the adjuvant treatment of patients with early-stage breast cancer.


The bisphosphonate (BP) drugs have a long established role in the management of osteoporosis, hypercalcemia of malignancy, and bone metastases from solid tumors and multiple myeloma. In the breast cancer population, zoledronic acid (ZA) and pamidronate have been widely used for over a decade in patients with bone metastases as an adjunct to radiotherapy, hormonal therapy, and chemotherapy, based on trials that have shown a reduction in skeletal-related events (SREs), including fractures, spinal cord compression, and worsening pain necessitating radiotherapy.[1] In addition, these agents are being suggested for premenopausal patients with bone loss from premature ovarian failure due to chemotherapy and in postmenopausal patients treated with aromatase inhibitors (AIs).[2] There is increasing interest in using these drugs to reduce the risk of breast cancer metastases, both bone and non-bone, independent of the established uses for bone-related indications; this is in light of a plausible mechanism of action based on preclinical evidence, some compelling observational data, and results from several interventional trials suggesting a role in some subpopulations of breast cancer patients. However, trial results with BPs are conflicting, and currently none of these agents have been designated by the US Food and Drug Administration (FDA) as being indicated for reducing breast cancer recurrence or improving disease-free survival (DFS) and overall survival (OS), so any use for this purpose in the US must be considered off-label and experimental.

This manuscript will review the preclinical and clinical data for the use of bone-modifying agents (BMAs) in the adjuvant treatment of early breast cancer. We will examine clinical trial results for these agents and will address issues of toxicity and cost-effectiveness. We will attempt to offer a perspective on their use in the absence of existing guidelines for the primary purpose of reducing breast cancer recurrence.

Bone-Modifying Agents and Early Breast Cancer: Preclinical Observations

In normal bone, particularly in young adults, there is a balance between osteoclastic bone resorption and osteoblastic bone formation. This can be altered by the presence of tumor cells in bone, which accelerate resorption by promoting osteoclast formation and activity through the release of tumor cell–derived factors, such as parathyroid hormone–related peptide (PTHrP), prostaglandin-E, and bone sialoprotein. PTHrP binds to receptors on osteoblasts, enhancing production of receptor activator of nuclear factor κβ ligand (RANKL). This pathway results in the differentiation of osteoclasts and their activation. On osteoclasts, RANKL binds to its receptor, RANK, promoting an increase in bone resorption.[3]

Osteoclast inhibition induced by bisphosphonates (BPs) can alter the bone microenvironment, making it less supportive of tumor cell proliferation, and preclinical data suggest that BPs can reduce the likelihood of developing bone metastases.[4] The mechanisms of antitumor activity of BPs have not been fully elucidated, but it is proposed that these drugs exert both indirect and direct antitumor effects. One potential indirect mechanism of action would be inhibition of bone resorption, in which BPs reduce the release of cytokines and other growth factors. This makes the bone environment less hospitable for tumor cell migration, decreasing the likelihood of cell adhesion and proliferation. Another indirect antitumor effect is the induction of a T cell–mediated immune response, in which BPs may inhibit angiogenesis by activating T-effector cells producing interferon-gamma.[3]

A potential direct mechanism of BPs is the inhibition of angiogenesis, as shown in particular with ZA.[5,6] The BPs also decrease the adhesion, invasion, and proliferation of tumor cells. Moreover, they may have synergistic antitumor activity with cytotoxic agents, mainly with taxanes and anthracyclines.[3] For instance, the combination of ZA and doxorubicin produced synergistic antitumor activity in a primary breast cancer murine model without extraskeletal disease.[7] Additionally, antitumor effects appear to be dose-dependent, and in some in vitro studies BPs may directly and dose-dependently induce apoptosis in breast cancer cell lines.[8-11]

The hypothesis of the “seed and soil” described by Paget[12] may further elucidate the antitumor properties of BPs. The “seed” represents the tumor cell and the “soil” represents the bone marrow, which would have the ideal microenvironment to receive tumor cells. Supportive stromal cells, growth factors, and other components of the extracellular matrix, including the vasculature, make the bone marrow microenvironment a favorable milieu for cancer cell proliferation and propagation.[13] Some preclinical evidence also suggests that the bone marrow is a “premetastatic niche,” and the engraftment of tumor cells onto a favorable bone marrow microenvironment would begin the evolution of micrometastasis, to macrometastasis, to distant, non-bone metastasis.[14] Thus, early intervention such as the use of BPs in the adjuvant setting may interfere with the formation of this premetastatic niche.


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