Bones, breasts, and bisphosphonates: rationale for the use of zoledronic acid in advanced and early breast cancer

Abstract

Abstract:Bisphosphonates inhibit osteoclast-mediated bone resorption, thereby inhibiting the release of growth factors necessary to promote cancer cell growth, differentiation, and tumor formation in bone. These agents have demonstrated efficacy for delaying the onset and reducing the incidence of skeletal-related events in the advanced breast cancer setting, and have been shown to prevent cancer therapy-induced bone loss in the early breast cancer setting. Emerging clinical data indicate that the role of bisphosphonates in advanced and early breast cancer is evolving. Retrospective analyses and recent clinical trial data show that zoledronic acid may improve outcomes in some patients with breast cancer. Data from ABCSG-12 and ZO-FAST suggest that zoledronic acid may improve disease-free survival in the adjuvant breast cancer setting in postmenopausal women or women with endocrine therapy-induced menopause, and recent data from a predefined subset of the AZURE trial added to the anticancer story. However, the overall negative AZURE trial also raises questions about the role of bisphosphonates as an anticancer agent in patients with breast cancer. Overall, these data suggest that the addition of zoledronic acid to established anticancer regimens may have potential anticancer benefits in specific patient populations, although more studies are required to define its role. Keywords: anticancer, adjuvant therapy, bone metastasis, skeletal, zoledronic acid The burden of bone metastases in women with advanced breast cancerThe impact of breast cancer continues to be felt worldwide with more than 1 million new cases identified each year, 1 and 254,650 new cases in 2009 in the United States alone.2 Although the primary tumor is often effectively treated with surgical resection and chemotherapy or endocrine therapy, cancer cells that escape the local site have a predilection for metastasis to bone, an environment that may help them survive during adjuvant therapy. As a result, distant metastases can develop in bone. Approximately 65% to 75% of women with advanced breast cancer will ultimately develop bone metastases, which can lead to skeletal-related events (SREs) such as pathologic fractures, spinal cord compression, hypercalcemia of malignancy, bone pain requiring palliative radiotherapy, and orthopedic surgery.3 Skeletal-related events can be severely debilitating, and may result in a significant reduction in functional independence and quality of life. Furthermore, SREs are associated with increased morbidity and mortality, and pathologic fractures have been associated with a significant increase in the risk of death in women with advanced breast cancer (32%; P , 0.01).

Denosumab for the Prevention of Skeletal‐Related Events in Patients with Bone Metastasis from Solid Tumor

“…Despite improvements in the treatment of these cancers, skeletal‐related events significantly decrease the quality of life of patients with advanced disease. These events include pathologic fractures, spinal cord compression, hypercalcemia due to malignancy, and bone pain or lesions requiring palliative radiation therapy or surgery to prevent or treat fractures . The goal for treatment of bone metastasis is to prevent, or at least reduce the frequency of, complications from skeletal‐related events, thus improving quality of life and functional independence of patients.…”