Sowing the Soil for Cure? Results of the ABCSG-12 Trial Open a New Chapter in the Evolving Adjuvant Bisphosphonate Story in Early Breast Cancer

Abstract

After their initial synthesis in 1865, bisphosphonates were largely used for industrial purposes to prevent calcium carbonate precipitation in the textile, agricultural, and oil sectors. More than 100 years later, bisphosphonates were shown to inhibit bone resorption in animal models. Since then, the role of bisphosphonates in the treatment of hypercalcemia, Paget’s disease, and osteoporosis, as well as in the reduction of morbidity associated with bone metastases from breast, prostate, and plasma cell malignancies, has been established. The American Society of Clinical Oncology recommends “the extensive and early use of bisphosphonates” to prevent skeletal complications, such as pathologic fractures, surgery for fracture or impending fracture, radiation, spinal cord compression, and hypercalcemia, in women with metastatic bone disease from breast cancer. A more recent international panel of experts concluded that bisphosphonates reduce the frequency and severity of skeletal complications in patients with bone metastases from a variety of different cancers. In the setting of cancer treatment–induced bone loss, the panel advised considering the use of bisphosphonates in patients presenting with risk factors for fractures but did not endorse the use of bisphosphonates in the adjuvant setting. Clinical trials with bisphosphonates in patients with metastatic breast cancer have failed to demonstrate an overall survival (OS) benefit. However, bisphosphonates might have an impact on longterm survival if used in earlier stages of disease. The dissemination of breast cancer cells to bone marrow instigates a vicious self-sustaining cycle of destruction, whereby individual tumor cells release growth factors that stimulate stromal cells and osteoblasts to produce the receptor activator for nuclear factor B ligand (RANKL), leading to the activation of osteoclasts. These activated osteoclasts resorb bone matrix–liberating potent growth factors that promote tumor cell colonization, inhibit apoptosis, and drive proliferation. Bisphosphonates are potent inhibitors of osteoclasts, thereby interrupting this self-perpetuating cycle. Three clinical trials with the non–nitrogen-containing oral bisphosphonate clodronate in early breast cancer produced mixed results. A single-center German study involving 302 women with early breast cancer and detectable bone marrow metastases demonstrated a striking reduction in bone and visceral metastases and improvement in disease-free survival (DFS) and OS with two years of adjuvant clodronate therapy. With longer follow-up, the gain in OS persisted, although differences in DFS and bone metastasis–free and visceral metastasis–free survival were no longer apparent. A larger placebo-controlled multicenter study found that a similar schedule of oral clodronate for 2 years in conjunction with standard therapy for stage I to III breast cancer reduced the incidence of bone metastasis and improved OS with no observed difference in nonosseous metastasis. However, a small Finnish trial reported that three years of adjuvant clodronate did not improve overall survival and had no effect on bone recurrences and a negative impact on nonskeletal recurrences, particularly in women with estrogen receptor–negative disease. There are concerns that these results were skewed by imbalances between the clodronate and observation groups. On the basis of the data, which remained unconvincing when pooled in a meta-analysis, the US Food and Drug Administration announced that it would not consider approving clodronate in adjuvant breast cancer therapy until the results from the NSABP (National Surgical Adjuvant Breast and Bowel Project) B-34 study—in which 3,323 women with stage I to II disease have been randomly selected to receive three years of clodronate or placebo—were available. There is reason to believe that newer generation bisphosphonates may deliver greater efficacy. Non–nitrogen-containing bisphosphonates, such as clodronate, can be metabolized to an adenosine triphosphate analog that is toxic for macrophages and osteoclasts. Nitrogen-containing bisphosphonates, including zoledronic acid and ibandronate, have a very different mechanism of action and are much more potent inhibitors of osteoclast-mediated bone resorption. They inhibit the mevalonate pathway that leads to the prenylation of key intracellular signaling proteins. Many of these proteins are guanosine triphosphate–binding peptides essential for signal transduction, including Rho and Ras, that regulate key osteoclast functions, including attachment and survival. Inhibition of prenylation alters cell membrane integrity and induces osteoclast apoptosis. Nitrogen-containing bisphosphonates have also been shown to directly induce tumor cell apoptosis, inhibit angiogenesis, and prevent JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 27 NUMBER 25 SEPTEMBER 1 2009