Adjuvant Zoledronic Acid Reduces Disease Recurrence in Breast Cancer: Antitumor Effects on the Seed and the Soil

Michael      Gnant

doi:10.2174/1573394711107020111

Abstract

Bisphosphonates are the standard of care for preventing skeletal morbidity in patients with malignant bone disease. In this setting, zoledronic acid (intravenous; 4 mg monthly) is approved for the prevention of skeletal-related events in patients with bone lesions from multiple myeloma or bone metastases from breast cancer and other solid tumors (eg, genitourinary malignancies, lung cancer). Recent data from large phase III studies show that zoledronic acid (4 mg every 6 months) preserves bone mineral density and reduces disease recurrence in bone and at other sites during adjuvant endocrine therapy for early breast cancer in both pre- and postmenopausal women. There is a strong preclinical and early clinical rationale that zoledronic acid can inhibit cancer cell proliferation and viability and interfere with various steps in the metastatic process (effects on the cancer “seed”). In addition, bisphosphonates alter bone metabolism and may render the bone microenvironment (“soil”) less conducive to tumor growth. This article will summarize the current evidence in the context of the “seed and soil” theory of tumor metastasis, and will discuss how emerging new data and ongoing trials of bisphosphonates for the prevention of metastases in various tumor types might expand their role in the adjuvant therapy setting.

Keywords: Adjuvant therapy, antitumor, bisphosphonate, bone metastases, zoledronic acid, Breast cancer, ABC transporters, MDR phenotype, endocrine regulation, chemotherapeutic agents, tamoxifen, doxorubicine, epirubicin, methotrexate, fluorescent, ATP hydrolysis, electrospray ionization, Atomic absorption spectroscopy, Cisplatin, Carboplatin, Gemcitabine, Cyclophosphamide, Vinorelbine