Relevance of Micrometastases and Targeting the Bone Marrow Niche with Zoledronic Acid in Breast Cancer

Abstract

During the course of cancer metastasis development, invasive tumor cells circulate through the blood stream and disseminate to other tissues. Circulating and disseminated tumor cells (CTCs and DTCs, respectively) may be the source of local and distant metastases and are a promising target for anticancer therapy. Multiple studies have shown that the detection of DTCs or CTCs correlates with increased risk of disease recurrence, suggesting that reducing the prevalence and persistence of these cells is clinically relevant. The development of metastases is a multistep process that involves complex biologic processes and a multitude of growth factors. The bone marrow provides a portion of these growth factors and a nutrient-rich microenvironment in which dormant cancer cells can survive and transition to metastasis-initiating cells. The molecular interactions between DTCs and the bone marrow microenvironment enable DTCs to evade cytotoxic chemotherapy, allowing them to lie dormant for extended periods of time before becoming active and metastasizing to secondary sites. Alteration of the bone marrow microenvironment with antiresorptive agents, such as bisphosphonates, may render the bone marrow less suitable for cancer cell growth, possibly interfering with the metastatic cascade. Clinical studies have shown that the nitrogen-containing bisphosphonate zoledronic acid can reduce the persistence and prevalence of DTCs in patients with breast cancer, suggesting that zoledronic acid may improve clinical outcomes. Targeting the metastatic niche by altering the microenvironment in the bone marrow may be an effective anticancer strategy.