Therapeutics targeting the metastatic breast cancer bone microenvironment

Breast cancer (BC) patient prognosis has improved over the past 2 decades with a 99% 5-year survival rate for localized BC, yet metastatic breast cancer (mBC) continues to cause high mortality with a 5-year survival rate of 29%. Approximately 70% of BC metastases occur in the bone, with estrogen receptor (ER) positive BC exhibiting a particular affinity to bone. Once BC metastasizes to the bone, curative treatments are not available, thus therapeutic approaches are focused on palliative care and prevention of skeletal related events while attempting to slow metastatic progression. Recent advances in molecularly targeted agents have enhanced the repertoire of options for mBC patients, but immunotherapies have not yet been fully translated to ER+ tumors. Thus mBC patients have yet to fully benefit from novel therapies, which is currently obstructing patient survival. The unique tumor microenvironment (TME) of mBC in bone offers an array of targets for therapeutic development. The mBC TME in bone presents a predominantly osteolytic or destructive bone pathology, where bone mineral loss is driven by increased resorption of bone by osteoclasts. We discuss therapeutics targeting the mBC cells, bone cells, immune cells, and other stromal cells in the bone TME, including treatments that are currently used in the clinic, under development, and are potential new avenues for therapy. Therapeutic advancements targeting the TME of mBC in bone could be applied to other bone-resident cancers, including myeloma and metastatic prostate cancer bone lesions. These precision oncology approaches to mBC treatment will improve the quality of life and clinical outcomes of patients with mBC bone lesions.