Circulating Osteocalcin-positive Cells in Breast Cancer Bone Metastasis

Overview

Bone metastasis (i.e. cancer cell spreading to bone) is the major clinical problem of advanced breast cancer patients. Bone metastasis is not curable nor preventable. Currently available therapeutic approaches are only palliative. The major hurdle for improving bone metastasis treatment is lack of sensitive diagnostic tools. Diagnosis of bone metastasis is heavily dependent on radiographic imaging of bone destruction that are detectable only when the lesion is significantly large. Accordingly, if bone metastasis can be detected at an earlier time point when bone destruction is minimal or incipient, treatments can be given earlier and the patients can expect better outcomes. We and others previously have found that a subset of bone-forming cells (i.e. circulating osteocalcin-positive cells) exists in the blood stream of the patients with bone diseases (e.g. bone metastasis and inflammation) or active bone formation (e.g. adolescence) in mouse models anf human samples. Extended from this laboratory observation, this clinical study proposes to test the hypothesis that circulating osteocalcin-positive cells are the early biomarker of breast cancer bone metastasis. For this aim, this study will measure circulating osteocalcin-positive cells in the blood samples of breast cancer patient, and examine whether the measure sensitively detects bone metastasis.

Bone is the most common site of breast cancer metastasis, and the skeletal-related events (SRE) of bone metastasis such as pathologic fractures, cord compression, hypercalcemia and severe pain, accounting for poor quality of life in the terminal stage of the afflicted patients. Since previous SREs are the major risk factors for subsequent SREs related to serious morbidity and mortality, the early detection of bone metastasis prior to clinical symptoms is essential to the better management of breast cancer patients. Currently, diagnosis of bone metastasis is dependent on imaging modalities such as whole-body bone scintigraphy (WBBS). However, detectability of radionuclide activity in the WBBS depends on gross structural bone destruction resulting from considerable progression of macro-metastasis. Circulating osteoprogenitor cells that is defined a small monocytic cells expressing osteocalcin, a late osteoblast differentiation marker, had been identified in human peripheral blood mononuclear cells (PBMCs). Flow cytometric analyses of the PBMCs using anti-osteocalcin antibody demonstrated that adolescents who are in the period of rapid bone growth showed higher fractions of osteocalcin-positive cells than adults. Moreover, these cells also positively correlated with pathologic changes of bone turnover in such conditions as fracture, hypoparathyroidism, or diabetes. Collectively, circulating osteoprogenitor cells reflects changes of bone turnover in either physiologic or pathologic status. The scientific hypothesis of this study is that circulating osteoprogenitor cells increases in the early phase of bone micro-metastasis, and the aim of this clinical study is to investigate the difference of circulating osteoprogenitor cells in metastatic breast cancer with or without bone metastasis. This study will also examine whether the patients who have higher number of osteocalcin-positive cells develop bone metastasis at an earlier time point, to validate the value of circulating osteoprogenitor cells in monitoring and/or predictinng the progression of bone metastasis.