Serum bone sialoprotein in patients with primary breast cancer is a prognostic marker for subsequent bone metastasis

Bone sialoprotein (BSP) is a noncollagenous bone matrix protein that is imp ortant for both mineralization and cell-cell interactions. Tissue studies i n primary breast cancers have shown that immunohistochemical expression of BSP is associated with a high incidence of bone metastases in the course of the disease. We used a RIA to investigate the importance of serum BSP as a marker for subsequent bone metastases, Between 1994 and 1996, preoperative blood samples were collected from 388 consecutive patients with nonmetasta tic breast cancer and from 30 control patients with benign breast disease. Serum BSP concentrations were measured in a blinded fashion by RIA, The cut off for elevated serum BSP values was 24 ng/ml, i.e., two SDs above the nor mal mean value, Serum BSP was correlated with the risk of metastasis and an alyzed with regard to its prognostic value. After a median follow-up period of only 20 months, 28 patients had developed metastases, Fourteen patients had bone metastases only, 9 visceral metastases only, and 5 a combination of osseous and visceral metastases, Of the 19 women with skeletal metastase s, 17 had preoperative serum BSP values in excess of 24 ng/ml (median BSP v alues: 48.3 ng/ml for isolated metastatic bone disease, 30.6 ng/ml for comb ined metastases), whereas none of the women with visceral metastases only h ad elevated serum BSP concentrations (median BSP value: 12.3 ng/ml), The me dian serum BSP value in the control group (benign breast disease) was 8.8 n g/ml serum BSP; levels correlated with the size of the primary tumor, but n ot with any other prognostic factors. Using a multivariate regression analy sis, serum BSP was found to be the most important independent prognostic fa ctor for the development of skeletal metastasis (P < 0.001; relative risk, 94); its specificity was 96.7%, and its sensitivity was 89.5%. Our study sh ows that patients with preoperatively elevated serum BSP levels are at high risk of subsequent bone metastases in the first years after primary surger y. The mechanism of BSP in the pathogenesis of skeletal metastases is uncle ar, Because BSP contains an integrin recognition sequence, its expression i n tumor cells may facilitate their adhesion to the bane surface, However, i t is possible that a proportion of circulation BSP is derived from normal o r tumor-induced bone turnover. Breast cancer patients with elevated serum B SP levels may benefit from osteoprotective adjuvant therapy with bisphospho nates.