Adjuvant oral clodronate improves the overall survival of primary breast cancer patients with micrometastases to the bone marrow: a long-term follow-up.

BACKGROUND: Adding oral clodronate to postoperative adjuvant breast cancer therapy significantly improves disease-free survival (DFS) and overall survival (OS). Long-term follow-up data from the prospective, randomized, controlled study are reported. PATIENTS AND METHODS: Patients with primary breast cancer received clodronate 1600 mg/day for 2 years or no treatment along with standard adjuvant breast cancer treatment. RESULTS: Analysis of 290 of 302 patients demonstrated that a significant improvement in OS was maintained in the clodronate group at a median follow-up of 103 +/- 12 months; 20.4% of patients in the clodronate group versus 40.7% of control group patients (P = 0.04) died during the 8.5 years following primary surgical therapy. Significant reductions in the incidence of bony and visceral metastases and improvement in duration of DFS at 36- and 55-month follow-up periods were no longer seen with clodronate. CONCLUSION: These long-term survival data extend the survival advantage reported in previous studies with oral clodronate in breast cancer.

Time independence of the prognostic impact of tumor cell detection in the bone marrow of primary breast cancer patients.

PURPOSE: Tumor cell detection (TCD) in bone marrow is an outstanding prognostic factor in breast cancer. There is only one other study that has investigated more than 300 patients with a median follow-up of more than 5 years (J. L. Mansi et al., Lancet, 354:197-202, 1999). We report data from 727 patients with a median follow-up period of 6.5 years. EXPERIMENTAL DESIGN: In a prospective study, intraoperatively aspirated bone marrow was screened for micrometastatic cancer cells. We used an immunocytological method (monoclonal mucin antibody 2E11; the avidin-biotin complex method). RESULTS: Forty-three percent of the patients were TCD positive. Sixty percent of the patients with distant metastases were tumor cell positive (155 of 258 patients). Forty-nine percent of the patients with positive TCD developed distant metastases (155 of 315 patients). TCD was an independent prognostic factor for clinical outcome after a median follow-up time of 6.5 years. The prognostic impact of TCD and tumor size remains constant with the time, whereas the impact of grading and progesterone receptor on risk seems to decrease with longer follow-up time. CONCLUSIONS: TCD remains an independent prognostic factor The impact of TCD does not change with longer follow-up time. TCD is a reliable prognostic factor and provides important information about the process of metastasis.

Metastatic breast cancer: clinical course, prognosis and therapy related to the first site of metastasis.

Although metastasis is a frequent event in breast cancer patients, insight into the clinical course, prognosis and therapy with respect to the site of the first metastases has been poor and contradictory in former investigations. Follow-up data from 648 patients with metastatic breast cancer were statistically analyzed. Patients with bone metastases at first relapse had better overall survival (median 71 vs. 48 months; p < 0.001) and survival after first metastases (median 24 vs 12 months; p < 0.001) than patients with visceral metastases at first relapse. Bone was the site of first metastasis in 46%, and 71% of patients with metastatic breast cancer developed bone metastases. The localization of the second metastatic site was of prognostic relevance in patients with first visceral metastases, but not in patients with first bone metastases. The presence of osseous metastases correlated significantly with estrogen and progesterone receptor positivity, tumor grading I/II and S-phase fraction <5%. The better prognosis of patients with bone metastases is not determined exclusively by hormone receptor status. The disease is significantly more stable in patients with first bone metastases than in those with first visceral metastases.

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

Bone sialoprotein (BSP) is a noncoflagenous bone matrix protein that is important for both mineralization and cell-cell interactions. Tissue studies in 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 nonmetastatic breast cancer and from 30 control patients with benign breast disease. Serum BSP concentrations were measured in a blinded fashion by RIA. The cutoff for elevated serum BSP values was 24 ng/ml, ie., two SDs above the normal mean value. Serum BSP was correlated with the risk of metastasis and analyzed 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 metastases, 17 had preoperative serum BSP values in excess of 24 ng/ml (median BSP values: 48.3 ng/ml for isolated metastatic bone disease, 30.6 ng/ml for combined metastases), whereas none of the women with visceral metastases only had elevated serum BSP concentrations (median BSP value: 12.3 ng/ml). The median serum BSP value in the control group (benign breast disease) was 8.8 ng/ml serum BSP; levels correlated with the size of the primary tumor, but not with any other prognostic factors. Using a multivariate regression analysis, serum BSP was found to be the most important independent prognostic factor 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 shows that patients with preoperatively elevated serum BSP levels are at high risk of subsequent bone metastases in the first years after primary surgery. The mechanism of BSP in the pathogenesis of skeletal metastases is unclear. Because BSP contains an integrin recognition sequence, its expression in tumor cells may facilitate their adhesion to the bone surface. However, it is possible that a proportion of circulation BSP is derived from normal or tumor-induced bone turnover. Breast cancer patients with elevated serum BSP levels may benefit from osteoprotective adjuvant therapy with bisphosphonates.

Prognostic relevance of cathepsin D detection in micrometastatic cells in the bone marrow of patients with primary breast cancer.

Patients with an elevated level of cathepsin D in breast cancer tissue have an adverse prognosis. This study evaluated the prognostic relevance of cathepsin D detection in disseminated tumour cells in bone marrow. Bone marrow was sampled intraoperatively from both anterior iliac crests in 290 patients with primary breast cancer. Interphase cells were enhanced and stained immunocytologically with two antibodies: BM2, which detects tumour-associated glycoprotein TAG 12, which is typically expressed by almost all breast cancer cells, and the anti-cathepsin D antibody. 67 of 149 BM2-positive women (45%) developed metastatic disease (median follow-up time: 69 months). Of these, 15 were cathepsin D-positive (22%). Patients with cathepsin D-positive cells in bone marrow (n = 26; 9%) had a significantly shorter metastasis-free interval (38 months) compared with women who were cathepsin D-negative (64.5 months). The worst prognosis was seen in patients positive for both markers (30.5 months), followed by those who were cathepsin D-negative and BM2-positive (48 months). The detection of cathepsin D on disseminated tumour cells characterises a subgroup of patients with a poorer prognosis who should undergo more aggressive adjuvant systemic therapy.

Reduction in new metastases in breast cancer with adjuvant clodronate treatment.

BACKGROUND: Bisphosphonates are effective against the increased bone resorption caused by certain diseases because they inhibit the activity of osteoclasts. In patients who have breast cancer and metastatic bone disease, the bisphosphonate clodronate (clodronic acid) reduces the frequency of skeletal complications. Experiments in animals and preliminary clinical observations indicate that early clodronate therapy reduces the incidence of new bony metastases in breast cancer. We investigated the effects of clodronate on the incidence and extent of new metastases in patients with breast cancer. METHODS: Between 1990 and 1995, 302 patients with primary breast cancer and tumor cells in the bone marrow (the presence of which is a risk factor for the development of distant metastases) were randomly assigned to receive clodronate at a dose of 1600 mg per day orally for two years (157 patients) or standard follow-up (145 patients). The median length of observation was 36 months. All patients in both groups received standard surgical treatment and customary hormonal therapy or chemotherapy. RESULTS: Distant metastases were detected in 21 patients in the clodronate group and in 42 patients in the control group (P<0.001). The incidence of both osseous and visceral metastases was significantly lower in the clodronate group than in the control group (P=0.003 for both osseous and visceral metastases). Six patients in the clodronate group died, as did 22 in the control group (P=0.001). The mean number of bony metastases per patient in the clodronate group was roughly half that in the control group (3.1 vs. 6.3). CONCLUSIONS: Clodronate can reduce the incidence and number of new bony and visceral metastases in women with breast cancer who are at high risk for distant metastases.

Results of iliac crest biopsies taken from 1465 patients with primary breast cancer.

This study was performed to analyze the relevance of iliac crest biopsy in patients with primary breast cancer with regard to metastases of the primary tumor and osteogenic disease. We performed intraoperative bilateral biopsy of the anterior iliac crests in 1465 patients with primary breast cancer. The bone specimens were histologically evaluated with regard to quality of the biopsy, tumor involvement, and osteogenic and hematogenic disease. Accurate and clear evaluation of the iliac crest biopsies was possible in 1365 patients (93%). Osteopenia was diagnosed in 48 patients (3.5%); 24 patients (1.7%) showed histological evidence of tumor involvement of the skeletal system. All these 24 patients received systemic (adjuvant) therapy after surgery. Ten patients had micrometastases, although in 5 of them both the postoperative bone scan and X-rays showed no pathological results. In 10 women with histologically negative bone biopsies, metastases to the bone were diagnosed by bone scan and radiological methods. Random perioperative iliac bone biopsy cannot be recommended in patients with primary breast cancer. Iliac crest biopsy is relevant in certain scenarios (e.g. suspected recurrence, doubtful bone scan).

Prognostic relevance of urokinase plasminogen activator detection in micrometastatic cells in the bone marrow of patients with primary breast cancer.

Patients with an elevated level of urokinase plasminogen activator (uPA) in breast cancer tissue have an adverse prognosis. This study evaluated the prognostic relevance of uPA detection in disseminated tumour cells in bone marrow. Bone marrow was sampled intraoperatively from both iliac crests in 280 patients with primary breast cancer. Interphase cells were enhanced and stained immunocytologically with two antibodies: 2E11, which detects TAG 12--a tumour-associated glycoprotein typically expressed by almost all breast cancer cells--and the anti-uPA antibody HD-UK9. Thirty-five of the 2E11-positive women (n = 132, 47%) developed metastatic disease (median follow-up time 44 months). Of these, most were uPA positive (n = 23, 65%) and only 12 were uPA negative. Patients with uPA-positive cells in bone marrow (n = 98, 35%) had a significantly shorter metastasis-free interval (36 months) than women who were uPA negative (44.5 months). The worst prognosis was seen in patients positive for both markers (29.5 months), followed by those who were uPA negative and 2E11 positive (37 months). The detection of uPA on disseminated tumour cells characterizes a subgroup of patients with an even worse prognosis, who should undergo more aggressive adjuvant systemic therapy. For the first time, it was possible to evaluate an important qualitative parameter involved in the process of breast cancer metastases.

Low-dose radioactive endovascular stents prevent smooth muscle cell proliferation and neointimal hyperplasia in rabbits.

BACKGROUND: Restenosis induced by smooth muscle cell (SMC) migration and proliferation and neointimal thickening limits the clinical success of balloon angioplasty and stent implantation. In this study, the long-term effect of endovascular irradiation via low-dose radioactive stents on neointima formation was compared with conventional stent implantation in a rabbit model. METHODS AND RESULTS: Palmaz-Schatz stents were made radioactive in a cyclotron. The stents had a very low activity (maximum, 35 microCi), and thus, manipulation did not require extensive radiation protection. One, 4, 12, and 52 weeks after the implantation of nonradioactive stents and radioactive stents in rabbit iliac arteries, neointimal thickening was analyzed by quantitative histomorphometry. Immunostaining for endothelial cell von Willebrand factor, macrophages, SMC alpha-actin, collagen type I, and proliferating cell nuclear antigen (PCNA) was performed to determine radiation-induced changes in the arterial wall. SMC proliferation was quantified by computer-assisted cell counting of PCNA-immunoreactive cells. Neointima formation was markedly suppressed by the implantation of radioactive stents in a dose-dependent fashion at all observed time points. At peak proliferative activity of SMCs 1 week after nonradioactive stent implantation, 30 +/- 2% of SMCs in the neointima were proliferating, compared with 0.5 +/- 0.1% of SMCs after implantation of stents with an initial activity of 35 microCi (P < .001). The neointima covering radioactive stents was characterized by decreased smooth muscle cellularity and increased extracellular matrix formation. Further, we observed a delayed endothelialization depending on the radiation dose. No difference in vascular thrombosis was found after nonradioactive and radioactive stent implantation. CONCLUSIONS: The results of this study clearly indicate that low-dose radioactive endovascular stents potently inhibit SMC proliferation and neointimal hyperplasia in rabbits.