Biomarker Signals Bone Metastases in Breast Ca

TORONTO — Increased urinary excretion of a biomarker of bone resorption signals the presence and extent of bone metastases in breast cancer patients, Dr. Diana J. Leeming said at a world congress on osteoporosis.

Technetium-99 (99Tc) bone scintigraphy remains the standard method of detecting skeletal metastases in cancer patients. However, this approach is not suitable for close, frequent monitoring because of significant radiation exposure, Dr. Leeming said.

She and her colleagues previously investigated a number of biomarkers to determine if their presence correlated with the number and extent of bone metastases (Cancer Epidemiol. Biomarkers Prev. 2006;15:32-8). Among these were the resorption markers ααCTX and ββCTX; bone-specific alkaline phosphatase (a bone-formation marker); and markers of osteoclastogenesis, such as osteoprotegerin.

They determined that ααCTX—which is the nonisomerized form of the C-telopeptide of collagen type I—correlated most closely with the Soloway score quantification of bone metastases. “We have shown that, for a Soloway score of 1, indicating fewer than six metastases, ααCTX is approximately 200% increased. With a Soloway score of 3, when more than 20 metastases are present, ααCTX is elevated more than 600%,” said Dr. Leeming of Nordic Bioscience A/S, Herlev, Denmark.

The current study included 90 patients with newly diagnosed breast cancer; 45 had bone metastases verified by 99Tc scintigraphy or other imaging studies. The concentration of CTX fragments was measured in morning urine using ELISA (amyloid-β peptide enzyme-linked immunosorbent assay). There were no differences in age or body mass index between patients with and without metastases.

Mean ααCTX in patients without metastases was 0.39 mcg/mmol, a level that correlates with that seen in normal, age-matched healthy controls. For the group with metastases, however, the level was significantly higher, at 1.23 mcg/mmol, according to Dr. Leeming. Analysis also revealed that the presence of one, two, and three metastases was associated with increases of 38%, 57%, and 81% in ααCTX, respectively.

“This suggests that ααCTX may be sufficiently sensitive to detect the first bone metastasis,” she said. Histologic analysis of bone biopsy specimens using cytokeratin and tartrate-resistant acid phosphatase (TRACP) staining confirmed the localized presence of ααCTX and an increased number of osteoclasts near the tumor. The production of CTX is part of a vicious cycle, in which breast cancer cells induce RANK-L (receptor activator of nuclear factor kappa β ligand) in osteoblasts by a number of cytokines, Dr. Leeming explained. This in turn increases the number and survival of osteoclasts, and when osteoclasts resorb bone they release proteins and growth factors from the matrix, further activating cancer cells.

“This high bone remodeling could explain the release of increased levels of ααCTX,” said Dr. Leeming at the meeting, which was sponsored by the International Osteoporosis Foundation.

TORONTO — Increased urinary excretion of a biomarker of bone resorption signals the presence and extent of bone metastases in breast cancer patients, Dr. Diana J. Leeming said at a world congress on osteoporosis.

Technetium-99 (99Tc) bone scintigraphy remains the standard method of detecting skeletal metastases in cancer patients. However, this approach is not suitable for close, frequent monitoring because of significant radiation exposure, Dr. Leeming said.

She and her colleagues previously investigated a number of biomarkers to determine if their presence correlated with the number and extent of bone metastases (Cancer Epidemiol. Biomarkers Prev. 2006;15:32-8). Among these were the resorption markers ααCTX and ββCTX; bone-specific alkaline phosphatase (a bone-formation marker); and markers of osteoclastogenesis, such as osteoprotegerin.

They determined that ααCTX—which is the nonisomerized form of the C-telopeptide of collagen type I—correlated most closely with the Soloway score quantification of bone metastases. “We have shown that, for a Soloway score of 1, indicating fewer than six metastases, ααCTX is approximately 200% increased. With a Soloway score of 3, when more than 20 metastases are present, ααCTX is elevated more than 600%,” said Dr. Leeming of Nordic Bioscience A/S, Herlev, Denmark.

The current study included 90 patients with newly diagnosed breast cancer; 45 had bone metastases verified by 99Tc scintigraphy or other imaging studies. The concentration of CTX fragments was measured in morning urine using ELISA (amyloid-β peptide enzyme-linked immunosorbent assay). There were no differences in age or body mass index between patients with and without metastases.

Mean ααCTX in patients without metastases was 0.39 mcg/mmol, a level that correlates with that seen in normal, age-matched healthy controls. For the group with metastases, however, the level was significantly higher, at 1.23 mcg/mmol, according to Dr. Leeming. Analysis also revealed that the presence of one, two, and three metastases was associated with increases of 38%, 57%, and 81% in ααCTX, respectively.

“This suggests that ααCTX may be sufficiently sensitive to detect the first bone metastasis,” she said. Histologic analysis of bone biopsy specimens using cytokeratin and tartrate-resistant acid phosphatase (TRACP) staining confirmed the localized presence of ααCTX and an increased number of osteoclasts near the tumor. The production of CTX is part of a vicious cycle, in which breast cancer cells induce RANK-L (receptor activator of nuclear factor kappa β ligand) in osteoblasts by a number of cytokines, Dr. Leeming explained. This in turn increases the number and survival of osteoclasts, and when osteoclasts resorb bone they release proteins and growth factors from the matrix, further activating cancer cells.

“This high bone remodeling could explain the release of increased levels of ααCTX,” said Dr. Leeming at the meeting, which was sponsored by the International Osteoporosis Foundation.

TORONTO — Increased urinary excretion of a biomarker of bone resorption signals the presence and extent of bone metastases in breast cancer patients, Dr. Diana J. Leeming said at a world congress on osteoporosis.

Technetium-99 (99Tc) bone scintigraphy remains the standard method of detecting skeletal metastases in cancer patients. However, this approach is not suitable for close, frequent monitoring because of significant radiation exposure, Dr. Leeming said.

She and her colleagues previously investigated a number of biomarkers to determine if their presence correlated with the number and extent of bone metastases (Cancer Epidemiol. Biomarkers Prev. 2006;15:32-8). Among these were the resorption markers ααCTX and ββCTX; bone-specific alkaline phosphatase (a bone-formation marker); and markers of osteoclastogenesis, such as osteoprotegerin.

They determined that ααCTX—which is the nonisomerized form of the C-telopeptide of collagen type I—correlated most closely with the Soloway score quantification of bone metastases. “We have shown that, for a Soloway score of 1, indicating fewer than six metastases, ααCTX is approximately 200% increased. With a Soloway score of 3, when more than 20 metastases are present, ααCTX is elevated more than 600%,” said Dr. Leeming of Nordic Bioscience A/S, Herlev, Denmark.

The current study included 90 patients with newly diagnosed breast cancer; 45 had bone metastases verified by 99Tc scintigraphy or other imaging studies. The concentration of CTX fragments was measured in morning urine using ELISA (amyloid-β peptide enzyme-linked immunosorbent assay). There were no differences in age or body mass index between patients with and without metastases.

Mean ααCTX in patients without metastases was 0.39 mcg/mmol, a level that correlates with that seen in normal, age-matched healthy controls. For the group with metastases, however, the level was significantly higher, at 1.23 mcg/mmol, according to Dr. Leeming. Analysis also revealed that the presence of one, two, and three metastases was associated with increases of 38%, 57%, and 81% in ααCTX, respectively.

“This suggests that ααCTX may be sufficiently sensitive to detect the first bone metastasis,” she said. Histologic analysis of bone biopsy specimens using cytokeratin and tartrate-resistant acid phosphatase (TRACP) staining confirmed the localized presence of ααCTX and an increased number of osteoclasts near the tumor. The production of CTX is part of a vicious cycle, in which breast cancer cells induce RANK-L (receptor activator of nuclear factor kappa β ligand) in osteoblasts by a number of cytokines, Dr. Leeming explained. This in turn increases the number and survival of osteoclasts, and when osteoclasts resorb bone they release proteins and growth factors from the matrix, further activating cancer cells.

“This high bone remodeling could explain the release of increased levels of ααCTX,” said Dr. Leeming at the meeting, which was sponsored by the International Osteoporosis Foundation.