AIM: Current diagnostics of bone metastatic disease is not satisfactory for early detection or regular process monitoring. The combination of biomarkers and the multiparametric approach was described as effective in other oncology diagnoses. The aim of the study was to improve the difference diagnostics between bone-metastatic disease and solid tumors using mutivariate logistic regression model. METHODS: We assessed the group of 131 patients with the following diagnoses: prostate cancer, breast cancer, lung cancer, and colorectal cancer. According to the results of scintigraphy, the cohort was divided into 2 groups based on the occurrence of bone metastases. Group 0 was a control group of 75 patients with no signs of bone metastases and group 1 included 56 patients with bone metastases. RESULTS: We used stepwise selection multivariate logistic regression for choosing the multimarker formula for calculation of risk score for bone metastases diagnostics. For detection of bone metastasis, it was shown to be most effective measurement of 3 biomarkers: procollagen type 1 N-terminal propeptide, growth differentiation factor-15, and osteonectin and combining with calculation of risk score by designating measured concentrations in mathematical formula: bone risk score = procollagen type 1 N-terminal propeptide × 0.0500 + growth differentiation factor-15 × 1.4179 + osteonectin × 0.00555. CONCLUSION: We identified growth differentiation factor-15 as the best individual marker for bone metastasis diagnostics. The best formula for risk score includes levels of 3 biomarkers-procollagen type 1 N-terminal propeptide, growth differentiation factor-15, and osteonectin. The new score has better performance described by higher area under the curve than individual biomarkers. A further study is necessary to confirm these findings incorporating a larger number of patients.

Biomedical Center Faculty of Medicine in Pilsen Charles University Plzen Czech Republic

Department of Immunochemistry University Hospital and Faculty of Medicine in Pilsen Charles University Plzen Czech Republic

Department of Oncology and Radiotherapy University Hospital and Faculty of Medicine in Pilsen Charles University Plzen Czech Republic

Osteocenter 2nd Internal Clinic University Hospital Pilsen Pilsen Czech Republic

Zobrazit více v PubMed

Huang Q, Ouyang X. Biochemical-markers for the diagnosis of bone metastasis: a clinical review. Cancer Epidemiol. 2012:36(1):94–98. PubMed

Virk MS, Lieberman JR. Tumor metastasis to bone. Arthritis Res Ther. 2007:9(suppl 1):S5. PubMed PMC

Eccles SA, Welch DR. Metastasis: recent discoveries and novel treatment strategies. Lancet. 2016:369(9574):1742–1757. PubMed PMC

Molina R, Marrades RM, Auge JM, et al. Assessment of a combined panel of six serum tumor markers for lung cancer. Am J Respir Crit Care Med. 2016:193(4):427–437. PubMed

Visintin I, Feng Z, Longton G, et al. Diagnostic markers for early detection of ovarian cancer. Clin Cancer Res. 2008:14(4):1065–1072. PubMed

Yurkovetsky Z, Skates S, Lomakin A, et al. Development of a multimarker assay for early detection of ovarian cancer. J Clinl Oncol. 2010:28(13):2159–2166. PubMed PMC

Kucera R, Smid D, Topolcan O, et al. Searching for new biomarkers and the use of multivariate analysis in gastric cancer diagnostics. Anticancer Res. 2016:36(4):1967–1971. PubMed

Tosoian JJ, Loeb S, Feng Z, et al. Association of (-2)proPSA with biopsy reclassification during active surveillance for prostate cancer. J Urol. 2012:188(4):1131–1136. PubMed PMC

Li C, Wang X, Casal I, et al. Growth differentiation factor 15 is a promising diagnostic and prognostic biomarker in colorectal cancer. J Cell Mol Med. 2016:20(8):1420–1426. PubMed PMC

Xue H, Lu B, Zhang J, et al. Identification of serum biomarkers for colorectal cancer metastasis using a differential secretome approach. J Proteome Res. 2010:9(1):545–555. PubMed

Suesskind D, Schatz A, Schnichels S, et al. GDF-15: a novel serum marker for metastases in uveal melanoma patients. Graefes Arch Clin Exp Ophthalmol. 2012:250(6):887–895. PubMed

Selander KS, Brown DA, Sequeiros GB, et al. Serum macrophage inhibitory cytokine-1 concentrations correlate with the presence of prostate cancer bone metastases. Cancer Epidemiol Biomarkers Prev. 2007:16(3):532–537. PubMed

Lee YC, Gajdosik MS, Josic D, et al. Secretome analysis of an osteogenic prostate tumor identifies complex signaling networks mediating cross-talk of cancer and stromal cells within the tumor microenvironment. Mol Cell Proteomics. 2015:14(3):471–483. PubMed PMC

Windrichova J, Fuchsova R, Kucera R, et al. MIC1/GDF15 as a bone metastatic disease biomarker. Anticancer Res. 2017:37(3):1501–1505. PubMed

Lumachi F, Santeufemia DA, Del Conte A, et al. Carboxy-terminal telopeptide (CTX) and amino-terminal propeptide (PINP) of type I collagen as markers of bone metastases in patients with non-small cell lung cancer. Anticancer Res. 2013:33(6):2593–2596. PubMed

Brasso K, Christensen IJ, Johansen JS, et al. Prognostic value of PINP, bone alkaline phosphatase, CTX-I, and YKL-40 in patients with metastatic prostate carcinoma. Prostate. 2006:66(5):503–513. PubMed

Brown JE, McCloskey EV, Dewar JA, et al. The use of bone markers in a 6-week study to assess the efficacy of oral clodronate in patients with metastatic bone disease. Calcif Tissue Int. 2007:81(5):341–351. PubMed

Brown J, Rathbone E, Hinsley S, et al. Associations between serum bone biomarkers in early breast cancer and development of bone metastasis: results from the AZURE (BIG01/04) trial. J Natl Cancer Inst. 2018;110(8):871–879. PubMed PMC

Ell B, Mercatali L, Ibrahim T, et al. Tumor-induced osteoclast miRNA changes as regulators and biomarkers of osteolytic bone metastasis. Cancer Cell. 2013:24(4):542–556. PubMed PMC

Johansen JS, Brasso K, Iversen P, et al. Changes of biochemical markers of bone turnover and YKL-40 following hormonal treatment for metastatic prostate cancer are related to survival. Clin Cancer Res. 2007:13(11):3244–3249. PubMed

D’Oronzo S, Brown J, Coleman R. The role of biomarkers in the management of bone-homing malignancies. J Bone Oncol. 2017;9:1–9. PubMed PMC

Liu X, Chi X, Gong Q, et al. Association of serum level of growth differentiation factor 15 with liver cirrhosis and hepatocellular carcinoma. Plos One. 2015:10(5):e0127518. PubMed PMC

Mohamed AA, Soliman H, Ismail M, et al. Evaluation of circulating ADH and MIC-1 as diagnostic markers in Egyptian patients with pancreatic cancer. Pancreatology. 2015:15(1):34–39. PubMed