Validity of bone marker measurements for monitoring response to bisphosphonate therapy with zoledronic acid in metastatic breast cancer

Aktas,Bahriye; Kasimir-Bauer,Sabine; Lehmann,Nils; Kimmig,Rainer; Tewes,Mitra

doi:10.3892/or.2013.2409

Validity of bone marker measurements for monitoring response to bisphosphonate therapy with zoledronic acid in metastatic breast cancer

Authors:
- Bahriye Aktas
- Sabine Kasimir-Bauer
- Nils Lehmann
- Rainer Kimmig
- Mitra Tewes
View Affiliations

Affiliations: Department of Gynecology and Obstetrics, University of Duisburg-Essen, D-45122 Essen, Germany, IMIBE, Institute for Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen, D-45122 Essen, Germany, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, D-45122 Essen, Germany
Published online on: April 22, 2013 https://doi.org/10.3892/or.2013.2409
Pages: 441-447

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Bone is the most common site of metastasis in breast cancer. Detection relies on imaging technology which is costly and can only be performed to a certain degree. Bone markers are non-invasive, inexpensive and may potentially serve as predictive and prognostic surrogate endpoints in detecting bone metastases and response to bisphosphonates. This study analyzed the value of the serum bone turnover markers PINP and ICTP for bone metastases in metastatic breast cancer patients receiving zoledronic acid. The results were compared with the serum levels of CEA and CA 15-3, and analyzed with respect to the number of bone metastases as well as clinical response. Forty patients with confirmed bone metastases who received chemotherapy and/or hormonal therapy and zoledronic acid i.v. q4 weeks participated in the present study. blood (5 ml) was collected at the start of the study and q3 months for a period of one year for the analysis of PINP, ICTP, CEA and CA 15-3 using radioimmunoassays and ELISA, respectively. Imaging of bone metastases was performed at the same time points. In 29 out of 40 patients, more than 3 bone metastases were confirmed by imaging and 11 out of 40 patients presented with 3 or less. At the start of the study, the median value for ICTP was 6 µg/l and for PINP 58.7 µg/l. At the end of the study the median values were 4.5 µg/l for ICTP and 21 µg/l for PINP. When patients were stratified into responders and non-responders, a decrease in both PINP (P<0.0001) and ICTP (P=0.048) was observed for the responders, while the level of ICTP (P=0.02) increased for the non-responders. Serum PINP and ICTP concentrations were significantly different when patients were stratified into groups of those having more than 3 bone metastases and 3 or less, respectively (P<0.05). CEA and CA 15-3 levels did not differ with respect to the number of bone metastases, while the tumor marker levels determined at the end of the study significantly distinguished responders from non-responders (P=0.002 and P=0.004). In conclusion, in contrast to serum tumor markers, the determination of PINP and ICTP allows inferences to the number of bone metastases and appears to be a useful tool for prediction and monitoring metastatic breast cancer patients undergoing bisphosphonate therapy with zoledronic acid for the treatment of bone metastases.

View Figures

View References

1	Plebani M, Bernardi D, Zanninotto M, De Paoli M, Secchiero S and Sciacovelli L: New and traditional serum markers of bone metabolism in the detection of skeletal metastases. Clin Biochem. 29:67–72. 1996. View Article : Google Scholar : PubMed/NCBI
2	Rosenthal DI: Radiologic diagnosis of bone metastases. Cancer. 80:1595–1607. 1997. View Article : Google Scholar : PubMed/NCBI
3	Jung K, Lein M, Stephan C, Von HK, Semjonow A and Sinha P: Comparison of 10 serum bone turnover markers in prostate carcinoma patients with bone metastatic spread: diagnostic and prognostic implications. Int J Cancer. 111:783–791. 2004. View Article : Google Scholar : PubMed/NCBI
4	O’Sullivan JM and Cook GJ: A review of the efficacy of bone scanning in prostate and breast cancer. Q J Nucl Med. 46:152–159. 2002.PubMed/NCBI
5	Costa L, Demers LM, Gouveia-Oliveira A, Schaller J, Costa EB, Moura MC and Lipton A: Prospective evaluation of the peptide-bound collagen type I cross-links N-telopeptide and C-telopeptide in predicting bone metastases status. J Clin Oncol. 20:850–856. 2002. View Article : Google Scholar : PubMed/NCBI
6	Lipton A, Costa L, Ali S and Demers L: Use of markers of bone turnover for monitoring bone metastases and the response to therapy. Semin Oncol. 28(4 Suppl 11): 54–59. 2001. View Article : Google Scholar : PubMed/NCBI
7	Green JR: Bisphosphonates: preclinical review. Oncologist. 9(Suppl 4): 3–13. 2004. View Article : Google Scholar
8	Coleman RE: The clinical use of bone resorption markers in patients with malignant bone disease. Cancer. 94:2521–2533. 2001. View Article : Google Scholar : PubMed/NCBI
9	Roodman GD: Mechanisms of bone metastases. N Engl J Med. 350:1655–1664. 2004. View Article : Google Scholar : PubMed/NCBI
10	Rosen LS, Gordon D, Kaminski M, Howell A, Belch A, Mackey J, Apffelstaedt J, Hussein MA, Coleman RE, Reitsma DJ, Chen BL and Seaman JJ: Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with non-small cell lung carcinoma and other solid tumors: a randomized, phase III, double-blind, placebo-controlled trial. Cancer. 98:1735–1744. 2003.PubMed/NCBI
11	Saad F, Gleason D, Murray R, Tchekmedyian S, Venner P, Lacombe L, Chin J, Vinholes J, Goas A and Zheng M; for the Zoledronic Acid Prostate Cancer Study Group. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst. 96:879–882. 2004. View Article : Google Scholar
12	Pecherstorfer M, Zimmer-Roth I, Schilling T, Woitge HW, Schmidt H, Baumgartner G, et al: The diagnostic value of pyridinium cross-links of collagen, serum total alkaline phosphatase, and urinary calcium excretion in neoplastic bone disease. J Clin Endocrinol Metab. 80:97–103. 1995.
13	Vogel CL, Schoenfelder J, Shemano I, Hayes DF and Gams RA: Worsening bone scan in the evaluation of antitumor response during hormonal therapy of breast cancer. J Clin Oncol. 13:1123–1128. 1995.PubMed/NCBI
14	Pollen JF, Witztum KF and Ashburn WL: The flare phenomenon on radionuclide bone scan in metastatic prostate cancer. AJR Am J Roentgenol. 142:773–776. 1984. View Article : Google Scholar : PubMed/NCBI
15	Huang Q and Ouyang X: Biochemical-markers for the diagnosis of bone metastasis: a clinical review. Cancer Epidemiol. 6:94–98. 2011.
16	Seibel MJ: Clinical use of markers of bone turnover in metastatic bone disease. Nat Clin Pract Oncol. 2:504–517. 2005. View Article : Google Scholar : PubMed/NCBI
17	Coleman R, Brown J, Terpos E, Lipton A, Smith MR, Cook R and Major P: Bone markers and their prognostic value in metastatic bone disease: clinical evidence and future directions. Cancer Treat Rev. 34:629–639. 2008. View Article : Google Scholar : PubMed/NCBI
18	Seibel MJ: The use of molecular markers of bone turnover in the management of patients with metastatic bone disease. Clin Endocrinol. 68:839–849. 2008. View Article : Google Scholar : PubMed/NCBI
19	Cremers S and Garnero P: Biochemical markers of bone turnover in the clinical development of drugs for osteoporosis and metastatic bone disease: potential uses and pitfalls. Drugs. 66:2031–2058. 2006. View Article : Google Scholar : PubMed/NCBI
20	Brown JE, Cook RJ, Major P, Lipton A, Saad F, Smith M, Lee KA, Zheng M, Hei YJ and Colemann RE: Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst. 97:59–69. 2005. View Article : Google Scholar : PubMed/NCBI
21	Pollmann D, Siepmann S, Geppert R, Wernecke KD, Possinger K and Lüftner D: The amino-terminal propeptide (PINP) of type I collagen is a clinically valid indicator of bone turnover and extent of metastatic spread in osseous metastatic breast cancer. Anticancer Res. 27:1853–1862. 2007.PubMed/NCBI
22	Costa L, Demers LM, Speicher T, Gouveia Curley E, Harvey H, et al: Biochemical markers of bone turnover correlate with the extent of metastatic bone disease. In: American Society of Clinical Oncology 35th Annual Meeting; Philadelphia. 1999
23	Berruti A, Dogliotti L, Gorzegno G, Torta M, Tampellini M, Tucci M, Cerutti S, Frezet MM, Stivanello M, Sacchetto G and Angeli A: Differential patterns of bone turnover in relation to bone pain and disease extent in bone in cancer patients with skeletal metastases. Clin Chem. 45:1240–1247. 1999.PubMed/NCBI
24	Demers LM: Biochemical markers in the management of patients with metastatic bone disease. Clin Chem. 45:1131–1132. 1999.PubMed/NCBI
25	Ikeda I, Miura T and Kondo I: Pyridinium cross-links as urinary markers of bone metastases in patients with prostate cancer. Br J Urol. 77:102–106. 1996. View Article : Google Scholar : PubMed/NCBI
26	Costa L, Demers LM, Gouveia A, Schalla J, Costa EB, Demoura MC and Lipton A: Correlation of urinary N-telopeptide levels with progression of bone metastases: a prospective study (Abstract 12). Cancer. 88(Suppl): 30942000.
27	Zafeirakis A: Collagenous and non-collagenous biochemical markers of bone metastases from prostate cancer. Hippokratia. 14:164–169. 2010.PubMed/NCBI
28	Lipton A, Cook R, Saad F, Major P, Garnero P, Terpos E, Brown JE and Coleman RE: Normalization of bone markers is associated with improved survival and elevated bone resorption receiving zoledronic acid. Cancer. 113:193–201. 2008. View Article : Google Scholar : PubMed/NCBI
29	Pons-Anicet DMF, Krebs BP, Mira R and Namer M: Value of CA 15:3 in the follow-up of breast cancer patients. Br J Cancer. 55:567–569. 1987. View Article : Google Scholar : PubMed/NCBI
30	Yildiz M, Oral B, Bozkurt M and Cobaner A: Relationship between bone scintigraphy and tumor markers in patients with breast cancer. Ann Nucl Med. 18:501–505. 2004. View Article : Google Scholar : PubMed/NCBI
31	Buamah PK, Bent DJ, Bodger WAH and Skillen AW: A profile of serum CA 15-3, carcinoembryonic antigen, alkaline phosphatase, and γ-glutamyl transferase levels in patients with breast cancer. J Surg Oncol. 53:84–87. 1993.PubMed/NCBI