Adjuvant pamidronate therapy prevents the development of bone metastases in breast cancer patients with four or more positive nodes

Kokufu,Ikuo; Kohno,Norio; Yamamoto,Masayuki; Takao,Shintaro

doi:10.3892/ol_00000044

Adjuvant pamidronate therapy prevents the development of bone metastases in breast cancer patients with four or more positive nodes

Authors:
- Ikuo Kokufu
- Norio Kohno
- Masayuki Yamamoto
- Shintaro Takao
View Affiliations

Affiliations: Department of Surgery, Itami City Hospital, Itami 664-8540, Japan
Published online on: March 1, 2010 https://doi.org/10.3892/ol_00000044
Pages: 247-252

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

Bisphosphonates are strongly efficacious in inhibiting osteoclast bone resorption and have beneficial effects on bone metastasis. Due to their mechanism of action, bisphosphonates are expected to prevent the development of bone metastases in breast cancer patients. Pamidronate is a potent inhibitor of osteoclast activity. We examined whether pamidronate was able to prevent the development of bone metastases in breast cancer patients at high risk for bone metastasis. Between 1997 and 2001, 90 patients with primary breast cancer with ≥4 positive nodes were assigned to receive 45 mg pamidronate 4 times every 2 weeks (33 patients) or standard follow-up (57 patients) based on patient self-preference. Patients underwent surgery and adjuvant therapy. The characteristics of the patients in the two groups were well-balanced. The median follow-up period was 5 years. Bone metastases were detected in 12.1% of patients in the pamidronate group and 40.4% in the control group (p=0.005). Distant metastases (36.4 vs. 56.1%, p=0.071) and non-osseous metastases (33.3 vs. 52.6%, p=0.077) were detected at a lower frequency in the pamidronate group. Thus, the rate of bone metastasis-free survival was significantly higher in the pamidronate group (85.9 vs. 64.0% at 5 years, p=0.023). Overall and disease-free survival rates did not differ between the two groups. In the pamidronate group, the incidence of bone metastases was significantly reduced and bone metastasis-free survival was significantly higher. Adjuvant pamidronate therapy therefore prevents the development of bone metastases in breast cancer patients with ≥4 positive nodes.

View Figures

View References

1	Rodan GA and Fleisch HA: Bisphosphonates: mechanisms of action. J Clin Invest. 97:2692–2696. 1996. View Article : Google Scholar : PubMed/NCBI
2	Hortobagyi GN, Theriault RL, Porter L, Blayney D, Lipton A, Sinoff C, Wheeler H, Simeone JF, Seaman J and Knight RD: Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group. N Engl J Med. 335:1785–1791. 1996. View Article : Google Scholar : PubMed/NCBI
3	Hughes DE, Wright KR, Uy HL, Sasaki A, Yoneda T, Roodman GD, Mundy GR and Boyce BF: Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo. J Bone Miner Res. 10:1478–1487. 1995. View Article : Google Scholar : PubMed/NCBI
4	Jagdev SP, Coleman RE, Shipman CM, Rostami HA and Croucher PI: The bisphosphonate, zoledronic acid induces apoptosis of breast cancer cells: evidence for synergy with paclitaxel. Br J Cancer. 84:1126–1134. 2001. View Article : Google Scholar : PubMed/NCBI
5	Crohns CA, Untch M and Konecny G: Different bisphosphonates have direct cytotoxic effects on three breast cancer cell lines and fresh breast cancer tumor tissue. Proc Am Soc Clin Oncol. 20:abs. 20052001.
6	Santini D, Vespasiani Gentilucci U, Vincenzi B, Picardi A, Vasaturo F, La Cesa A, Onori N, Scarpa S and Tonini G: The antineoplastic role of bisphosphonates: from basic research to clinical evidence. Ann Oncol. 14:1468–1476. 2003. View Article : Google Scholar : PubMed/NCBI
7	Teronen O, Heikkila P, Konttinen YT, Laitinen M, Salo T, Hanemaaijer R, Teronen A, Maisi P and Sorsa T: MMP inhibition and down-regulation by bisphosphonates. Ann NY Acad Sci. 878:453–465. 1999. View Article : Google Scholar : PubMed/NCBI
8	Paterson AH: The potential role of bisphosphonates as adjuvant therapy in the prevention of bone metastases. Cancer. 88:3038–3046. 2000. View Article : Google Scholar : PubMed/NCBI
9	Sasaki A, Boyce BF, Story B, Wright KR, Chapman M, Boyce R, Mundy GR and Yoneda T: Bisphosphonate risedronate reduces metastatic human breast cancer burden in bone in nude mice. Cancer Res. 55:3551–3557. 1995.PubMed/NCBI
10	Van der Pluijm G, Vloedgraven H, Van Beek E, Van der Wee-Pals L, Lowik C and Papapoulos S: Bisphosphonates inhibit the adhesion of breast cancer cells to bone matrices in vitro. J Clin Invest. 98:698–705. 1996.
11	Diel IJ, Solomayer EF, Costa SD, Gollan C, Goerner R, Wallwiener D, Kaufmann M and Bastert G: Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med. 339:357–363. 1998. View Article : Google Scholar : PubMed/NCBI
12	Diel IJ, Solomayer EF, Gollan C, Schutz F and Bastert G: Bisphosphonates in the reduction of metastases in breast cancer - results of the extended follow-up of the first study population. Proc Am Soc Clin Oncol. 19:abs. 3142000.
13	Jaschke A, Bastert G, Solomayer EF, Costa S, Schuetz F and Diel IJ: Adjuvant clodronate treatment improves the overall survival of primary breast cancer patients with micrometastases to bone marrow - a longtime follow-up. J Clin Oncol. 22:abs. 5292004.
14	Powles T, Paterson S, Kanis JA, McCloskey E, Ashley S, Tidy A, Rosenqvist K, Smith I, Ottestad L, Legault S, Pajunen M, Nevantaus A, Mannisto E, Suovuori A, Atula S, Nevalainen J and Pylkkanen L: Randomized placebo-controlled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol. 20:3219–3224. 2002. View Article : Google Scholar : PubMed/NCBI
15	Powles T, Paterson A, McCloskey E, Kurkilahti M and Kanis J: Oral clodronate for adjuvant treatment of operable breast cancer: results of a randomized, double-blind, placebo-controlled multicenter trial. J Clin Oncol. 22:abs. 5282004.PubMed/NCBI
16	Saarto T, Blomqvist C, Virkkunen P and Elomaa I: Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5-year results of a randomized controlled trial. J Clin Oncol. 19:10–17. 2001.PubMed/NCBI
17	Saarto T, Vehmanen L, Blomqvist C and Elomaa I: Ten-year follow-up of a randomized controlled trial of adjuvant clodronate treatment in node-positive breast cancer patients. J Clin Oncol. 22:abs. 5272004.PubMed/NCBI
18	Colleoni M, O’Neill A, Goldhirsch A, Gelber RD, Bonetti M, Thurlimann B, Price KN, Castiglione-Gertsch M, Coates AS, Lindtner J, Collins J, Senn HJ, Cavalli F, Forbes J, Gudgeon A, Simoncini E, Cortes-Funes H, Veronesi A, Fey M and Rudenstam CM: Identifying breast cancer patients at high risk for bone metastases. J Clin Oncol. 18:3925–3935. 2000.PubMed/NCBI
19	Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thurlimann B and Senn HJ: Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol. 18:1133–1144. 2007. View Article : Google Scholar : PubMed/NCBI
20	Michiqami T, Wiliams P and Dallas M: Bisphosphonate may increase metastases to soft tissue sites in breast cancer and B-cell lymphoma. J Bone Miner Res. 12(Suppl 1): s106abs 115. 1997.
21	Leyvraz S, Hess U, Flesch G, Bauer J, Hauffe S, Ford JM and Burckhardt P: Pharmacokinetics of pamidronate in patients with bone metastases. J Natl Cancer Inst. 84:788–792. 1992. View Article : Google Scholar : PubMed/NCBI
22	Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Poestlberger S, Menzel C, Jakesz R, Kubista E, Marth C and Greil R; on behalf of the ABCSG. Adjuvant ovarian suppression combined with tamoxifen or anastrozole, alone or in combination with zoledronic acid, in premenopausal women with hormone-responsive, stage I and II breast cancer: First efficacy results from ABCSG-12. J Clin Oncol. 26:abs. LBA 42008.