Bone Metastases in Breast Cancer: How to Prevent?
Authors: Mahmut Ozsahin, Marco Colleoni, Aron Goldhirsch, Alan Coates, Rich Gelber, Monica Castiglione-Gertsch
Journal: Journal of Clinical Oncology (2001)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2001.19.10.2764 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11352970 Bone Metastases in Breast Cancer: How to Prevent? Mahmut OzsahinxMahmut OzsahinSearch for articles by this author Marco ColleonixMarco ColleoniSearch for articles by this author , Aron GoldhirschxAron GoldhirschSearch for articles by this author , Alan CoatesxAlan CoatesSearch for articles by this author , Rich GelberxRich GelberSearch for articles by this author , Monica Castiglione-GertschxMonica Castiglione-GertschSearch for articles by this author , Show More Centre Hospitalier Universitaire Vaudois, Lausanne, SwitzerlandEuropean Institute of Oncology, Milan, ItalyUniversity of Sydney, Royal Prince Alfred Hospital, Sydney, AustraliaInternational Breast Cancer Study Group Statistical Center, Frontier Science and Technology Research Foundation, Boston, MAInternational Breast Cancer Study Group Coordination Center, Bern, Switzerland https://doi.org/10.1200/JCO.2001.19.10.2764 First Page Full Text PDF Figures and Tables © 2001 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse15052001In Reply:Our article describing identification of populations at high risk for bone metastases1 stimulated Dr Ozsahin to raise two interesting issues, though neither is directly related to the data or conclusions of our study. First, we agree that the role of biphosphonates in preventing bone metastases remains controversial. Second, the role of postmastectomy radiation therapy in improving local control of disease and reducing subsequent metastases has been supported by the recent overview,2 and this may also apply to metastases to bone, although that information is not available from the overview.A statistically significant reduction of new bone (and also visceral) metastases was observed with the clodronate treatment in one study on 302 patients.3 A second study on 1,079 patients with primary breast cancer demonstrated a clinically relevant reduction in the incidence of bony lesions with oral clodronate when compared with placebo (RR = 0.51; 95% confidence interval, 0.30 to 0.88; P = .012).4 A third study conducted on 282 patients and presented with a 5-year follow-up showed that the use of oral clodronate did not improve overall outcome and did not have a beneficial effect on the incidence of bone metastases.5 As shown in our paper,1 long-term high incidence of bone relapse can be predicted especially after estrogen receptor–positive primaries, suggesting that a more prolonged follow-up might be required to better define the role of bisphosphonates. Therefore, we concluded that there is enough evidence to support further well-designed studies on the effects of these compounds, especially within a subpopulation at high risk of bone metastases, a conclusion that is entirely in agreement with the American Society of Clinical Oncology guidelines for the use and research on bisphosphonates in breast cancer.6Available results from the Early Breast Cancer Trialists’ Collaborative Group on the effects of radiotherapy for patients with early breast cancer indicated that radiotherapy was associated with a reduced risk of death caused by breast cancer (ratio of survival at 20 years, 0.911; SE, 0.017; 2P = .0001) but an increased risk of death from other causes (ratio of survival, 1.061; SE, 0.02; 2P = .0003).2 The balance between these favorable and unfavorable effects was related to absolute risk and patient age.2 Three recent trials have shown that postmastectomy irradiation added to a chemotherapy regimen containing cyclophosphamide, methotrexate, and fluorouracil (CMF)7,8 or tamoxifen9 improved disease-free and overall survival. The CMF regimens used in the Danish and Canadian trials were altered from the classical CMF regimen first reported as an effective adjuvant therapy almost 30 years ago. Several randomized trials have shown that departure from the classical CMF regimen compromises its efficacy in metastatic breast cancer,10 as we have previously commented.11,12 In the second trial by the Danish Group, tamoxifen was given for the duration of 1 year, clearly a suboptimal systemic therapy. Further clinical trials now being conducted in Europe and the United States may help to clarify the role of radiation therapy after mastectomy. Radiotherapy is clearly indicated if it is still possible in patients with excised local recurrence. Meanwhile, it is reasonable to investigate the role of bisphosphonates in combination with optimal systemic treatment and with radiation therapy, if the risk of local recurrence and patient age suggest the probability of net benefit.2 An efficacy study of this question will be facilitated by selection of a study population at increased risk of bone metastasis. The definition of such a population was the purpose of our article.1. Colleoni M, O’Neill A, Goldhirsch A, et al: Identifying breast cancer patients at high risk for bone metastases. J Clin Oncol 18:: 3925,2000-3935, Link, Google Scholar2. Early Breast Cancer Trialists’ Collaborative Group: Favourable and unfavourable effects on long term survival of radiotherapy for early breast cancer: An overview of the randomized trials. Lancet 355:1757-1770, 2000 Google Scholar3. Diel IJ, Solomayer EF, Costa SD, et al: Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 339:: 357,1998-363, Crossref, Medline, Google Scholar4. Powles TJ, McCloskey E, Paterson A, et al: Adjuvant clodronate will reduce the incidence of bone metastases in patients with primary operable breast cancer. Twenty-First Annual San Antonio Breast Cancer Symposium, San Antonio TX, December 12-15, 1998 (abstr) Google Scholar5. Saarto T, Blomqvist C, Virkkunen P, et al: 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:: 10,2001-17, Link, Google Scholar6. Hillner BE, Ingle JN, Berenson JR, et al: American Society of Clinical Oncology guideline on the role of bisphosphonates in breast cancer. J Clin Oncol 18:: 1378,2000-1391, Link, Google Scholar7. Overgaard M, Hansen PS, Overgaard J, et al: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 337:: 949,1997-955, Crossref, Medline, Google Scholar8. Ragaz J, Jackson SM, Le N, et al: Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast. N Engl J Med 337:: 956,1997-962, Crossref, Medline, Google Scholar9. Overgaard M, Jensen MB, Overgaard J, et al: Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Dansish Breast Cancer Cooperative Group DBCG 82c randomized trial. Lancet 353:: 1641,1999-1648, Crossref, Medline, Google Scholar10. Engelsman E, Klijn JC, Rubens RD, et al: “Classical” CMF versus a 3-weekly intravenous CMF schedule in postmenopausal patients with advanced breast cancer: An EORTC Breast Cancer Cooperative Group phase III trial (10808). Eur J Cancer 27:: 966,1991-970, Crossref, Medline, Google Scholar11. Goldhirsch A, Colleoni M, Coates AS, et al: Adding adjuvant CMF chemotherapy to either radiotherapy or tamoxifen: Are all CMFs alike? Ann Oncol 9:: 489,1998-493, Crossref, Medline, Google Scholar12. Goldhirsch A, Coates AS, Colleoni M, et al: Radiotherapy and chemotherapy in high-risk breast cancer. N Engl J Med 338:: 330,,1998 (letter) Medline, Google Scholar