Sixty Is the New Forty-or Is It the Other Way Around?

Bisphosphonates and denosumab (Xgeva) are approved by the US Food and Drug Administration to reduce the risk of skeletal-related events in breast cancer patients with bone metastases, and for the treatment of osteoporosis.[1] Preclinical studies and emerging clinical observations have suggested that, in addition to improving bone health, bisphosphonates may possess inherent antitumor activity and be synergistic with chemotherapy.[2] Data have been reported from adjuvant breast cancer clinical trials evaluating the oral bisphosphonates clodronate and ibandronate (Boniva)[3-6] as well as the intravenous bisphosphonates zoledronic acid and pamidronate,[7-11] with mixed results.

The review article by Drs. Figueroa-Magalhes and Miller provides a concise description of adjuvant bisphosphonate studies and contains well-constructed summary tables.[12] The authors review preclinical data suggesting that bisphosphonates can inhibit angiogenesis, prevent tumor cell invasion and adhesion in bone, and induce tumor cell apoptosis. They provide the current evidence for use of bone-modifying agents as part of adjuvant treatment in patients with early-stage breast cancer,[12] highlighting the potential benefit of adjuvant bisphosphonate in postmenopausal and/or older women as noted in subset analyses. Figueroa-Magalhes and Miller emphasize the results of the Austrian Breast and Colorectal Cancer Study Group 12 (ABCSG-12)[9] and the Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trials,[11] as they discuss the potential benefit of off-label use of zoledronic acid in the adjuvant setting in postmenopausal women. It is perplexing that the prospectively collected data from the adjuvant bisphosphonate studies need to be scrutinized to find subsets of patients who may gain potential benefit and that bone metastases are not significantly affected. At present, the subset analyses are hypothesis-generating.

Much is being made of the theory of the “low-estrogen state,”[13] but it is difficult to accept that women treated with 3 years of ovarian ablation are the “menopausal equivalent” of women who are more than 5 years postmenopausal. The cutoff for “older” in the adjuvant bisphosphonate studies may be 40, 50, or 60 years of age, depending on the study and the subset analysis. Although not discussed by Figueroa-Magalhes and Miller, the randomized phase II study of zoledronic acid (neo)adjuvant therapy in women with clinical stage II/III breast cancer suggests that at a median follow-up of 62 months, addition of zoledronic acid to standard therapy improved disease-free and overall survival only in women with estrogen receptor–negative tumors.[14] The suggestion that the estrogen status of tumor may impact the significance of bisphosphonate therapy is consistent with the findings of Park et al in metastatic breast cancer.[15] The variability within the studies and their analyses does not build a cohesive argument for a specific patient population likely to benefit from a specific adjuvant bisphosphonate therapy. At present, if bisphosphonates do alter the course of breast cancer in certain subsets, the most advantageous drug, dose, scheduling, time of initiation, and duration of therapy are not known.[16]

Additional noteworthy reports include the recent clinical outcomes data from the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) MA.37 clinical trial.[17] This prospective clinical trial randomized 7576 postmenopausal women to anastrozole (Arimidex) or exemestane (Aromasin) for 5 years. An exploratory subset analysis evaluating 1294 patients on (unspecified) osteoporosis therapy found a significant improvement in event-free survival (hazard ratio [HR] = 0.7; P < .00001). Similarly, epidemiologic studies have suggested that the use of bisphosphonates for osteoporosis may decrease the risk of developing breast cancer.[18] As mentioned by Figueroa-Magalhes and Miller, the Southwest Oncology Group trial S0307, which randomized patients with stage I to III breast cancer to 3 years of zoledronic acid, clodronate, or ibandronate, in addition to standard adjuvant therapy, closed to accrual in February 2010.[19] In addition, a phase III clinical trial investigating the impact of denosumab on breast cancer recurrence is ongoing.[20] The primary data and correlative analyses from these, and other, clinical trials are eagerly awaited.

It is conceivable that bone-modifying agents impact the viability of tumor cells, through osteoclast inhibition or an unformulated mechanism. We believe that addressing such fundamental questions is an opportunity to learn about bone biology, cancer metastasis, and bone-modifying agents. Until more data are available, we reserve bisphosphonates for women with evidence of decreased bone mineral density who are at increased risk of fracture and for those on clinical trials.

Financial Disclosure: Dr. Van Poznak has received research funding from Amgen and Novartis. Dr. Barginear has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References

1. Barginear MF, Van Poznak CH. Treatment of bone metastases in breast cancer: an update. Curr Breast Cancer Rep. Online First™, August 17, 2012. Available from: http://www.springerlink.com.

2. Winter MC, Holen I, Coleman RE. Exploring the anti-tumour activity of bisphosphonates in early breast cancer. Cancer Treat Rev. 2008;34:453-75.

3. Diel IJ, Solomayer EF, Costa SD, et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med. 1998;339:357-63.

4. Diel IJ, Jaschke A, Solomayer EF, et al. Adjuvant oral clodronate improves the overall survival of primary breast cancer patients with micrometastases to the bone marrow: a long-term follow-up. Ann Oncol. 2008;19:2007-11.

5. Saarto T, Blomqvist C, Virkkunen P, 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. 2001;19:10-7.

6. Paterson A, Anderson S, Lembersky B, et al. NSABP Protocol B-34: a clinical trial comparing adjuvant clodronate vs. placebo in early stage breast cancer patients receiving systemic chemotherapy and/or tamoxifen or no therapy - final analysis. CTRC-AACR San Antonio Breast Cancer Symposium. 2011; abstr S2-3.

7. Brufsky A, Harker WG, Beck JT, et al. Zoledronic acid inhibits adjuvant letrozole-induced bone loss in postmenopausal women with early breast cancer. J Clin Oncol. 2007;25:829-36.

8. Bundred NJ, Campbell ID, Davidson N, et al. Effective inhibition of aromatase inhibitor-associated bone loss by zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: ZO-FAST Study results. Cancer. 2008;112:1001-10.

9. Gnant M, Mlineritsch B, Stoeger H, et al. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol. 2011;12:631-41.

10. Gnant M, Mlineritsch B, Luschin-Ebengreuth G, et al. Long-term follow-up in ABCSG-12: significantly improved overall survival with adjuvant zoledronic acid in premenopausal patients with endocrine-receptor-positive early breast cancer. CTRC-AACR San Antonio Breast Cancer Symposium. 2011; abstr S1-2.

11. Coleman RE, Marshall H, Cameron D, et al. Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med. 2011;365:1396-405.

12. Figueroa-Magalhães MC, Miller RS. Bone-modifying agents as adjuvant therapy for early stage breast cancer. Oncology (Williston Park). 2012;26: 955-62.

13. Wilson C, Holen I, Coleman RE. Seed, soil and secreted hormones: potential interactions of breast cancer cells with their endocrine/paracrine microenvironment and implications for treatment with bisphosphonates. Cancer Treat Rev. 2012;38:877-89.

14. Aft RL, Naughton M, Trinkaus K, Weilbaecher K. Effect of (Neo)adjuvant zoledronic acid on disease-free and overall survival in clinical stage II/III breast cancer. Br J Cancer. 2012;107:7-11.

15. Park IH, Ro J, Nam BH, et al. Potential antitumor effects of nitrogen-containing bisphosphonate in hormone receptor negative breast cancer patients with bone metastases. BMC Cancer. 2009;9:154.

16. Barginear MF, Van Poznak C. Bisphosphonates: do we know their role in adjuvant breast cancer treatment? Oncology (Williston Park). 2010;24:475-80.

17. Shepherd LE, Chapman J-AW, Ali SM, et al. Effect of osteoporosis in postmenopausal breast cancer patients randomized to adjuvant exemestane or anastrozole: NCIC CTG MA.27. J Clin Oncol. 2012;30(suppl): abstr 501.

18. Chlebowski RT, Chen Z, Cauley JA, et al. Oral bisphosphonate use and breast cancer incidence in postmenopausal women. J Clin Oncol. 2010;
28:3582-90.

19. SWOG. Zoledronate, clodronate, or ibandronate in treating women who have undergone surgery for stage I, stage II, or stage III breast cancer. S0307. [Updated May 19, 2012.] Available from: www.clinicaltrials.gov.

20. Goss PE, Barrios CH, Bell R, et al. Denosumab versus placebo as adjuvant treatment for women with early-stage breast cancer who are at high risk of disease recurrence (D-CARE): an international, randomized, double-blind, placebo-controlled phase III clinical trial. J Clin Oncol. 2012;30(suppl): abstr TPS670.