Optimal Use of Bone-Targeted Agents in Breast Cancer

Oncology (Williston Park). 30(8):703–704.

In his review of the impact of bone-targeted treatments on bone health and breast cancer in this issue of ONCOLOGY, Dr. Coleman highlights the various indications for use of bisphosphonates and denosumab in this setting.[1] Three aspects of clinical management are comprehensively described: therapy-induced bone loss in patients receiving adjuvant treatment with an aromatase inhibitor, the incidence of bone recurrence in patients with early-stage breast cancer, and skeletal-related events (SREs) in patients with breast cancer metastatic to the bone. Despite strong trial data supporting their use in breast cancer, it appears that these medications are not employed as frequently as they ought to be.[2-4] Herein, we will attempt to explain why this may be the case.

Prevention of Bone Loss Induced by Aromatase Inhibitor Therapy

Patients with hormone receptor (HR)-positive early-stage breast cancer have a 1% to 3% annual risk of late recurrences, even after 10 years from the time of initial diagnosis.[5] Extended use of aromatase inhibitors is expected to decrease the risk of recurrence, as shown in the recently published MA17R study.[6] Analysis of the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT) has indicated that premenopausal women at high risk for breast cancer recurrence could have an improvement of 5% to 15% in the 5-year breast cancer–free interval with the use of aromatase inhibitors in combination with ovarian function suppression (OFS), compared with the results of tamoxifen treatment alone.[7]

However, interventions with aromatase inhibitors are associated with significant bone morbidity. In the MA17R trial, 14% of women treated with a total of 10 years of letrozole sustained a bone fracture, compared with 9% of women treated with letrozole for 5 years followed by placebo for 5 years.[6] Of note, 46% of the study participants received at least one dose of a bisphosphonate. In the Austrian Breast and Colorectal Cancer Study Group (ABCSG)-18 trial, which investigated the use of denosumab in patients receiving adjuvant aromatase inhibitor therapy, the estimated rate of first clinical fracture after 7 years was 11.1% in the denosumab arm and 26.2% in the placebo arm.[8] The bone morbidity caused by the use of aromatase inhibitors may be much more significant than is currently understood, with significant implications for survivorship care. It is hoped that better understanding of this issue will result in expanded use of bone-targeted agents in patients with early-stage breast cancer. Dr. Coleman notes that in addition to improving bone mineral density, both bisphosphonates and denosumab reduce the risk of fractures.[8,9] In addition, we would like to reiterate the importance of careful assessment of fracture risk, regular monitoring of bone mineral density, and the routine use of calcium and vitamin D supplements.

Prevention of Bone Metastasis and Breast Cancer-Related Mortality

We agree with the author that the controversial question of whether bisphosphonates have an anticancer effect in early-stage breast cancer can now be laid to rest. The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) meta-analysis showed that adjuvant use of bisphosphonates reduced the risk of cancer recurrence in bone and reduced breast cancer-related mortality in postmenopausal women (including women who underwent OFS).[9] The results of the EBCTCG meta-analysis were consistent in a sensitivity analysis that excluded data from the two large hypothesis-generating trials (AZURE and ABCSG-12).[10,11] We also know that bisphosphonates are well tolerated, with an extremely low risk for adverse events such as osteonecrosis of the jaw (at rates ranging from < 1% to 2%).[9]

Nevertheless, there are important issues that require greater clarity. For instance, the duration of bisphosphonate therapy and the frequency of medication administration are unclear. We agree with Dr. Coleman that at least 2 to 3 years of treatment with bisphosphonates may be necessary before definitive conclusions can be drawn about its effectiveness as an anticancer agent. We also agree that, of all available bisphosphonates, zoledronic acid has the best data supporting its use in this setting, and a dosing frequency of 1 dose every 6 months could be implemented in clinical practice. Another important question is whether bisphosphonates play a significant role in patients with triple-negative or human epidermal growth factor receptor 2 (HER2)-amplified cancers. Holen and colleagues conducted an elegant experiment demonstrating that the dissemination and growth of bone-metastatic cancer cells occurs in an environment of increased bone resorption mediated by osteoclasts-similar to the mechanism of bone resorption seen in states of estrogen deficiency, regardless of HR status.[12] Zoledronic acid inhibited tumor growth in both HR-positive and HR-negative tumors. The EBCTCG meta-analysis also noted a similar benefit from treatment with adjuvant bisphosphonates, regardless of the patient' HR status. There is also evidence that bisphosphonates bind to HER receptors and exert an antitumor effect.[13] Since, compared with HR-positive tumors, the frequency of bone metastasis is lower in triple-negative and HER2-amplified tumors, bisphosphonates may show less of an impact on prevention of bone metastasis in this population. Unfortunately, bisphosphonates are currently off-patent. As a result, pharmaceutical companies have less incentive to conduct further clinical trials; therefore, some of these questions may remain unanswered.

Due to the widespread availability of generic versions of bisphosphonates, adjuvant use could be even more cost-effective than was previously believed.[14] In fact, bisphosphonates may prove to be a valuable adjunctive medication in developing countries, where the overall breast cancer mortality and case-fatality rates are very high.[15] We agree with Dr. Coleman that although denosumab may eventually prove to have a beneficial effect on preventing recurrences, there are currently no data to support its use as an adjuvant anticancer therapy (eg, as evidenced by the D-CARE trial; ClinicalTrials.gov identifier: NCT01077154).

Treatment of Skeletal-Related Events

In our opinion, the question of whether to use bone-targeted agents such as bisphosphonates and denosumab in patients with bone-metastatic breast cancer should not be a contentious issue.[4] It is unequivocally clear that bone-targeted agents prevent or delay SREs. Denosumab was found to be superior to zoledronic acid in preventing or delaying the incidence of SREs.[16] In addition, denosumab has a more convenient route of administration (subcutaneous) compared with zoledronic acid (intravenous). However, it is important to bear in mind that zoledronic acid may be more cost-effective, especially since generic versions are now available.[17] Regarding dosing frequency of bisphosphonates, it is becoming more clear that less-frequent dosing may not be inferior to a monthly dosing schedule.[18] However, we believe that patients with significant osteolytic lesions should receive monthly doses for at least 1 year before a dose-deintensification strategy is adopted. Unfortunately, there are no good-quality data on dose deintensification of denosumab; a clinical trial is currently recruiting patients in order to investigate this issue (ClinicalTrials.gov identifier: NCT02051218).

It is quite obvious that bone morbidity has a negative impact on our patients with breast cancer. The use of bone-modifying agents in this setting can yield significant quality-of-life benefits.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

1. Coleman RE. Impact of bone-targeted treatments on skeletal morbidity and survival in breast cancer. Oncology (Williston Park). 2016;30:695-702.

2. Fick EM, Katalinic A, Waldmann A. The frequency of and risk factors for the use of bisphosphonates in the adjuvant setting of primary breast cancer in Germany. Cancer Res Treat. 2015;47:747-56.

3. Hatoum HT, Lin SJ, Smith MR, et al. Treatment persistence with monthly zoledronic acid is associated with lower risk and frequency of skeletal complications in patients with breast cancer and bone metastasis. Clin Breast Cancer. 2011;11:177-83.

4. Mathew A, Brufsky A. Bisphosphonates in breast cancer. Int J Cancer. 2015;137:753-64.

5. Colleoni M, Sun Z, Price KN, et al. Annual hazard rates of recurrence for breast cancer during 24 years of follow-up: results from the International Breast Cancer Study Group trials I to V. J Clin Oncol. 2016;34:927-35.

6. Goss PE, Ingle JN, Pritchard KI, et al. Extending aromatase-inhibitor adjuvant therapy to 10 years. N Engl J Med. 2016 Jun 5. [Epub ahead of print]

7. Regan MM, Francis PA, Pagani O, et al. Absolute benefit of adjuvant endocrine therapies for premenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer: TEXT and SOFT trials. J Clin Oncol. 2016 Apr 4. [Epub ahead of print]

8. Gnant M, Pfeiler G, Dubsky PC, et al. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015;386:433-43.

9. Early Breast Cancer Trialists' Collaborative Group; Coleman R, Powles T, Paterson A, et al. Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet. 2015;386:1353-61.

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

11. 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.

12. Holen I, Walker M, Nutter F, et al. Oestrogen receptor positive breast cancer metastasis to bone: inhibition by targeting the bone microenvironment in vivo. Clin Exp Metastasis. 2016;33:211-24.

13. Stachnik A, Yuen T, Iqbal J, et al. Repurposing of bisphosphonates for the prevention and therapy of nonsmall cell lung and breast cancer. Proc Natl Acad Sci U S A. 2014;111:17995-8000.

14. Lamond NW, Skedgel C, Rayson D, Younis T. Cost-utility of adjuvant zoledronic acid in patients with breast cancer and low estrogen levels. Curr Oncol. 2015;22:e246-e253.

15. Sandhu GS, Erqou S, Patterson H, Mathew A. Prevalence of triple-negative breast cancer in India: systematic review and meta-analysis. J Clin Oncol. 2016;34(suppl):abstr e12561.

16. Stopeck AT, Lipton A, Body JJ, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010;28:5132-9.

17. Ford J, Cummins E, Sharma P, et al. Systematic review of the clinical effectiveness and cost-effectiveness, and economic evaluation, of denosumab for the treatment of bone metastases from solid tumours. Health Technol Assess. 2013;17:1-386.

18. Ibrahim M, Mazzarello S, Shorr R, et al. Should de-escalation of bone-targeting agents be standard of care for patients with bone metastases from breast cancer? A systematic review and meta-analysis. Ann Oncol. 2015;26:2205-13.