Advances in treatment of metastatic breast cancer with bone metastasis

Introduction

Clinically, the incidence of bone metastasis (BM) count for 60–70% of all the metastatic breast cancer (MBC) (1-3). Common complications of BM include pathological fracture, spinal compression, hypercalcemia and persistent pain. One important concept of BM treatment is called skeletal-related events (SREs), which are defined as: a pathologic fracture, a spinal cord compression, a necessity for radiation to bone (for pain or impending fracture) or surgery to bone (4). Once an SRE is developed, the 5-year survival rate of MBC patients drops from 8.3% for patients with bone metastases to 2.5% for those with both bone metastases and SREs (5). Thus, one major goal of BM management is to prevent SREs.

Treatments include systemic treatment and specified therapy for bone.

Systemic treatment

Around 60–70% of the BM patients were hormone receptor positive and HER2 negative (3,6,7). If the patient presents with a luminal breast cancer with BM only, then sole endocrine therapy is reasonable for the start (8). If the patient is presented with other tumor subtypes or luminal subtype with visceral crisis, then chemotherapy is urgently needed.

One interesting issue is that do we concern the operation of the primary tumor in de novo MBC with BM? One randomized clinical trial (RCT) from Turkish directly compares loco-regional surgery (LRS) of the primary tumor site followed by appropriate systemic therapy (ST) versus ST alone in treatment naive stage IV BC patients. It turned out that overall survival (OS) was similar between the two groups. However, in unplanned subgroup analyses, OS was statistically higher in LRS group than ST group: ER/PR (+) (HR =0.64, 95% CI: 0.46–0.91, P=0.01), HER2 (−) (HR =0.64, 95% CI: 0.45–0.91; P=0.01), patients <55 years (HR =0.57, 95% CI: 0.38–0.86; P=0.006), and solitary bone only metastasis (HR =0.47, 95% CI: 0.23–0.98; P=0.04) (9).

Thus, in the latest European Society for Medical Oncology (ESMO) consensus, 70.4% of the panel agreed with the idea that “the removal of the primary tumor in patients with de novo stage IV breast cancer has not been associated with prolongation of survival, with the possible exception of the subset of patients with bone only disease.” (8).

Loco-regional treatment of the bone

Surgery of the bone/radiotherapy (RT)

If a fracture of the bone has occurred or is likely to occur, then an orthopedic assessment is necessary to determine if a surgical intervention is needed before RT or RT alone is adequate. In emergent cases where a spinal compression has occurred, surgical decompression is the optimal treatment of choice. If surgery is not feasible, then an emergent RT is also an option (8,10).

Bone modifier

Bisphosphonates and denosumab are two targeted drugs approved in MBC patients with BM. To date, no study of either drug has demonstrated an impact on OS in patients with metastatic disease. However, they could reduce the risk of SREs and improve the quality of life of the patients (10).

Bisphosphonates

Bisphosphonates target osteoclast farnesyl pyrophosphate synthase (FPPS) and inhibit protein prenylation, thus prevent SREs by inhibiting osteoclast-mediated bone resorption (11). A Cochrane analysis showed that bisphosphonates could reduce the risk of SREs by 14% in MBC patients with BM compared with placebo/no bisphosphonates, and delay the median time to an SRE and reduce bone pain (2). Either oral or intravenous administration exhibits this persistent benefit. Intravenously pamidronate and zoledronic acid are approved in United States, while oral ibandronate and clodronate are approved in European countries.

Though one RCT comparing intravenous zoledronic acid at 4 mg every 3–4 weeks or oral ibandronic acid revealed a lower SREs rate in zoledronic acid group (43.5% vs. 49.9%, RR =1.148, 95% CI: 0.967–1.362). The oral ibandronic acid group showed lower renal toxicity (12), which might also be an option for patients with impaired renal function.

The optimal duration of bisphosphonate administration is under discussion and investigation due to safety and economic concerns of prolonged usage. Currently more and more evidence suggest that a 12-week schedule could replace the original 4-week schedule after a period of initial use (around 1 year) (13,14).

Two RCTs directly compared 12-week schedule zoledronic acid and 4-week zoledronic acid with non-inferior hypothesis. In OPTIMIZE-2, patients with bone metastases from breast cancer who had previously received 10 to 15 months of bisphosphonate therapy were randomly assigned to receive sequential 4-week or 12-week zoledronic acid. The SREs rate was 22.0% in the 4-week group and 23.2% in the 12-week group (noninferiority P=0.02) showing a non-inferior efficacy (13). In ZOOM trial, which was similarly designed as OPTIMIZE-2, the skeletal morbidity rate was 26% in the 12-week group and 22% in the 4-week group (15). In this trial “The between-group difference was 0.04 and the upper limit of the one tailed 97.5% CI was 0.17”, indicating that the 12-week schedule was non-inferior to the 4-week schedule. However, when considering cost-effective (CE) issue, initial 12-week zoledronic acid is the more CE option and more reasonable alternative to 4-week zoledronic acid (16).

The latest recommendations from the National Comprehensive Cancer Network (NCCN) and ESMO are still to start with the 4-week schedule for the first year and then switch to a 12-week schedule. The overall duration of bisphosphonate are still not clear yet, but long-term toxicity should be taken in to account in clinical practice.

Denosumab

Denosumab is a fully human monoclonal antibody that inhibits osteoclasts by binding to the receptor activator of nuclear factor kappa B ligand (RANK) (17). In an RCT, denosumab delays the onset of the first and subsequent SREs compared to zoledronic acid in MBC patients with BM (18). Based on this evidence, NCCN guideline recommends that women who were candidate of bisphosphonate might also consider denosumab for the treatment (10).

In a Cochrane analysis that involved 44 RCTs, denosumab reduced the risk of SREs by 22% compared with bisphosphonates (2). The rate of adverse events and severe adverse events are similar between these two drugs.

New drugs

A great amount of new drugs targeting bone metastatic sites are under development and going through clinical trials.

Curcuminoids is a class of phenols isolated from the dried rhizomes of turmeric. A study from Wright et al. showed that curcuminoids prevent TGF-β induction of PTHrP and reduce osteolytic bone destruction by blockade of Smad signaling in breast cancer cells (19).

Schroeder et al. evaluated the effect of angiogenesis inhibitor sunitinib in an in vivo model of MBC with BM, and showed that sunitinib could also reduce tumor growth and limit changes in microvascular properties in breast cancer growth in bone (20).

Another new strategy is to combine chemo-regimen with antigen-specified nano particles to maximally reduce adverse events. For example, integrin β3 (β3) was strongly expressed on bone metastatic cancer cells, but not primary tumors or other metastatic sites. Micelle-based nanoparticle therapy with αvβ3-MP-docetaxel, which recognizes integrin αvβ3 in breast cancer cells in the bone, showed great anti-tumor activity with less bone destruction and less hepatotoxicity compared with equal doses of free docetaxel (21).

Conclusions

BM is the most common metastasis in breast cancer. Current treatment strategies of the bone are surgeries, radiotherapies, bisphosphonates and denosumab. New interventions with more precise target on bone including small-molecular inhibitors and nano particles are very promising in the near future.

Acknowledgements

Funding: This work is supported by grants from the Nurturing Fund of Renji Hospital (grant number PYMDT-002) and the Seed Fund of Renji Hospital (grant number RJZZ14-007). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

References

1. Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res 2006;12:6243s-9s. [Crossref] [PubMed]
2. O'Carrigan B, Wong MH, Willson ML, et al. Bisphosphonates and other bone agents for breast cancer. Cochrane Database Syst Rev 2017;10. [PubMed]
3. Parkes A, Clifton K, Al-Awadhi A, et al. Characterization of bone only metastasis patients with respect to tumor subtypes. NPJ Breast Cancer 2018;4:2. [Crossref] [PubMed]
4. Ibrahim A, Scher N, Williams G, et al. Approval summary for zoledronic acid for treatment of multiple myeloma and cancer bone metastases. Clin Cancer Res 2003;9:2394-9. [PubMed]
5. Yong M, Jensen AÖ, Jacobsen JB, et al. Survival in breast cancer patients with bone metastases and skeletal-related events: a population-based cohort study in Denmark (1999-2007). Breast Cancer Res Treat 2011;129:495-503. [Crossref] [PubMed]
6. Ignatov A, Eggemann H, Burger E, et al. Patterns of breast cancer relapse in accordance to biological subtype. J Cancer Res Clin Oncol 2018;144:1347-55. [Crossref] [PubMed]
7. Cosphiadi I, Atmakusumah TD, Siregar NC, et al. Bone Metastasis in Advanced Breast Cancer: Analysis of Gene Expression Microarray. Clin Breast Cancer 2018. [Epub ahead of print]. [Crossref] [PubMed]
8. Cardoso F, Costa A, Senkus E, et al. 3rd ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 3). Ann Oncol 2017;28:3111. [Crossref] [PubMed]
9. Atilla Soran VO, Serdar Ozbas, Hasan Karanlik, Mahmut Muslumanoglu. A randomized controlled trial evaluating resection of the primary breast tumor in women presenting with de novo stage IV breast cancer: Turkish Study (Protocol MF07-01). J Clin Oncol 2016;34:abstr 1005.
10. Network NCC. NCCN Clinical Practice Guidelines in Oncology Breast Cancer (Version 1.2018). Available online: https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
11. Kavanagh KL, Guo K, Dunford JE, et al. The molecular mechanism of nitrogen-containing bisphosphonates as antiosteoporosis drugs. Proc Natl Acad Sci U S A 2006;103:7829-34. [Crossref] [PubMed]
12. Barrett-Lee P, Casbard A, Abraham J, et al. Oral ibandronic acid versus intravenous zoledronic acid in treatment of bone metastases from breast cancer: a randomised, open label, non-inferiority phase 3 trial. Lancet Oncol 2014;15:114-22. [Crossref] [PubMed]
13. Hortobagyi GN, Van Poznak C, Harker WG, et al. Continued Treatment Effect of Zoledronic Acid Dosing Every 12 vs. 4 Weeks in Women With Breast Cancer Metastatic to Bone: The OPTIMIZE-2 Randomized Clinical Trial. JAMA Oncol 2017;3:906-12. [Crossref] [PubMed]
14. Himelstein AL, Foster JC, Khatcheressian JL, et al. Effect of Longer-Interval vs. Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases: A Randomized Clinical Trial. JAMA 2017;317:48-58. [Crossref] [PubMed]
15. Amadori D, Aglietta M, Alessi B, et al. Efficacy and safety of 12-weekly versus 4-weekly zoledronic acid for prolonged treatment of patients with bone metastases from breast cancer (ZOOM): a phase 3, open-label, randomised, non-inferiority trial. Lancet Oncol 2013;14:663-70. [Crossref] [PubMed]
16. Shapiro CL, Moriarty JP, Dusetzina S, et al. Cost-Effectiveness Analysis of Monthly Zoledronic Acid, Zoledronic Acid Every 3 Months, and Monthly Denosumab in Women With Breast Cancer and Skeletal Metastases: CALGB 70604 (Alliance). J Clin Oncol 2017;35:3949-55. [Crossref] [PubMed]
17. Gül G, Sendur MA, Aksoy S, et al. A comprehensive review of denosumab for bone metastasis in patients with solid tumors. Curr Med Res Opin 2016;32:133-45. [Crossref] [PubMed]
18. 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. [Crossref] [PubMed]
19. Wright LE, Frye JB, Lukefahr AL, et al. Curcuminoids block TGF-beta signaling in human breast cancer cells and limit osteolysis in a murine model of breast cancer bone metastasis. J Nat Prod 2013;76:316-21. [Crossref] [PubMed]
20. Schroeder M, Viezens L, Wellbrock J, et al. Sunitinib treatment reduces tumor growth and limits changes in microvascular properties after minor surgical intervention in an in vivo model of secondary breast cancer growth in bone. J Surg Oncol 2016;113:515-21. [Crossref] [PubMed]
21. Ross MH, Esser AK, Fox GC, et al. Bone-Induced Expression of Integrin beta3 Enables Targeted Nanotherapy of Breast Cancer Metastases. Cancer Res 2017;77:6299-312. [Crossref] [PubMed]