Bone-Modifying Agents in Early Breast Cancer

Introduction

Bisphosphonates inhibit osteoclast-mediated bone resorption. Denosumab is a RANK ligand inhibitor that prevents bone turnover. As a result, these medications have several therapeutic roles. Primarily, they were used as antiosteoporosis medications. Later, these drugs were used to prevent or delay skeletal-related events such as fractures and bone pain in patients with metastatic cancers with disease in the bones. Bisphosphonates are also used to prevent bone loss associated with aromatase inhibitors, which are used for adjuvant management of breast cancer in postmenopausal women and result in bone loss and hastened osteoporosis. Therefore, in breast oncology, bisphosphonates are important supportive care medications in two indications: prevent or delay skeletal-related events in metastatic breast cancer involving bones, and prevent or treat aromatase inhibitor–induced bone loss.

Bone is the commonest site of distant metastatic disease in breast cancer. Tumor microenvironment plays an important role in cancer proliferation. Bisphosphonates alter the bone microenvironment and may have an anticancer effect. Backed by preclinical studies that showed such an effect, several adjuvant bisphosphonate and denosumab clinical trials were conducted. In this chapter, we will summarize these clinical trials ( Table 73.1 ) and discuss the findings of an individual patient-level data meta-analysis that aimed to evaluate the anticancer role of adjuvant bisphosphonates.

Table 73.1

Adjuvant Bisphosphonate Trials in Early-Stage Breast Cancer

Study Details	Study Population	Study Arms	Primary End Point	Conclusions
Clodronate 1600 mg PO
Diel et al., 1998	Pre- and postmenopausal (n = 302) ^a	Clodronate vs. standard care for 2 years	Incidence of distant metastasis	At 3 years of follow-up, distant metastases rate was 13% in clodronate group vs. 29% in control group ( P < 0.001)
Powles et al., 2002	Pre- and postmenopausal (n = 1069)	Clodronate vs. placebo for 2 years	Incidence of bone metastasis	At 6 years of follow-up, there was no difference in bone metastasis rates between the two groups
Saarto et al., 2004	Pre- and postmenopausal ^b (n = 299)	Clodronate vs. standard care for 3 years	Not specified	At 10 years of follow-up, disease-free survival was lower in clodronate group vs. control ( P = 0.01)
Paterson et al., 2012 NSABP B-34 trial	Pre- and postmenopausal (n = 3323)	Clodronate vs. placebo for 3 years	Disease-free survival (DFS)	At 7.5 years of follow-up, there was no difference in DFS between two groups. Subgroup analyses found benefit in older patients (≥50 years) with the secondary end points such as DFS, and bone metastasis-free interval favoring clodronate arm of the study
Ibandronate 50 mg PO
Von Minckwitz et al., 2013 GAIN study	Pre- and postmenopausal (n = 2994) ^c	Ibandronate vs. standard care for 2 years	DFS	At 3 years of follow-up, there was no difference in DFS between two groups
Zoledronate 4 mg IV
Gnant et al., 2015 ABCSG-12 study	Premenopausal (n = 1803) ^d	Zoledronate vs. standard care for 3 years	DFS	Final analysis after 8 years of follow-up showed improvement in DFS with the use of zoledronate ( P = 0.042). These results were statistically significant at 5 years of follow-up as well.
Brufsky et al., 2012 Z-FAST trial	Postmenopausal (n = 602)	Zoledronate: upfront vs. delayed for 5 years ^f	BMD ^e	At 5 years of follow-up, disease recurrence or death rates were similar between the upfront vs. delayed groups (9.8% vs. 10.5%; P = 0.63) ^g
Coleman et al., 2013 ZO-FAST trial	Postmenopausal (n = 1065)	Zoledronate: upfront vs. delayed for 5 years ^f	BMD ^e	At 5 years of follow-up, upfront group had a decrease in incidence of DFS events vs. delayed zoledronate group ( P = 0.0375)
Coleman et al., 2014 AZURE trial	Pre- and postmenopausal (n = 3360) ^h	Zoledronate vs. standard care for 5 years ⁱ	DFS	At 5 years, there was no difference in DFS between the two groups ( P = 0.30). Zoledronate reduced the incidence of bone metastases and improved DFS in postmenopausal women.

a All patients had tumor cells in bone marrow.

b Around 50% of patients received adjuvant chemotherapy.

c All patients received adjuvant chemotherapy.

d All patients received goserelin to suppress ovarian function. Around 5% of patients received adjuvant chemotherapy.

e Change in lumbar spine bone mineral density (BMD), DFS was a secondary end point.

f Delayed therapy was initiated when patients became osteopenic, developed pathologic fracture, or had an asymptomatic vertebral fracture.

g Around 25% of patients in the delayed group received zoledronate by 5 years.

h Around 95% patients received chemotherapy.

i Zoledronate 4 mg IV was given every 3 to 4 weeks for six cycles, then every 3 months for eight doses, followed by every 6 months for five cycles.

Bisphosphonates—Mechanism of Action

Bisphosphonates are pyrophosphate analogs that bind to bone hydroxyapatite. Bone remodeling is mediated by osteoblasts and osteoclasts—the former ensure bone formation, and the latter ensure bone resorption. In normal bone, the remodeling process works in equilibrium. Bone metastasis results in secretion of cytokines from cancer cells, which leads to a disproportionate activation of osteoclasts and a disruption in the osteoblast-osteoclast equilibrium. Bisphosphonates are internalized by osteoclasts and cause apoptosis of these bone-resorptive cells.

Types of Bisphosphonates

There are two types of bisphosphonates: aminobisphosphonates contain a nitrogen atom; non-aminobisphosphonates do not contain the nitrogen atom.

Aminobisphosphonates ( N -containing) include alendronic acid (alendronate; oral), pamidronate (intravenous), risedronate (oral), ibandronate (oral and intravenous), and zoledronate (intravenous). The antiapoptotic effect is mediated by inhibition of farnesyl pyrophosphate synthase enzyme in the mevalonic acid pathway of cholesterol synthesis. Protein prenylation (posttranslational modification of GTP-binding proteins) is inhibited, resulting in apoptosis of osteoclasts.
Non-aminobisphosphonates (non- N -containing) include clodronate (oral and intravenous) and etidronate (oral). These are metabolized into hydrolysis-resistant analogs of adenosine triphosphate in the osteoclasts and cause apoptosis.

Rationale for an Anticancer Effect for Bisphosphonates

Breast cancer is a systemic disease, rather than a local problem. Patients with a distant site of metastatic breast cancer are thought to have had the disease from the time of initial diagnosis of primary breast cancer. The aim of adjuvant treatment using chemotherapy or hormonal agents is to kill cancer cells that may be hiding in a distant site, such as bone. Osteoclasts, immune cells, and stromal cells secrete cytokines and various growth factors, which in turn stimulate further production of osteoclasts. Bisphosphonates break this vicious cycle of osteoclast production in the bone. By inhibiting osteoclasts, bisphosphonates produce a bone microenvironment that is less conducive for tumor cell adhesion, proliferation, and metastases. Apart from the effect on bone microenvironment, bisphosphonates may also have direct antitumor effects such as impaired adhesion, inhibition of migration, induction of apoptosis, and inhibition of angiogenesis. These direct and indirect effects of bisphosphonates on the tumor cell may help prevent or delay the incidence of bone metastases and improve breast cancer–related outcomes.

Denosumab—Mechanism of Action

RANK ligand is an important mediator of bone turnover. Inhibition of RANK ligand using the monoclonal antibody drug called denosumab prevents maturation and survival of osteoclasts. As a result, bone resorption is inhibited. One distinct advantage of denosumab over bisphosphonates relates to its safety in patients with renal insufficiency. The drug is administered subcutaneously.

Clinical Trials on Adjuvant Bisphosphonates in Breast Cancer

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