Where Do Bone-Targeted Agents RANK in Breast Cancer Treatment?

Abstract

Breast cancer cells preferentially metastasise to the skeleton, owing, in part, to the fertile environment provided by bone. Increased bone turnover releases growth factors that promote tumour cell growth. In turn, tumour cells release factors that stimulate further bone turnover, resulting in a vicious cycle of metastasis growth and bone destruction. The RANK-RANK ligand (RANKL) pathway plays a key role in this cycle, and inhibition of RANKL using the fully-human monoclonal antibody denosumab, has demonstrated efficacy in delaying skeletal complications associated with bone metastases in three phase 3 trials. Preclinical studies suggest that the RANKL pathway also plays a role in breast cancer tumourigenesis and migration to bone. In a subgroup analysis of the negative Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trial, the bisphosphonate zoledronic acid showed potential for improving survival in patients who were postmenopausal; however, a prospective study in this patient population is required to validate this observation. Ongoing trials are examining whether adjuvant blockade of the RANKL pathway using denosumab can prevent disease recurrence in patients with high-risk breast cancer. These are building on analogous studies that have shown that denosumab improves bone metastasis-free survival in prostate cancer and suggested that it confers an overall survival benefit in non-small-cell lung cancer.

Keywords: RANK ligand; adjuvant therapy; bisphosphonates; bone metastasis; bone metastasis-free survival; bone-targeted agents; breast neoplasms; denosumab; skeletal-related event.

Figure 1

The “vicious cycle” of bone destruction in metastatic bone disease.

Figure 2

RANKL in mammary gland epithelial cell proliferation. Following the binding of progesterone to its receptor, RANKL is produced and acts in a paracrine fashion to stimulate mammary gland epithelial cell expansion. PR, progesterone receptor. Reprinted from [32].

Figure 3

Blockade of RANK through pharmacological inhibition or genetic inactivation inhibits tumour formation in mice. Tumour growth following the administration of the carcinogen 7,12-dimethylbenzanthracene (DMBA) and the progesterone derivative medroxyprogesterone acetate (MPA), with and without concomitant treatment with the RANK inhibitor RANK-Fc, in (A) transgenic mice overexpressing RANK and (B) wild-type mice [29]. Reprinted from [29].

Figure 4

RANK knock-out from mammary gland epithelia inhibits tumour formation. Tumour growth following the administration of the carcinogen DMBA and the progesterone derivative MPA in mice with inactivated mammary gland epithelial cell RANK expression (RANK^Δmam) and in wild-type mice (control) [31]. Reprinted from [31].