RANK ligand (RANKL), a key factor for bone remodeling and metastasis, is crucial for the development of mouse mammary glands during pregnancy. RANKL functions as a major paracrine effector of the mitogenic action of progesterone in mouse and human mammary epithelium via its receptor RANK and has a role in ovarian hormone-dependent expansion and regenerative potential of mammary stem cells. Pharmacologic inhibition of RANKL attenuates the development of mammary carcinoma and inhibits metastatic progression in multiple mouse models.~In a retrospective analysis of 601 patients treated in the GeparTrio study with chemotherapy (TAC) it could be demonstrated that elevated expression of RANK (immunohistochemical score > 8.5 using the N-1H8 antibody by Amgen) was found in 14.5% of patients overall, with a significant predominance in patients with hormone-receptor-negative disease (33.7% vs 6.4% tumors positive for RANK). Expression of RANK was associated with a higher pathological complete response rate (pCR) (23.0% vs 12.6%) but with a shorter disease-free and overall survival. The ABCSG-18 study showed that adjuvant denosumab reduces clinical fractures, improves bone health, and can be administered without added toxicity. Moreover denosumab improves disease-free survival in postmenopausal woman with hormone receptor positive breast cancer.~It appears therefore reasonable to test denosumab, a clinically available antibody against RANKL in patients with hormone-receptor-negative primary breast cancer as an adjunct to neoadjuvant chemotherapy for its ability to increase pCR rate and improve outcome in relation to the expression of RANK.
Pharmacologic inhibition of RANKL attenuates the development of mammary carcinoma and inhibits metastatic progression in multiple mouse models.~In a retrospective analysis it could be demonstrated that elevated expression of RANK was found in 14.5% of patients overall, with a significant predominance in patients with hormone-receptor-negative disease. Expression of RANK was associated with a higher pathological complete response rate but with a shorter disease-free and overall survival. The ABCSG-18 study showed that adjuvant denosumab reduces clinical fractures, improves bone health, and can be administered without added toxicity.~It appears therefore reasonable to test denosumab, a clinically available antibody against RANKL in patients with hormone-receptor-negative primary breast cancer as an adjunct to neoadjuvant chemotherapy for its ability to increase pCR rate and improve outcome in relation to the expression of RANK.