Denosumab induces tumor reduction and bone formation in patients with giant-cell tumor of bone.

Abstract

PURPOSE:

Giant-cell tumor of bone (GCTB) is a locally aggressive, benign osteolytic tumor in which bone destruction is mediated by RANK ligand (RANKL). The RANKL inhibitor denosumab is being investigated for treatment of GCTB. We describe histologic analyses of GCTB tumor samples from a phase II study of denosumab in GCTB.

EXPERIMENTAL DESIGN:

Adult patients with recurrent or unresectable GCTB received subcutaneous denosumab 120 mg every 4 weeks (with additional doses on days 8 and 15). The primary histologic efficacy endpoint was the proportion of patients who had a 90% or more elimination of giant cells from their tumor. Baseline and on-study specimens were also evaluated for overall tumor morphology and expression of RANK and RANKL.

RESULTS:

Baseline tumor samples were typically composed of densely cellular proliferative RANKL-positive tumor stromal cells, RANK-positive rounded mononuclear cells, abundant RANK-positive tumor giant cells, and areas of scant de novo osteoid matrix and woven bone. In on-study samples from 20 of 20 patients (100%), a decrease of 90% or more in tumor giant cells and a reduction in tumor stromal cells were observed. In these analyses, thirteen patients (65%) had an increased proportion of dense fibro-osseous tissue and/or new woven bone, replacing areas of proliferative RANKL-positive stromal cells.

CONCLUSIONS:

Denosumab treatment of patients with GCTB significantly reduced or eliminated RANK-positive tumor giant cells. Denosumab also reduced the relative content of proliferative, densely cellular tumor stromal cells, replacing them with nonproliferative, differentiated, densely woven new bone. Denosumab continues to be studied as a potential treatment for GCTB.

• Authors: Daniel G Branstetter, Scott D Nelson, J Carlos Manivel, Jean-Yves Blay, Sant Chawla, David M Thomas, Susie Jun, Ira Jacobs
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 16 Pg. 4415-24 (Aug 15 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22711702 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• RANK Ligand
• Receptor Activator of Nuclear Factor-kappa B
• Denosumab

Topics

• Adult
• Antibodies, Monoclonal, Humanized (pharmacology, therapeutic use)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Bone Neoplasms (drug therapy, metabolism, pathology)
• Denosumab
• Female
• Giant Cell Tumor of Bone (drug therapy, metabolism, pathology)
• Humans
• Male
• Osteogenesis (drug effects)
• RANK Ligand (antagonists & inhibitors, metabolism)
• Receptor Activator of Nuclear Factor-kappa B (metabolism)
• Treatment Outcome
• Young Adult