Denosumab’s Emerging Role in Breast Cancer Immune Response

Denosumab, a drug commonly used to treat osteoporosis and prevent bone complications in cancer patients, is being investigated for a potential new application in breast cancer treatment. Early results from a clinical trial suggest that while denosumab does not directly reduce the proliferation of breast cancer cells, it may enhance the body’s immune response against tumors.

Immunotherapy challenges in breast cancer

Immunotherapy, which harnesses the immune system to combat cancer, has become an important strategy in oncology. However, its effectiveness varies by cancer subtype. Luminal B breast cancer, which accounts for a significant portion of hormone receptor-positive cases, tends to respond less well to current immunotherapies. This trial provides new clinical data that may open avenues to improve immune responses in this subgroup.

Collaborative approach linking science and patient care

This study is the product of collaboration between researchers, clinicians, and patients at the Catalan Institute of Oncology (ICO), the Institute for Biomedical Research of Bellvitge (IDIBELL) and the Spanish National Cancer Research Centre (CNIO). The work underscores how integrating basic science, clinical research and patient involvement can accelerate progress in biomedical fields.

Denosumab and the RANK pathway

Denosumab targets the receptor activator of nuclear factor kappa-B (RANK) pathway by blocking its ligand, RANKL. This pathway plays a key role in bone remodeling and has been implicated in breast cancer development and progression. Laboratory and preclinical studies previously indicated that inhibiting the RANK pathway could reduce tumor growth and metastasis in breast cancer models.

Clinical trial design and patient cohort

The D-BIOMARK clinical trial enrolled 60 women diagnosed with early-stage breast cancer. The study aimed to investigate the biological effects of denosumab administered before surgery. Patients represented various breast cancer subtypes, enabling evaluation across a spectrum of tumor profiles.

Key findings on tumor proliferation and immune infiltration

Analysis of tumor samples after denosumab treatment revealed no significant reduction in cancer cell proliferation or survival markers. However, a notable increase in tumor-infiltrating immune cells was observed across all subtypes, with the most marked effect in luminal B tumors. These immune cells include T cells and other components critical for mounting an anti-tumor immune response.

Potential implications for treatment

Although the trial did not demonstrate direct anti-proliferative effects of denosumab on tumor cells, its ability to enhance immune cell infiltration suggests it could complement existing immunotherapies. Luminal B breast cancer’s lower response rate to immune checkpoint inhibitors makes this finding clinically relevant. Further studies are underway to elucidate the mechanisms by which RANK pathway inhibition modulates the tumor microenvironment.

Safety profile and clinical relevance

An advantage of exploring denosumab in this new context is that the drug is already approved for clinical use in other indications, with a known safety profile. Its side effects are well documented and manageable, which may facilitate its potential repurposing for breast cancer treatment if further evidence supports efficacy.

Ongoing research and future directions

The research team is continuing investigations to understand how denosumab stimulates immune activation within tumors. These analyses aim to identify biomarkers that predict which patients might benefit most from combined treatment strategies incorporating denosumab and immunotherapy.

Acknowledging patient contributions

Researchers emphasize the critical role of patient participation in the trial. The willingness of patients to take part allowed for the collection of valuable biological data that links basic science discoveries with clinical outcomes. This approach exemplifies the collaborative model necessary for advancing cancer therapies.

Reference: Vethencourt A, González-Suarez E, Falo C, et al. Denosumab as an immune modulator in HER2-negative early breast cancer: results of the window-of-opportunity D-BIOMARK clinical trial. Breast Cancer Res. 2025. doi:10.1186/s13058-025-01996-w

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