A clinical trial investigating denosumab, a drug widely used to treat osteoporosis and prevent bone complications in cancer patients, has revealed promising new applications in breast cancer treatment. While the drug does not directly reduce cancer cell proliferation, it significantly enhances the body's immune response against tumors, according to results from the D-BIOMARK clinical trial.
The study, conducted by researchers from the Catalan Institute of Oncology (ICO), the Institute for Biomedical Research of Bellvitge (IDIBELL), and the Spanish National Cancer Research Centre (CNIO), enrolled 60 women with early-stage breast cancer to evaluate the biological effects of denosumab administered before surgery.
Enhancing Immune Response in Breast Cancer
Analysis of tumor samples following denosumab treatment showed a notable increase in tumor-infiltrating immune cells across all breast cancer subtypes evaluated, with the most pronounced effect observed in luminal B tumors. These immune cells, including T cells and other components, are critical for mounting an effective anti-tumor immune response.
"Although denosumab did not reduce cancer cell proliferation or survival markers as we initially hypothesized, its ability to enhance immune cell infiltration suggests it could complement existing immunotherapies," explained Dr. Eva González-Suarez, leader of the Transformation and Metastasis research group at IDIBELL and CNIO.
This finding is particularly significant for luminal B breast cancer patients, who typically show lower response rates to current immunotherapies. The trial provides new clinical data that may open avenues to improve immune responses in this challenging subgroup.
The RANK Pathway Connection
Denosumab works by targeting the receptor activator of nuclear factor kappa-B (RANK) pathway, blocking its ligand, RANKL. This pathway plays a key role in bone remodeling but has also been implicated in breast cancer development and progression.
Dr. Andrea Vethencourt, clinical researcher and medical oncologist at ICO, noted, "The RANK pathway, mediated by RANK and RANKL proteins, normally transmits information provided by hormones like progesterone and sends essential signals for proper mammary gland development. However, dysregulation of this pathway can lead to uncontrolled cell replication and potentially cancer."
Previous laboratory and preclinical studies had indicated that inhibiting the RANK pathway could reduce tumor growth and metastasis in breast cancer models. While the clinical trial did not confirm direct anti-proliferative effects, it revealed the unexpected immune-modulating properties of denosumab.
Repurposing an Established Drug
An advantage of exploring denosumab in this new context is that the drug is already approved for clinical use in other indications, with a well-established safety profile. Its side effects are well documented and manageable in routine practice, which may facilitate its potential repurposing for breast cancer treatment if further evidence supports efficacy.
"Leveraging an existing pharmacological agent with a known risk-benefit ratio allows us to potentially accelerate the translation of molecular discoveries into tangible clinical benefits," said Dr. Catalina Falo, clinical researcher in the IDIBELL Breast Cancer research group and medical oncologist at ICO.
Future Directions and Ongoing Research
Following these promising results, 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.
The researchers are particularly interested in exploring whether denosumab could enhance the efficacy of immune checkpoint inhibitors in breast cancer subtypes that typically show resistance to these therapies.
A Collaborative Approach
The D-BIOMARK trial exemplifies the importance of collaboration between basic scientists, clinical oncologists, and patients in advancing cancer research. Years of preclinical studies elucidating the role of the RANK/RANKL axis in breast pathology laid the groundwork for this clinical evaluation.
"This result could only be achieved thanks to the synergy between basic science, which for years has studied the ins and outs of the RANK pathway role in breast cancer; the clinical experience of oncologists committed to the search for better treatments; and especially, the generosity and commitment of the patients who participated in the trial," the research team emphasized.
The window-of-opportunity design of the trial allowed for the assessment of biological drug effects within a short preoperative timeframe, minimizing patient exposure while providing critical data on immunomodulatory mechanisms.
Implications for Immunotherapy
Immunotherapy has become an important strategy in oncology, but its effectiveness varies by cancer subtype. The ability of denosumab to increase immune infiltration into tumors opens a valuable avenue of clinical interest, particularly for luminal B breast cancer patients who currently have limited options for effective immunotherapy.
By potentially relieving local immunosuppression within the tumor environment, denosumab could transform from a bone-targeting agent into an immuno-oncological adjuvant capable of reprogramming the tumor microenvironment toward an anti-tumor state.
As investigations continue, researchers hope these findings will translate into improved survival and quality of life for breast cancer patients worldwide, demonstrating once again how repurposing established drugs can provide novel therapeutic options and deeper insights into the complex interplay between cancer cells and the immune system.
