Denosumab May Benefit Postmenopausal Patients with Hormone Receptor-Negative Breast Tumors and RANK Protein Expression
Breast cancer is one of the leading causes of cancer deaths among women worldwide. The disease is complex and heterogeneous, and various factors, such as age, genetics, lifestyle, and hormonal status, influence its development and progression. Hormone receptor-negative (HR-) breast cancer is a subtype of breast cancer that does not express estrogen receptor (ER) and progesterone receptor (PR). HR- tumors are usually more aggressive, and treatment options are limited. However, recent studies have shown that denosumab, a monoclonal antibody that inhibits the RANK/RANKL pathway, may improve outcomes in postmenopausal women with HR- breast cancer.
RANK (receptor activator of nuclear factor kappa-B) is a protein expressed in various tissues, including bone, breast, and immune cells. RANK signaling is essential for bone remodeling, immune system function, and mammary gland development during pregnancy and lactation. However, aberrant RANK activation has been linked to breast cancer initiation and progression. RANK expression is higher in breast cancer tissues compared to normal breast tissue, and RANK-positive tumors are associated with a higher risk of recurrence and metastasis.
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Denosumab is a human monoclonal antibody that targets RANKL (receptor activator of nuclear factor kappa-B ligand), the ligand that binds to RANK and activates downstream signaling. Denosumab blocks RANKL from binding to RANK, thus inhibiting bone resorption and suppressing RANK-mediated signaling in other tissues, including breast cancer cells. In preclinical studies, denosumab has been shown to reduce tumor growth and metastasis in RANK-positive breast cancer models. In clinical trials, denosumab has been approved for the treatment of osteoporosis and bone metastases in breast cancer patients.
Recently, several studies have investigated the role of denosumab in HR- breast cancer patients. In a phase II clinical trial, postmenopausal women with HR- breast cancer who received denosumab in addition to standard therapy (chemotherapy and/or endocrine therapy) had significantly longer disease-free survival (DFS) compared to those who received standard therapy alone. The benefit of denosumab was more pronounced in patients with high RANK expression levels, indicating that RANK status may serve as a biomarker for denosumab response. In another study, denosumab improved bone health and reduced the risk of skeletal-related events in postmenopausal women with early-stage HR+ breast cancer receiving aromatase inhibitors.
These findings suggest that denosumab may have a dual benefit in breast cancer patients by inhibiting bone loss and suppressing RANK-mediated signaling in tumor cells. However, more research is needed to determine the optimal dosing, duration, and timing of denosumab therapy in breast cancer patients. Moreover, identifying biomarkers that predict denosumab response and monitoring treatment-related adverse effects are crucial for optimizing patient outcomes.
In conclusion, denosumab is a promising therapy for postmenopausal women with HR- breast cancer, particularly those with high RANK expression levels. By blocking RANKL signaling, denosumab may improve bone health and inhibit tumor growth and metastasis. Further studies are warranted to establish denosumab as a standard therapy for HR- breast cancer and to identify biomarkers for patient selection and monitoring.
Keywords: breast cancer, hormone receptor-negative, RANK, denosumab, biomarkers, bone health, metastasis, patient selection
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