Most breast cancers exhibit low T–lymphocyte infiltration and do not respond satisfactorily to immune correceptor inhibitors, leading to the need for new therapeutic strategies that act on anti-tumor immune activation mechanisms
The RANK (receptor activator of nuclear factor kappa-Β) and RANKL (ligand) have immunomodulatory potential. Previous data have shown that RANK pathway inhibitors, such as denosumab, used for the treatment of bone metastases, can prevent and/or treat breast cancer, by also acting on the immune regulation of the tumor microenvironment. However, the population of breast cancer patients who would benefit from denosumab still needs to be identified.
In this context, during ESMO Breast Cancer 2021, preliminary results of D-BIOMARK (NCT03691311), a randomized clinical trial with biomarkers designed to test the antitumor activity of denosumab in patients with early breast cancer candidates for surgery, were presented.
Patients with early-stage HER2-negative breast cancer were included and randomized in a 2:1 ratio for denosumab or control (without treatment). The experimental arm received a total of two doses (one per week) of 120mg denosumab subcutaneously prior to surgery (scheduled to occur between two and four weeks later).
Primary endpoints included changes in tumor cell proliferation by Ki67 (analyzed by immunohistochemistry) and cell survival by cleaved caspase 3. Stromal tumor-infiltrating lymphocytes quantified on hematoxylin and eosin between the biopsy specimen (baseline) and the surgical specimen were also evaluated.
The researchers presented the results of the first 36 enrolled patients out of a total of 60. Clinical and tumor characteristics were well balanced between the groups. No relevant toxicities were reported.
No clinically significant differences were observed in Ki67 and cleaved caspase-3 after treatment with denosumab. Interestingly, a statistically significant increase in tumor-infiltrating lymphocytes was observed in the group treated with denosumab (p = 0.03), but not in the control group (p = 0.80). It was observed that 33% of patients treated with denosumab showed an increase ≥ 10% of tumor-infiltrating lymphocytes versus 0% in the control group (p = 0.05).
According to the authors, preliminary data suggest that short-term use of neoadjuvant denosumab increases the number of tumor-infiltrating lymphocytes.