Trastuzumab deruxtecan in patients with bone metastases from HR+/HER2-low breast cancer: efficacy enhanced by denosumab.

Approximately 60% of human epidermal growth factor receptor 2-negative (HER2-) breast cancers (BCs) are HER2-low [immunohistochemistry (IHC) 1+ or 2+/in situ hybridization (ISH)-]. The proportion of BC patients with hormone receptor-positive (HR+)/HER2- are more likely to metastasize to bone. The phase 3 Destiny-Breast04 study led to the approval of the antibody drug conjugate trastuzumab deruxtecan (T-DXd) in HER2-low patients, even HR+, after lines of endocrine therapy and one line of chemotherapy. Recently, the Destiny-Breast06 study showed a progression-free survival advantage of T-DXd also in first-line. T-DXd has an immunological effect as it can produce antibody-dependent cellular cytotoxicity-like effects by recruiting dendritic cells and CD8+ T cells. This immunological effect can be enhanced using immune checkpoint inhibitors but also the anti-RANK-ligand (RANKL) antibody denosumab, which can be used for the prevention of skeletal-related events (SREs). RANK modulates HER2-driven carcinogenesis because both RANK and HER2 activate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Thus, increased RANK signaling may contribute to the development of resistance to anti-HER2 therapy through NF-κB activation. It remains to be seen whether patients with HER2-positive or HER2-low BC that express RANK may benefit from concomitant HER2 and RANK inhibition therapy. Except for the Destiny-Breast06 study, which included only 3% of enrolled patients with exclusive bone metastases, we have no clinical data on the efficacy of T-DXd in bone metastases and on the concomitant use of T-DXd and denosumab, although the biological rationale for the increased efficacy of the combination is strong.