Irelli Azzurra, Patruno Leonardo Valerio, Cannita Katia
Medical Oncology Unit, Department of Oncology, "Giuseppe Mazzini" Hospital, Teramo, Italy.
Transl Breast Cancer Res. 2025 May 6;6:25. doi: 10.21037/tbcr-24-50. eCollection 2025.
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.
大约60%的人表皮生长因子受体2阴性（HER2-）乳腺癌（BC）为HER2低表达[免疫组织化学（IHC）1+或2+/原位杂交（ISH）-]。激素受体阳性（HR+）/HER2-的BC患者更有可能发生骨转移。3期Destiny-Breast04研究使得抗体药物偶联物曲妥珠单抗德瓦鲁单抗（T-DXd）在HER2低表达患者（即使是HR+）中获得批准，这些患者经过了多线内分泌治疗和一线化疗。最近，Destiny-Breast06研究表明T-DXd在一线治疗中也具有无进展生存优势。T-DXd具有免疫效应，因为它可以通过募集树突状细胞和CD8+T细胞产生抗体依赖性细胞毒性样效应。使用免疫检查点抑制剂以及抗核因子κB受体活化因子配体（RANKL）抗体地诺单抗可以增强这种免疫效应，地诺单抗可用于预防骨相关事件（SREs）。RANK调节HER2驱动的致癌作用，因为RANK和HER2都能激活活化B细胞的核因子κB轻链增强子（NF-κB）。因此，RANK信号增加可能通过NF-κB激活导致对抗HER2治疗产生耐药性。HER2阳性或HER2低表达且表达RANK的BC患者是否能从HER2和RANK联合抑制治疗中获益仍有待观察。除了仅纳入3%单纯骨转移患者的Destiny-Breast06研究外，我们没有关于T-DXd在骨转移中的疗效以及T-DXd与地诺单抗联合使用的临床数据，尽管联合用药疗效增加的生物学原理很充分。
