In 2020, breast cancer replaced lung cancer as the most common cancer worldwide; this cancer type is the leading type of cancer in women and the leading cause of cancer-related deaths according to the summary of cancer statistics for adolescents and young adults (ages 15–39) (Miller et al., 2020). In 2020, Chinese patients with breast cancer accounted for 24% of newly diagnosed cancer cases and 30% of cancer-related deaths globally, whereas in 2023 the U.S. is projected to account for 31% of new breast cancer cases and 15% of cancer-related deaths globally (Siegel et al., 2022, Siegel et al., 2023). Thus, Chinese women generally have a lower risk of developing breast cancer than women in high-income countries; however, younger Chinese women presently have a higher risk of developing breast cancer than did women of previous generations (Fan et al., 2014). By 2040, the incidence of new breast cancer cases on all six continents may increase by 49% from the 2020 levels, and death incidence may increase by 62% (Cao et al., 2021).

Breast cancer is categorized into three major subtypes based on the presence or absence of molecular markers for estrogen or progesterone receptors and human epidermal growth factor receptor 2 (ERBB2; formerly HER2): hormone receptor-positive/ERBB2 negative (70% of patients), ERBB2 positive (15–20%), and triple-negative (tumors lacking all three standard molecular markers; 15%) (Waks and Winer, 2019). Treatment options for breast cancer are pluralistic and include surgery, radiation therapy, and systemic therapy (chemotherapy, hormone therapy, or biological therapy). Surgery is the first option for most patients with early-stage breast cancer (ductal carcinoma in situ and small tumors that are clinically lymph node-negative) (Matsen and Neumayer, 2013). Generally, the therapeutic options for patients without metastatic disease include eliminating the tumor and avoiding recurrence. In previous studies, targeted therapy was the first choice for the clinical treatment of HER2-low/positive advanced breast cancer, with paclitaxel–trastuzumab being the standard treatment for patients with small lymph node-negative ERBB 2+ tumors. Pertuzumab and neratinib treatment in patients with high-risk ERBB 2+ breast cancer further reduced the risk of recurrence (Waks and Winer, 2019). HER2-targeted therapy improves disease outcomes; however, it is ineffective in treating locally advanced or metastatic disease, leading to disease progression in most patients (Harbeck et al., 2019). Notably, most patients with advanced HER2-positive breast cancer eventually die because of resistance to primary or acquired therapy and because patients with HER2-positive early-stage breast cancer have residual invasive disease despite preoperative systemic therapy, resulting in a higher risk of distant failure and death (Choong et al., 2020). The monoclonal antibodies trastuzumab (Fehrenbacher et al., 2020) and pertuzumab (Gianni et al., 2010) have not demonstrated robust efficacy in patients with HER2-low breast cancer, and the survival rate after diagnosis is difficult to determine because recurrence has not been documented in patients with breast cancer. In addition, it is particularly difficult to meet the long-term medical and psychological–social needs of survivors in low- and middle-income countries, whose emerging problems include but are not limited to the common long-term side effects of cancer treatment such as loss of physical strength, sexual dysfunction, deterioration of bone health, and physical and mental health problems (Harbeck et al., 2019).

To address these issues, the current focus of breast cancer treatment has shifted to combining different HER2-targeting agents and extending the duration of HER2-targeted therapy (Goutsouliak et al., 2020).

Trastuzumab deruxtecan (DS-8201; T-DXd) is an antibody-drug conjugate (ADC) composed of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor (Shitara et al., 2019). Its mechanism of action is hypothesized to involve the cleavage of DS-8201a by lysosomal enzymes and the release of DXd, which exerts a tumor-killing effect by specifically attacking target molecules in tumor cells after binding to the HER2 receptor and internalizing it in tumor cells (Ogitani et al., 2016). T-DXd induces remission in most patients with advanced HER2-positive breast cancer (Modi et al., 2020b). In January 2019, T-DXd received accelerated approval in the U.S. based on the results of the Phase II DESTINY-Breast 01 trial (Keam, 2020). Based on systemic therapy for HER2-positive advanced breast cancer, clinicians should recommend a combination of trastuzumab, patuzumab, and paclitaxel analogs as first-line therapy; if HER2-positive advanced breast cancer progresses during or after first-line HER 2-targeted therapy (and the patient is not receiving T-Dxd), clinicians should recommend T-Dxd as a second-line therapy (Giordano et al., 2022). According to experimental findings, T-DXd not only treated patients with trastuzumab emtansine (T-DM1)-refractory and HER2-positive breast cancer but also demonstrated antitumor activity in patients with HER2-low breast cancer (Ogitani et al., 2016, Doi et al., 2017). The external validity of the results of randomized controlled trials (RCTs) is generally low, with inconsistent outcomes for T-DXd for HER2-low/positive advanced breast cancer; further studies are needed to determine the true utility of combination therapy in clinical practice (Modi et al., 2022, Modi et al., 2020a). Over the past 2 years, several relevant studies have emerged whose cumulative analysis may contribute to the initial clinical validation of RCT results. The present study aimed to determine the safety and efficacy of T-DXd in treating HER2-low/positive advanced breast cancer through a meta-analysis of several RCTs, including DESTINY-Breast02 (NCT03523585), DESTINY-Breast03 (NCT03529110), and DESTINY-Breast04 (NCT03734029).