Introduction

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) accounts for 15–20% of all BC cases and is characterized by HER2 overexpression, aggressive tumor growth, and poor prognosis (Slamon et al. 1989). With the advent of targeted therapies, treatment outcomes for patients with HER2-positive BC have significantly improved, resulting in a 7-year disease-free survival rate of 93.3% (Romond et al. 2005; Tolaney et al. 2019). Despite standardized treatments, metastasis still occurs in 20–30% of patients with HER2-positive BC (Bear et al. 2015).

Advanced breast cancer (ABC), including both locally advanced breast cancer and metastatic breast cancer, represents a specific subgroup of breast cancer that is resistant to curative surgical interventions. Docetaxel combination with trastuzumab and pertuzumab used in CLEOPATRA trial defines the classic first-line treatment regimen for ABC (Giordano et al. 2022). However, the continuous emergence of drugs is gradually resha** the treatment landscape, these varying combinations targeted agents offer diverse benefits. For instances, the PHILA study (Xu et al. 2022), the introduction marked a significant departure from the established dual-targeted treatment paradigm for advanced settings, offering new promise for first-line therapy. This study showcased the potential of a trastuzumab and tyrosine kinase inhibitors (TKIs) combination regimen, which demonstrated a numerical advantage over dual-targeted therapy in terms of progression-free survival (PFS). Given the late emergence of pertuzumab, few clinical trials have directly compared it head-to-head with dual-targeted therapy. Consequently, there is a growing need for comprehensive comparisons of all first-line regimens to inform and guide physicians in their choice of therapeutic strategies.

Triple-positive breast cancer (TPBC) characterized as being hormone receptor (HR)-positive and HER2-positive, encompasses various subtypes including Luminal type B and HER2 overexpression type. These subtypes exhibit distinct molecular functions, biological processes, signaling pathways, and clinical behaviors. Furthermore, they demonstrate varying sensitivities to treatment and diverse intrinsic biological features, ultimately reflecting different responses to therapeutic interventions (Zhao et al. 2022).

TPBC represents a distinct clinical entity. While HER2 positivity is generally an independent predictor of poor prognosis, high HR expression is associated with a better outcome (Parise and Caggiano 2016; Kay et al. 2021). Thus, patients with HR-positive/HER2-positive status tend to have a better prognosis than their HR-negative/HER2-positive counterparts but fare worse than HR-positive/HER2-negative patients. Notably, crosstalk between the HR and HER2 pathways complicates treatment, as monochemotherapy targeting either pathway alone can lead to suboptimal results and potential drug resistance. For example, the CLEOPATRA study (Swain et al. 2020) showed reduced benefits from dual-targeted chemotherapy in HR-positive patients compared to HR-negative patients. The BIG 1–98 study (Rasmussen et al. 2008) reported poorer outcomes for patients with HER2-positive BC treated with endocrine therapy alone. Our analysis indicates that combining dual-targeted therapy with endocrine therapy yields the highest SUCRA of PFS for TPBC patients, outperforming both monochemotherapy plus dual-targeted and monochemotherapy plus single-targeted and endocrine therapy (Fig. 5B). Although this recommendation is based on data from the phase II PERTAIN trial (Rimawi et al. 2018) alone, it is supported by findings from the MonarcHER (André et al. 2022) and SYSUCC-002 (Hua et al. 2022) studies, suggesting that this combined approach represents a promising and effective strategy for managing TPBC.

For patients with cardiac comorbidity or risk factors for heart disease, cardiac function testing is required to exclude contraindications for trastuzumab and anthracycline drugs. Our research has found that T-DM1, which has no significant cardiac toxicity, is a good alternative for such patients (Fig. 6).

While improved PFS is a notable outcome, it is not a definitive marker of treatment effectiveness unless it translates into a benefit in OS (Adunlin et al. 2015). Unfortunately, only the regimen of monochemotherapy plus dual-targeted therapy is currently benefiting on the OS (Supplemental File D3). We acknowledge that the OS data in many of these studies remain immature due to the lengthy process of OS data collection. As a result, only OS results from a small number of studies were included in our current analysis. We anticipate future research that comprehensively evaluates treatment options from the perspective of OS.

Limitations

All of our studies enrolled RCTs to improve accuracy and reliability and utilized PFS, OS, ORR and ≥ 3 AEs to comprehensively assess the efficacy and safety of the regimens. It was also analyzed for the triple-positive subgroup. But our study still have some shortcomings: we excluded single-arm studies to form a closed loop; Some studies did not publish information on randomization and allocation methods, which can lead to potential bias; Some studies did not include all endpoints, or the endpoints were immature, and our analysis based on existing published data would have resulted in potential bias; Some studies enrolled patients on first and second line treatments, and it was not possible to extract data on first-line treatments separately.

Conclusion

This NMA utilizing Bayesian modeling provides valuable insights into the first-line treatment options for HER2-positive ABC. Monochemotherapy (Docetaxel) plus dual-target (Trastuzumab and Pertuzumab) therapy emerged as the optimal choice based on their efficacy outcomes of OS and a comprehensive analysis of both PFS and ≥ 3 AEs. Additionally, the combination of trastuzumab with TKIs (Pyrotinib) offered a more favorable PFS and ORR, but further data are warranted to confirm the survival benefit.