Efficacy and Safety of Anti-HER2 Targeted Therapy for Metastatic HR-Positive and HER2-Positive Breast Cancer: A Bayesian Network Meta-Analysis

Abstract

Despite the development of HER2-targeted drugs, achieving favorable outcomes for patients with HR+/HER2+MBC remains challenging. This study utilized Bayesian Network Meta-analysis to compare the efficacy and safety of anti-HER2 combination regimens. The primary analysis focused on progression-free survival (PFS), while secondary analyses included objective response rate, overall survival (OS) and the incidence rate of grade 3/4 adverse events (AEs). A comprehensive search across seven databases identified 25 randomized controlled trials for inclusion in this meta-analysis. For patients eligible for endocrinotherapy, our findings revealed that dual-target combined endocrine therapy, such as Her2-mAb+Her2-mAb+Endo (HR = 0.38; 95%CrI: 0.16-0.88) and Her2-mAb+Her2-tki+Endo (HR = 0.45; 95%CrI: 0.23-0.89), significantly improved PFS compared to endocrine therapy alone. According to the surface under the cumulative ranking curves (SUCRAs), Her2-mAb+Her2-mAb+Endo and Her2-mAb+Her2-tki+Endo ranked highest in terms of PFS and OS, respectively. For patients unsuitable for endocrine therapy, anti-HER2 dual-target combined chemotherapy, such as Her2-mAb+Her2-mAb+Chem (HR = 0.76; 95%CrI: 0.6-0.96) and Her2-mAb+Her2-tki+Chem (HR = 0.48; 95%CrI: 0.29-0.81), demonstrated significant improvements in PFS compared to Her2-mAb+Chem. The results were the same when compared with Her2-tki+Chem. According to the SUCRAs, Her2-mAb+Her2-tki+Chem and Her2-mAb+Her2-mAb+Chem ranked highest for PFS and OS, respectively. Subgroup analyses consistently supported these overall findings, indicating that dual-target therapy was the optimal approach irrespective of treatment line.

Keywords: Bayesian network meta-analysis; HER2-positive; HR-positive; metastatic breast cancer; targeted therapy.

Figure 1

Study selection process based on the PRISMA guideline. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-analysis.

Figure 2

The assessment of bias risk of included studies. (A) Bias risk summary. Bias risk was classified as low (+), unclear (?), or high (−). (B) Bias risk graph. Reviewing authors’ judgements about the bias risk of each item, and they were shown as percentages across all included studies.

Figure 3

Network plots of each targeted treatment regimen for ORR and PFS (A) ORR^#1; (B) ORR^#2; (C) PFS^#1; (D) PFS^#2. Her2-ADC: trastuzumab deruxtecan, trastuzumab emtansine; Her2-mAb: pertuzumab, trastuzumab; Her2-tki: afatinib, lapatinib, neratinib, pyrotinib, tucatinib; Chem: capecitabine, docetaxel, doxorubicin, paclitaxel, physician’s choice Chemtherapy, taxane, vinorelbine; Endo: anastrozole, fulvestrant, letrozole; CDK/4/6: abemaciclib, palbociclib; mTOR: everolimus; PD-L1: atezolizumab. Each node represents a treatment option, and the lines between them depict direct comparisons in this study. The size of the nodes and the thickness of the lines correspond to the number of direct comparisons made between the treatment options. Larger nodes and thicker lines indicate a higher number of direct comparisons conducted in this study (ORR: objective response rate; PFS: progression free survival).

Figure 4

Network plots of each targeted treatment regimen for OS (A) OS^#1; (B) OS^#2. Her2-mAb: pertuzumab, trastuzumab; Her2-tki: afatinib, lapatinib, neratinib, pyrotinib, tucatinib; Chem: capecitabine, docetaxel, doxorubicin, paclitaxel, physician’s choice Chemtherapy, taxane, vinorelbine; Endo: anastrozole, fulvestrant, letrozole; CDK/4/6: abemaciclib, palbociclib. Each node represents a treatment option, and the lines between them depict direct comparisons in this study. The size of the nodes and the thickness of the lines correspond to the number of direct comparisons made between the treatment options. Larger nodes and thicker lines indicate a higher number of direct comparisons conducted in this study (OS: overall survival).

Figure 5

Network plot of each targeted treatment regimen for the grade 3/4 adverse event rate. Her2-mAb:pertuzumab, trastuzumab; Her2-tki: afatinib, lapatinib, neratinib, pyrotinib, tucatinib; Chem: capecitabine, docetaxel, doxorubicin, paclitaxel, physician’s choice Chemtherapy, taxane, vinorelbine; Endo: anastrozole, fulvestrant, letrozole; CDK/4/6: abemaciclib, palbociclib. Each node represents a treatment option, and the lines between them depict direct comparisons in this study. The size of the nodes and the thickness of the lines correspond to the number of direct comparisons made between the treatment options. Larger nodes and thicker lines indicate a higher number of direct comparisons conducted in this study.