Relative efficacy of antibody-drug conjugates and other anti-HER2 treatments on survival in HER2-positive advanced breast cancer: a systematic review and meta-analysis

Kang et al. BMC Cancer (2024) 24:708 https://doi.org/10.1186/s12885-024-12478-1 BMC Cancer Open Access RESEARCH Relative efficacy of antibody-drug conjugates and other anti-HER2 treatments on survival in HER2-positive advanced breast cancer: a systematic review and meta-analysis Zian Kang1, Yuqing Jin2, Huihui Yu3, Su Li1 and Yingjie Qi1* Abstract Background Novel antibody-drug conjugates (ADCs) drugs present a promising anti-cancer treatment, although survival benefits for HER2-positive advanced breast cancer (BC) remain controversial. The aim of this meta-analysis was to evaluate the comparative effect of ADCs and other anti-HER2 therapy on progression-free survival (PFS) and overall survival (OS) for treatment of HER2-positive locally advanced or metastatic BC. Methods Relevant randomized controlled trials (RCTs) were retrieved from five databases. The risk of bias was assessed with the Cochrane Collaboration’s tool for RCTs by RevMan5.4 software. The hazard ratio (HR) and 95% confidence intervals (CIs) were extracted to evaluate the benefit of ADCs on PFS and OS in HER2-positive advanced BC by meta-analysis. Results Meta-analysis of six RCTs with 3870 patients revealed that ADCs significantly improved PFS (HR: 0.63, 95% CI: 0.49–0.80, P = 0.0002) and OS (HR: 0.79, 95% CI: 0.72–0.86, P < 0.0001) of patients with HER2-positive locally advanced or metastatic BC. Subgroup analysis showed that PFS and OS were obviously prolonged for patients who previously received HER2-targeted therapy. Sensitivity analysis and publication bias suggested that the results were stable and reliable. Conclusion Statistically significant benefits for PFS and OS were observed with ADCs in HER2-positive locally advanced or metastatic BC, especially for those who received prior anti-HER2 treatment. Keywords Antibody-drug conjugates, Breast cancer, Overall survival, Progression-free survival, Meta-analysis *Correspondence: Yingjie Qi 1 Department of Pharmacy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning Province 110042, China 2 School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China 3 Department of Cancer Prevention and Control, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Kang et al. BMC Cancer (2024) 24:708 Introduction Breast cancer (BC) is a leading cause of cancer-related morbidity and mortality of women aged 20–59 years [1, 2]. Human epidermal growth factor receptor-2 (HER2) is overexpressed in about 20–25% of BC and closely correlated to the proliferative and invasive capabilities of BC cells [3]. The biological behavior is characterized by high recurrence, metastasis, drug resistance and poor prognosis [4]. Conventional treatments include large molecule monoclonal antibodies, small molecule tyrosine kinase inhibitors and cytotoxic chemotherapy regimens. However, these modalities often fall short due to their limited efficacy or serious adverse drug reactions [5–7]. Thus, more effective and safer treatment strategies are urgently needed [8]. Antibody-drug conjugates (ADCs) targeting HER2 gene amplification or protein overexpression can greatly improve the prognosis of patients with HER2-positive locally advanced or metastatic BC. ADCs are composed of a monoclonal antibody, cytotoxic agent and chemical linker. When the monoclonal antibody omponent of the ADC complex is endocytosed, the linker is cleaved by the low pH of lysosomes, which releases the cytotoxic agent to cause damage to DNA or microtubule proteins, resulting in death of tumor cells [9–11]. Therefore, ADCs has the capacity for precise targeting, stable therapeutic efficacy and low toxicity [12, 13]. Numerous clinical trials have investigated the efficacy of ADCs targeting HER2 for treatment of HER2-positive locally advanced or metastatic BC. In terms of PFS, the international multicenter phase III clinical EMILIA trial [14, 15] validated that trastuzumab emtansine (T-DM1) significantly improved (p < 0.001) progression-free survival (PFS) of patients with HER2-positive advanced BC. Notably, MARIANNE study [16] revealed that T-DM1 did not bring obvious PFS benefits compared to other anti-HER2 treatments. In terms of OS, the TH3RESA study [17, 18] underscored the median OS was significantly prolonged in T-DM1 group. However, MARIANNE study found that the OS of the intervention group containing T-DM1 was not inferior to that of trastuzumab combined with taxanes. In consideration of the conflicting outcomes of previous individual clinical trial, the aims of this systematic review and meta-analysis were to explore the efficacy of ADCs on PFS and OS for treatment of HER2-positive locally advanced and metastatic BC and identify patients who would most benefit from treatment. Materials and methods This systematic review and meta-analysis followed the principle of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [19]. The protocol was registered in PROSPERO (CRD42023477508). Page 2 of 10 Search strategy Relevant clinical studies of the efficacy of ADCs targeting HER2-positive advanced BC were retrieved from the PubMed, Web of Science, Cochrane Library, Embase, and Clinical Trials databases (from inception to March 2023). The main therapy-related search terms were (human epidermal growth factor receptor 2 OR HER-2 protein OR EGFR2 protein) AND (Antibody-Drug Conjugates OR ADCs OR ADC) AND (survival OR overall survival OR OS OR progression-free survival OR PFS). The diseaserelated search term was breast cancer OR breast neoplasm OR breast tumor. Supplementary File. 1 described the detailed methods used to search. Also, the reference sections of all articles were manually searched to identify other eligible studies. Eligibility criteria The eligibility criteria of prospective studi (...truncated)