Signal Transduction and Targeted Therapy | Efficacy and Safety Evaluation of PEGylated Liposomal Doxorubicin Combined with Dual-Targeted Therapy in Neoadjuvant Treatment of HER2-Positive Breast Cancer

This study provides critical data for neoadjuvant treatment strategies in HER2-positive breast cancer, confirming that early introduction of dual-targeted therapy significantly improves pathological complete response rates, offering direct evidence for optimizing clinical trial designs.

 

Literature Overview

This article, titled "Neoadjuvant concurrent or sequential anthracycline-containing chemotherapy and HER2-targeted agents for HER2-positive breast cancer: a randomized phase 2 study (METIS)," published in Signal Transduction and Targeted Therapy, systematically explores the efficacy and safety comparison between a concurrent administration regimen of PEGylated liposomal doxorubicin (PLD) combined with dual-targeted agents (trastuzumab and pertuzumab) and the traditional sequential anthracycline-based regimen in the neoadjuvant treatment of HER2-positive breast cancer.

Background Knowledge

This study aims to address the core concern of cardiotoxicity arising from the combination of anthracyclines and HER2-targeted agents in HER2-positive breast cancer treatment. Currently, although dual-targeted therapy has become standard, there is still a lack of conclusive evidence regarding whether anthracyclines can be used concurrently in the early stages to maximize efficacy. Traditional regimens often adopt a sequential strategy due to concerns over cardiotoxicity, potentially missing the optimal treatment window. The continuous activation of the HER2 pathway is closely related to tumor invasiveness. How to enhance tumor cell killing effects by adjusting administration timing and drug carriers (such as using PLD) while ensuring cardiac safety is a key entry point for current drug development and clinical strategy optimization.

 

 

Research Methods and Core Experiments

The authors conducted a multicenter, randomized, open-label Phase II clinical trial (METIS), enrolling 156 patients with stage II-III HER2-positive breast cancer. Patients were randomly divided into two groups: the experimental group received a PLD-based concurrent regimen (ACHP: PLD + cyclophosphamide + trastuzumab + pertuzumab), followed by paclitaxel combined with dual-targeted therapy; the control group received the traditional sequential regimen of epirubicin and cyclophosphamide (EC), followed by paclitaxel combined with dual-targeted therapy. Key evidence supporting the conclusions was derived from comparing the pathological complete response rate (pCR), event-free survival (EFS), and changes in left ventricular ejection fraction (LVEF) between the two groups, with particular attention paid to the incidence of cardiotoxicity.

Key Conclusions and Perspectives

• The PLD-based concurrent regimen significantly improved the pathological complete response rate (67.5% vs. 48.7%), with more pronounced benefits observed in the hormone receptor-positive subgroup and stage II patients, suggesting that early dual-targeted intervention effectively enhances tumor regression.
• Although the follow-up period was limited, the concurrent group showed a trend towards superior event-free survival (HR=0.35), and the achievement of pCR was significantly associated with EFS improvement, validating the reliability of pCR as a prognostic indicator.
• In terms of safety, the incidence of cardiotoxicity was comparable between the two groups. No symptomatic cardiac dysfunction occurred in the concurrent group, confirming the cardiac safety advantage of PLD when combined with HER2-targeted therapy, thereby challenging the traditional notion that anthracyclines and targeted agents must be strictly administered sequentially.

Research Significance and Prospects

From a research perspective, this finding provides a new direction for combination strategies in drug development for HER2-positive breast cancer, particularly for clinical monitoring scenarios where T-DXd cannot be used or where cost-effective solutions are required. This study supports further exploration of concurrent administration modes of anthracyclines and targeted agents based on liposomal technology in disease modeling and subsequent Phase III trials to optimize the care system for high-risk patients.

 

 

Conclusion

This study, through a rigorous randomized controlled trial, challenges the traditional notion that anthracyclines and HER2-targeted therapy must be administered sequentially. The results indicate that leveraging the cardioprotective properties of PLD to introduce dual-targeted therapy early not only significantly improves the pathological complete response rate in HER2-positive breast cancer but also does not increase the risk of cardiotoxicity. This finding is a milestone for improving the prognosis of high-risk patients, providing solid evidence for clinicians to formulate more aggressive and safer neoadjuvant treatment regimens. In the future, this strategy is expected to become an important component of the standard treatment for HER2-positive breast cancer, demonstrating significant clinical translation value, particularly in patient populations with limited drug accessibility or those requiring avoidance of specific toxic drugs.

 

Qiufan Zheng, Shusen Wang, Zhiyong Wu, Zhongyu Yuan, and Wen Xia. Neoadjuvant concurrent or sequential anthracycline-containing chemotherapy and HER2-targeted agents for HER2-positive breast cancer: a randomized phase 2 study (METIS). Signal Transduction and Targeted Therapy.