SABCS Voice of China | Professors Qiang Liu and Yaping Yang: Final Results of the National Multicenter Clinical Study on AC*4 Sequential T*4 Combined with Full-Course Dual-Target Neoadjuvant Treatment for HER2-Positive Breast Cancer Disclosed

Led by Professor Qiang Liu and Professor Yaping Yang from the Sun Yat-sen Memorial Hospital’s Breast Tumor Hospital at Sun Yat-sen University, the final clinical study results of a new neoadjuvant treatment regimen for HER2-positive breast cancer were disclosed for the first time. The results were presented in the form of a POSTER at the SABCS conference to scholars worldwide. The study demonstrates that the regimen, based on pegylated liposomal doxorubicin as part of the AC*4 protocol followed by a T*4 chemotherapy regimen combined with a full-course dual-target treatment, offers good antitumor efficacy and cardiac safety as a neoadjuvant treatment for patients with HER2-positive breast cancer. This article introduces the research.

Background: The standard neoadjuvant treatment regimen for HER2-positive breast cancer involves dual-targeting HP combined with chemotherapy, with patients achieving pathological complete response (pCR) benefiting from improved survival. Despite recent guideline updates recommending the docetaxel plus platinum and dual-target HP regimen as one of the first-choice neoadjuvant treatments for HER2-positive breast cancer, anthracyclines are more commonly used in clinically high-risk cases, especially those with lymph node metastasis. Anthracycline drugs combined with H might offer better antitumor efficacy, but due to traditional anthracycline cardiac safety concerns, they are generally not used with H. However, pegylated liposomal doxorubicin (PLD) exhibits significantly better cardiac safety, leading to the design of a Phase II single-arm study of the AC-T regimen in combination with HP dual-targeting. The efficacy and cardiac safety data of this regimen were presented in a POSTER at the conference, allowing high-risk HER-2 positive patients to use HP dual-targeting earlier in neoadjuvant treatment and also to use anthracycline drugs.

Study Design: This single-arm, open-label, multicenter, Phase II study enrolled 78 patients with early-stage HER2-positive breast cancer. Patients received neoadjuvant treatment for 4 cycles of PLD (30-35 mg/m^2) and cyclophosphamide (600 mg/m^2), followed by 4 cycles of a taxane drug (docetaxel, 100 mg/m^2 or albumin-bound paclitaxel, 260 mg/m^2), combined with 8 cycles of trastuzumab (loading dose 8 mg/kg, then 6 mg/kg) and pertuzumab (loading dose 840 mg, then 420 mg), every 3 weeks. Efficacy endpoints included the primary endpoint of total pathological complete response (tpCR, ypT0/is ypN0) rate and secondary endpoints of objective response rate (ORR) at cycles 4 and 8. Safety endpoints mainly focused on cardiac safety and other treatment-related adverse effects. Biomarker analysis examined the expression of topoisomerase IIα (TOP2A) by immunohistochemistry (IHC) in breast primary tumor tissue at initial diagnosis, assessed by independent pathology review.

Study Results: As of March 31, 2023, all 78 eligible patients completed neoadjuvant treatment and underwent surgical treatment, with 42 patients (53.8%) undergoing breast-conserving surgery. After neoadjuvant treatment, 47 patients (60.3%, 95% CI, 48.5%-71.2%) achieved total pathological complete response (tpCR), and 49 patients (62.8%) reached breast pathological complete response (bpCR). The objective response rates (ORR) after 4 and 8 cycles of neoadjuvant treatment were 76.9% (95% CI, 66.0%-85.7%) and 93.6% (95% CI, 85.7%-97.9%), respectively. It’s important to note that the tpCR rates for patients with lymph node-positive were 63.6%, for Stage III patients were 69.6%, and for ER-positive patients were also high at 56%, all significantly higher than the efficacy reported in previous studies like the Kristine study, indicating that this regimen has substantial therapeutic value for HER2-positive breast cancer patients with high tumor burden or ER positivity.

After the first treatment cycle, all patients (100%) achieved disease control.9patients (11.5%) experienced asymptomatic declines in left ventricular ejection fraction (LVEF) (≥10% decrease from baseline), but all values were >55%, requiring no clinical intervention. No treatment-related abnormal changes were observed in cardiac function parameters including NT-proBNP, cardiac troponin I, and high-sensitivity cardiac troponin. None of the patients experienced any symptomatic cardiac events leading to dose reduction or discontinuation of PLD. Biomarker analysis showed that although TOP2A status was not associated with tpCR, patients with expression ≥15% had a 12.6% higher pCR rate than those with <15%.

Conclusion: The regimen based on pegylated liposomal doxorubicin (PLD) as part of the AC*4 followed by T*4 chemotherapy combined with full-course dual-target treatment shows excellent antitumor efficacy, particularly for patients with high tumor burden or ER positivity. With fewer side effects and good cardiac safety, it promises to be an optimal neoadjuvant treatment choice for patients with HER2-positive breast cancer.

Following these results, a national multicenter Phase III randomized controlled open clinical study led by Professor Qiang Liu is underway. This study compares the “pegylated liposomal doxorubicin + cyclophosphamide followed by taxane combined with trastuzumab and pertuzumab (PLD+C+HP followed by THP)” regimen with the “taxane combined with carboplatin combined with trastuzumab and pertuzumab (TCbHP)” regimen for neoadjuvant treatment of HER-2 positive breast cancer, inviting interested centers to join this research.