Breast cancer (BC) is the most prevalent malignancy among women globally and the leading cause of cancer-related mortality among females. In Vietnam, breast cancer is the most common cancer in females with 24,563 (28.9%) new cases in 2022, ranked as the fourth leading cause of death (10,003 deaths) in both genders.¹ The HER2-positive breast cancer subtype is often associated with a poor prognosis, aggressive progression, and an increased likelihood of early recurrence.²

Neoadjuvant systemic therapy has become the standard of care for patients with HER2-positive breast cancer presenting with locally advanced disease (≥ T2) or regional lymph node involvement. Pathological complete response (pCR) is characterized by the complete absence of invasive carcinoma in the resected breast tissue and all evaluated regional lymph nodes following neoadjuvant treatment (ypT0/Tis ypN0).^3,4 Achievement of pCR at the time of surgery has been shown to correlate with improved clinical outcomes, particularly in patients with HER2-positive, hormone receptor (HR)-negative breast cancer, as evidenced by the pooled analysis from the CTNeoBC study. Across all the subgroups analyzed, pCR was significantly associated with enhanced event-free survival (EFS) (HR 0.48; 95% CI 0.43–0.54) and overall survival (OS) (HR 0.36; 95% CI 0.31–0.42).⁵

The integration of trastuzumab into neoadjuvant chemotherapy regimens has been demonstrated to significantly enhance both pathological complete response (pCR) rates and event-free survival (EFS) compared to chemotherapy alone, as illustrated by findings from the NOAH trial.⁶ Consistent improvements in pCR outcomes have also been reported in the TECHNO and GeparQuattro studies, where trastuzumab was incorporated into standard chemotherapy protocols.^7,8

Pertuzumab exerts its anti-tumor effect by binding to the extracellular domain II of HER2, thereby inhibiting ligand-dependent HER2–HER3 dimerization.⁹ This mechanism of action complements that of trastuzumab. The NeoSphere trial reported a pCR rate of approximately 45% in patients treated with pertuzumab plus trastuzumab and docetaxel, compared to 29% in those receiving trastuzumab and docetaxel alone.¹⁰ The combination of pertuzumab with trastuzumab and docetaxel was further investigated in the CLEOPATRA trial, which demonstrated a significant overall survival benefit (56.5 months vs 40.8 months).¹¹ Based on these findings, dual HER2-blockade with trastuzumab and pertuzumab in combination with standard neoadjuvant chemotherapy has become the established standard of care.¹²

Despite these advances, access to dual HER2-targeted therapy (trastuzumab-pertuzumab) remains limited for many HER2-positive breast cancer patients in Vietnam due to various socioeconomic and healthcare-related barriers. A 2024 survey in Vietnam revealed that only 37.5% of patients with HER2 overexpression received trastuzumab for at least one cycle (partially covered by insurance at 60%), and a mere 2.1% were treated with pertuzumab (not covered by insurance).¹³ Due to this limitation, there is a paucity of data regarding the efficacy of dual HER2-targeted therapy in the neoadjuvant treatment of breast cancer in Vietnam. In Vietnam, anthracycline-containing regimens such as 4AC (anthracycline/cyclophosphamide)-4THP (taxane/trastuzumab/pertuzumab) remain widely used due to their proven efficacy, long-term data, flexible implementation in available healthcare settings, and acceptable tolerability. Meta-analyses and long-term follow-up support the use of anthracyclines as a cornerstone for high-risk breast cancer when used in appropriate patients with safe cumulative doses and careful cardiac monitoring. Cardiac safety data from TRYPHAENA and BERENICE trials showed low rates of grade 3–4 heart failure (< 2%), with most left ventricular dysfunction reversible after treatment interruption. These findings indicate that anthracyclines can be safely incorporated into neoadjuvant regimens for HER2-positive breast cancer with proper cardiac surveillance. Therefore, this research was conducted to evaluate the response rate of the 4AC-4THP regimen in Vietnamese women with HER2-positive breast cancer.

The rate of pathological complete response (pCR) is often a primary endpoint in neoadjuvant breast cancer treatment studies. Studies have indicated that achieving pCR is associated with decreased rates of recurrence and mortality.¹⁶ The combination of chemotherapy with trastuzumab and pertuzumab significantly improves pCR rates in neoadjuvant treatment settings.¹²

In the present study, the total pCR rate was achieved at 78.0%, with pCR rates for breast tumors and lymph nodes found to be 80.0% and 94.1%, respectively. These results are significantly higher than those from the NEOSPHERE study. In the NEOSPHERE study, the population was stratified into four treatment groups, which included trastuzumab combined with docetaxel, pertuzumab combined with trastuzumab and docetaxel, trastuzumab combined with pertuzumab, and docetaxel combined with pertuzumab. The primary objective of the NEOSPHERE study was to evaluate the overall histopathological response at the time of surgical intervention. The results indicated that the group treated with the neoadjuvant regimen of docetaxel combined with trastuzumab and pertuzumab achieved a complete histopathological response in breast tumors (bpCR) of 45.8% and an overall total pathological complete response (pCR) for both breast and lymph nodes of 39.3%, which was statistically significant compared to the other groups; however, these rates were lower than those found in the current study. It is hypothesized that the lower pCR rates observed in the NEOSPHERE study may be partially attributed to the specific chemotherapy regimen utilized, as their protocol employed docetaxel as a single-agent therapy.¹⁰ In practice, combination therapies involving HER2-targeted agents such as ACTH(P) or TCH(P) are generally associated with higher response rates. Consequently, to achieve higher response rates, the AC-THP regimen was selected, which is also incorporated into several guidelines for neoadjuvant treatment of HER2-positive breast cancer.

In the TRYPHAENA study pCR rates were reported to range from 54.7% to 63.6% across treatment groups, with the highest response rate observed in the TCHP group. While the primary objective of the TRYPHAENA study was not to evaluate pCR, its secondary outcomes yielded pCR results in the TCHP group that were closely aligned with the findings of the current study, despite differences in the chemotherapy regimens utilized.¹⁷ Thus, the AC-THP regimen demonstrates efficacy comparable to that of larger international studies. Our results are higher than those reported by Phùng Thị Huyền (2020), who found a pCR rate of 64.1% (n=39 patients) for the ACTH or TCH regimen.¹⁸ Furthermore, Phùng Thị Huyền (2021) published findings indicating a pCR rate of 80% with the ACTHP and TCHP regimens among 20 patients, which closely aligns with the results of our study.¹⁹ These findings, along with data from other studies, suggest that the addition of pertuzumab to chemotherapy regimens combined with trastuzumab enhances the likelihood of achieving pCR in HER2-positive breast cancer.

Numerous studies have sought to identify predictive factors for pCR among the studied populations. The TECHNO study found no significant differences in pCR rates when comparing variables such as age (< 40; ≥ 40), histological type, tumor grade, tumor stage, lymph node status, and hormone receptor status.⁷ Conversely, the Gepar Quattro study reported a higher pCR rate in the hormone receptor-negative group (43.5%), while the hormone receptor-positive group achieved only 23.4% ($p < 0.001$).⁸ The NOAH study noted significant differences in pCR rates between stage II (75%) and stage III (40%) with $p = 0.03$.⁶ After conducting univariate logistic regression analyses for all candidate variables, age and tumor grade met the selection threshold (p < 0.2) and were included in the multivariable model, in accordance with the events-per-variable constraint. In multivariable analysis, neither age nor tumor grade was significantly associated with pCR. Specifically, patients aged ≥ 40 years had a lower, though not statistically significant, likelihood of achieving pCR compared with those < 40 years ($p = 0.214$; OR 0.334, 95% CI: 0.059–1.881). Likewise, higher tumor grade was not significantly associated with pCR ($p = 0.268$; OR 0.441, 95% CI: 0.104–1.875). The results of our study are consistent with the TECHNO study, as there were no significant correlations between the investigated factors and pCR rates.⁷

Several factors may explain why no variables were identified as significant predictors of pCR. The overall pCR rate was very high (78%), leaving few non-pCR cases and limiting statistical discrimination between the subgroups. The small sample size (n = 50) further reduced analytical power and restricted the number of variables eligible for multivariable modeling. Moreover, all the patients received the same neoadjuvant regimen (4AC–4THP), resulting in substantial clinical and biological homogeneity. Some subgroups contained very few patients, producing unstable OR estimates. Collectively, these factors likely contributed to the absence of statistically significant predictors of pCR.

Our study demonstrated that the 4AC-4THP neoadjuvant regimen was generally well-tolerated, with no cases of symptomatic heart failure or treatment discontinuation due to cardiotoxicity. Although 80% of the patients experienced some degree of LVEF reduction, the mean decline was modest (8.05%) and no patient met the threshold for clinically significant cardiotoxicity (LVEF < 50% or ≥ 10-point drop). These findings are consistent with contemporary reports showing that dual HER2 blockade combined with anthracycline-based therapy can cause measurable but mostly reversible decreases in LVEF, particularly when cardiac monitoring is performed rigorously. Regarding non-cardiac adverse events, grade 3–4 neutropenia occurred in 18% of patients—predominantly during the dose-dense AC phase—which aligns with the known myelosuppressive risk of anthracyclines. Other severe toxicities were uncommon, and no grade 3–4 anemia, thrombocytopenia, diarrhea, neuropathy, or infusion reactions were observed. Mucositis was infrequent and confined to the AC component. Overall, the toxicity profile observed in our cohort suggests that the 4AC-4THP regimen is manageable with appropriate supportive care and may be safer than previously reported for sequential anthracycline and dual HER2 blockade.

The 4AC-4THP regimen in neoadjuvant treatment for HER2-positive breast cancer has shown high therapeutic efficacy, achieving a pathological complete response (pCR) rate of 78.0%. Based on these findings, it is imperative to undertake additional research to investigate the survival benefit associated with this treatment protocol in HER2-positive breast cancer patients.