Comparison of pathological complete response (pCR) between short-term (<6 cycles) and long-term (≥6 cycles) neoadjuvant trastuzumab therapy for HER2-positive breast cancer: a systematic review and meta-analysis of randomized controlled trials

Introduction

Breast cancer has the highest incidence rate among women (1). The expression of human epidermal growth factor receptor 2 (HER2) has been found to have a distinct influence on the biological characteristics of breast cancer (2,3). HER2-positive breast cancer accounts for approximately 15–20% of all breast cancers (4). It is defined as a distinct molecular subtype (5). Consequently, the HER2 target is pivotal for the treatment of the HER2-positive breast cancer subtype. The humanized HER2 antibody, trastuzumab (Herceptin), was approved by the US Food and Drug Administration (FDA) for metastatic breast cancer in 1998. Subsequently, when combined with cytotoxic chemotherapy as first-line or adjuvant therapy, it demonstrated clinical benefits (6,7). In 2005, the results of the HERA study established that one-year adjuvant treatment with trastuzumab became the standard treatment for early-stage HER2-positive breast cancer (8).

With the evolution of treatment modalities, neoadjuvant therapy (NAT), which encompasses chemotherapy, targeted therapy, immunotherapy, endocrine therapy, etc., administered prior to breast cancer surgery, was proposed in 1970 (9). It serves to further enhance the surgical success rate, enabling patients who were initially ineligible for surgery or unsuitable for breast-conserving surgery to have better surgical opportunities. Meanwhile, research has indicated that NAT helps control tumor micrometastasis, reduces the risk of recurrence and metastasis, and can predict patients’ sensitivity to drug treatment at an early stage, guiding the adjustment of subsequent treatment plans (10,11). NOAH trial revealed that neoadjuvant trastuzumab treatment significantly improves prognosis of HER2-positive patients (12). The pathological complete response (pCR) rate achieved by HER2-positive breast cancer patients after NAT and surgery can also reflect long-term clinical benefits for patients (13). With the development of targeted drugs, adding other targeted therapies such as pertuzumab and lapatinib to trastuzumab can further increase the pCR (14-16).

However, in recent years, there has been an ongoing debate regarding the duration of anti-HER2 treatment during the NAT phase. In the NeoSphere trial, trastuzumab was used in combination with docetaxel for 4 cycles in NAT (14), while in the TRAIN-2 trial, trastuzumab was used for 9 cycles (17). In clinical practice, multiple factors, including tumor stage and patients’ physical tolerance, need to be comprehensively considered to determine the specific number of trastuzumab treatment cycles, aiming to achieve the optimal treatment effect while minimizing adverse reactions. This meta-analysis primarily reviews and analyzes published clinical trials of neoadjuvant trastuzumab treatment for HER2-positive breast cancer, aiming to comprehensively evaluate the efficacy and safety of different treatment durations of trastuzumab, with the goal of achieving the best treatment outcome while minimizing the occurrence of adverse reactions. We present this article in accordance with the PRISMA reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-25/rc).

Methods

All authors contributed to formulating the study protocol and it was then registered with the International Prospective Register of Systematic Reviews (PROSPERO Registration ID: CRD42024613903).

Search strategy

To identify relevant studies that would be suitable for inclusion in this meta-analysis, a comprehensive literature search was conducted across multiple databases including PubMed, EMBASE, and Web of Science on 20 April 2024. Search terms included “Trastuzumab”, “Neoadjuvant Therapy”, “Randomized Controlled Trials as Topic” and “Breast cancer”, which were linked with Boolean operators, “AND” and “OR”. Included studies were limited to clinical trials published in the English language and were not restricted by year of publication. The search was focused on articles conducting clinical trials on patients with breast cancer. Our focus was on randomized controlled trials (RCTs) comparing short-term versus long-term neoadjuvant trastuzumab therapy in patients with HER2-positive breast cancer. The short-term therapy was defined as the duration of trastuzumab therapy lasted less than 6 cycles, each cycle was precisely defined as a 21-day period. The long-term therapy was defined as the duration of trastuzumab therapy lasted six or more cycles. Studies that solely consisted of single-arm designs, metastatic stage investigations, or retrospective studies were excluded from our analysis.

Inclusion and exclusion criteria

Studies meeting the following inclusion criteria were included: (I) patients in the clinical trials were pathologically confirmed to have HER-2 positive breast cancer; (II) any phase clinical trial evaluating the pCR rate between short-term and long-term neoadjuvant trastuzumab therapy in HER2 positive breast cancer, with a focus solely on the duration of trastuzumab administration irrespective of concomitant HER2-targeted agents or chemotherapy regimens. Short-term therapy was defined as <6 cycles (each cycle =21 days), and long-term therapy as ≥6 cycles. Trials like NEOSPHERE (4 cycles, 21-day intervals) were excluded because they did not include a long-term (≥6 cycles) comparison arm for trastuzumab duration. pCR defined as no evidence of residual invasive tumor in the breast, irrespective of ductal carcinoma in situ, and no regional lymph node metastasis (ypT0/is+ypN0). If the data of ypT0/is+ypN0 as pCR did not provided in the article, then the data of ypT0/is as pCR would be included. Selection process: studies meeting any of the following exclusion criteria were excluded from this meta-analysis: (I) in the form of laboratory articles, meta-analysis, review articles or letters; (II) using other treatment strategies without using trastuzumab alone; (III) not in English; (IV) non-comparative studies or studies without available data can be extracted.

Selection process

The literature search was performed by two independent reviewers (S.C.) and (Z.Y.) using the previously discussed predesigned search strategy. All duplicate studies were manually removed, before titles and abstracts were screened, and studies considered appropriate had their full text reviewed. Retrieved studies were reviewed to ensure inclusion criteria was met. In cases of discrepancies of opinion, a third author was asked to arbitrate (L.Z.).

Data extraction and quality assessment

The following data was extracted from all eligible articles: (I) study name; (II) study period; (III) study design; (IV) study phase; (V) treatment received; (VI) number of participants; (VII) pathological complete rate; (VIII) type and number of adverse events, numbers of all grade and grade ≥3 adverse events. Adverse events were monitored continuously and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. An adaptation of the Newcastle-Ottawa Scale was used to assess the risk of bias of the included studies.

Statistical analysis

Risk ratios (RRs) and 95% confidence intervals (CIs) were used as effect indicators for pCR rate and adverse events. Statistical heterogeneity between the results of the included studies was analyzed by using a Q-test (test level set at α=0.10). The results were analyzed by using a fixed-effects model if the heterogeneity was small (I²<50%), otherwise a random-effects model or descriptive analysis was used. A Z-test was used to test the significance of the pooled RRs (considered significant at P<0.05). Subgroup analyses were conducted according to anti-HER2 therapy and estrogen receptor (ER) status, to assess their potential contributions to outcomes. The meta-analysis was performed using RevMan software (ver. 5.3) and STATA software (version 11.0).

Results

Search results

A total of 1,344 potentially relevant articles were searched in PubMed, Embase and Web of Science in April 2024. As a result of the evaluations, five RCTs analysis (JBCRG-10, neoCARH, TBCRC023, TRYPHAENA, and Z1041) were found suitable for this meta-analysis (18-22). The flow chart of the literature search and selection/exclusion process is shown in Figure 1.

Figure 1 Flow chart of study selection.

Characteristics of included studies

The total number of patients in the five RCTs included was 799. Studies included 4 phase II and 1 phase III randomized trials. TBCRC023, Z1041 and some participants in JBCRG-10, trastuzumab was given 4 mg/kg first dose and 2 mg/kg for subsequent doses on days 1, 8, and 15 of a 21-day cycle. TRYPHAENA, neoCARH and some participants in JBCRG-10, trastuzumab was given at an initial dose of 8 mg/kg, followed by 6 mg/kg. In the context of NAT, the trastuzumab administration schedules were 4 cycles versus 6 cycles in both the JBCRG-10 and neoCARH trials, 4 cycles versus 8 cycles in the TBCRC023 and Z1041 trials, and 3 cycles versus 6 cycles in the TRYPHAENA trial. Patient characteristics of the included studies are presented in Table 1. The risk of bias for each study is reported in Table 2.

pCR rate

Pooled analysis of the five included trials revealed no significant difference in pCR between the short-term and long-term neoadjuvant trastuzumab therapy (RR =0.78, 95% CI: 0.60–1.02; P=0.07; I²=62%) (Figure 2). Due to the high heterogeneity among these trials, a sensitivity analysis was performed (Figure 3). The heterogeneity was minimized when the Z1041 trial was excluded. According to the pooled analysis of the four remaining trials after excluding the Z1041, pCR was better in the long-term arm (RR =0.69, 95% CI: 0.50–0.95; P=0.02; I²=50%) (Figure S1).

Figure 2 Forest plot of risk ratios comparing pCR of patients treated with shorter-term versus long-term trastuzumab. CI, confidence interval; M-H, Mantel-Haenszel; pCR, pathological complete response.

Figure 3 Sensitivity analysis of the relationships between short- and long-term trastuzumab neoadjuvant chemotherapy and pCR. CI, confidence interval; pCR, pathological complete response.

Adverse events

All five included trials reported on adverse events of grades 3–4. Based on the pooled analysis of these trials, the incidence of grade 3–4 adverse events was 18.9% in the short-term arm and 21.3% in the long-term arm (RR =0.75, 95% CI: 0.59–0.96; P=0.02; I²=0%) (Figure 4).

Figure 4 Forest plot of risk ratios comparing adverse events of patients treated with shorter- vs. long-term trastuzumab. CI, confidence interval; M-H, Mantel-Haenszel.

Subgroup analyses according to anti-HER2 therapy for pCR

Among the five included trials, two trials (TBCRC023 and TRYPHAENA) performed dual anti-HER2 therapy during the neoadjuvant treatment phase. Specifically, the TRYPHAENA trial performed trastuzumab and pertuzumab. TBCRC023 trial performed trastuzumab and lapatinib. The remaining three trials (JBCRG-10, neoCARH, and Z1041) performed only trastuzumab as the anti-HER2 therapy. We defined that single anti-HER2 therapy group (3 trials: JBCRG-10, neoCARH and Z1041): trastuzumab combined with chemotherapy without additional anti-HER2 agents (no pertuzumab/lapatinib). Dual anti-HER2 therapy group (2 trials: TBCRC023 and TRYPHAENA): trastuzumab + lapatinib (TBCRC023) or trastuzumab + pertuzumab combined with chemotherapy (TRYPHAENA). A pooled analysis of these trials revealed no significant difference in pCR between long-term and short-term NAT (dual anti-HER2 therapy: RR =0.73, 95% CI: 0.37–1.46; P=0.38; I²=53%; single anti-HER2 therapy: RR =0.74, 95% CI: 0.48–1.15; P=0.18; I²=77%) (Figure S2). Due to the high heterogeneity among these trials, and the heterogeneity was mainly from Z1041, a subgroup analysis was performed after excluding Z1041. In the single anti-HER2 therapy subgroup, long-term arm had a better pCR rate than short-term arm (RR =0.61, 95% CI: 0.45–0.84; P=0.002; I²=0%) (Figure 5).

Figure 5 Forest plot for pCR of subgroup by anti-HER2 therapy (except Z1041). CI, confidence interval; HER2, human epidermal growth factor receptor 2; M-H, Mantel-Haenszel; pCR, pathological complete response.

Subgroup analyses according to hormone receptor (HR) status for pCR

neoCARH, TBCRC023 and Z1041 trials reported the outcome of pCR according to HR status. A pooled analysis of these studies found no significance difference in pCR between short-term and long-term neoadjuvant trastuzumab therapy, regardless of HR status (HR−: RR =0.87, 95% CI: 0.72–1.06; P=0.18; I²=0%; HR+: RR =0.68, 95% CI: 0.30–1.56; P=0.37; I²=76%) (Figure S3). Similarly, due to the high heterogeneity in the HR+ subgroup, analysis excluding the Z1041 trial revealed that long-term arm had a better pCR than short-term arm in the HR+ subgroup (HR−: RR =0.79, 95% CI: 0.52–1.20; P=0.26; I²=0%; HR+: RR =0.45, 95% CI: 0.24–0.83; P=0.01; I²=2%) (Figure 6).

Figure 6 Forest plot for pCR of subgroup by estrogen receptor status (except Z1041). CI, confidence interval; HR, hormone receptor; M-H, Mantel-Haenszel; pCR, pathological complete response.

Discussion

In recent years, the optimal duration of neoadjuvant anti-HER2 treatment cycles for HER2-positive breast cancer has been a subject of controversy. The TRAIN-3 study found that the number of neoadjuvant treatment cycles required for different patients to achieve pCR varies (23). This finding has once again brought the issue of the duration of anti-HER2 treatment cycles to the forefront. This meta-analysis included 5 RCT studies involving 799 patients, focusing mainly on the clinical benefits of long-term (≥6 cycles) versus short-term (<6 cycles) neoadjuvant trastuzumab treatment in HER2-positive breast cancer.

The meta-analysis results of the five included trials showed that there was no significant difference in the pCR between long-term and short-term neoadjuvant trastuzumab treatment, although long-term trastuzumab treatment trended towards a higher pCR. Due to the high heterogeneity among these trials, sensitivity analysis was performed. The Z1041 trial, which had a substantial impact on heterogeneity, was excluded and the analysis was redone. At this point, the results showed that the pCR of long-term neoadjuvant trastuzumab treatment was significantly better than that of short-term treatment. Regarding the heterogeneity of Z1041, we analyzed as follows. In Z1041, the pCR after long- and short-term neoadjuvant trastuzumab treatment was 56.5% and 54.2% respectively, which was higher than that of other neoadjuvant trastuzumab treatments (12), approaching the pCR of dual anti-HER2 therapy (14). In Z1041, the short-term neoadjuvant trastuzumab treatment was 4 cycles of FEC followed by 4 cycles of TH, and the long-term was 4 cycles of TH followed by 4 cycles of FECH. It was the only one among the 5 included clinical trials that combined anthracyclines with trastuzumab, and the drug was administered on a weekly basis, potentially resulting in a higher treatment intensity. Therefore, it achieved a pCR result superior to that of other single anti-HER2 therapy, which may be one of the sources of heterogeneity. In clinical practice, considering that both anthracyclines and trastuzumab can cause cardiotoxicity, they are generally not used in combination (24,25). In the results reported by Z1041, the left ventricular ejection fraction (LVEF) decreased to varying degrees, with a relatively larger decrease when anthracyclines and trastuzumab were used simultaneously. The previous BCIRG-06 study also compared the efficacy of the TCbH and AC-TH regimens in the neoadjuvant treatment of HER2-positive breast cancer and found them to be comparable, with AC-TH having an advantage in cardiac safety (26). Both of these suggest that in the neoadjuvant treatment of HER2-positive breast cancer, it is unnecessary to use anthracyclines as a chemotherapy regimen in combination or sequentially with trastuzumab to obtain a higher pCR. Another possible reason for the heterogeneity of Z1041 is that the pCR criterion used was ypT0/is (bpCR), and there was no data on ypT0/is, ypN0 (tpCR) provided in the article. bpCR lacks information on lymph node metastasis after neoadjuvant treatment, which may overestimate the prognosis (27).

To better interpret the results of the meta-analysis, a subgroup analysis was conducted on whether to add other anti-HER2 therapies to neoadjuvant trastuzumab treatment. Among the 5 included studies, 3 trials (JBCRG-10, neoCARH and Z1041) used trastuzumab alone as the anti-HER2 therapy during the neoadjuvant treatment stage, while the other 2 added pertuzumab (TRYPHAENA) or lapatinib (TBCRC023) to trastuzumab. The results of the subgroup meta-analysis showed that there was no significant difference in pCR in the dual anti-HER2 therapy subgroup. The pCR of the TRYPHAENA trial was around 50–60%, similar to previous studies. The pCR of TRAIN-2 after 9-cycle neoadjuvant dual anti-HER2 therapy was 68% (17), the pCR of PHERGain after 6-cycle neoadjuvant dual anti-HER2 therapy was 56.4% (28), and the pCR of NeoSphere after 4-cycle dual anti-HER2 therapy was 45.8% (14), all consistent with the results of this study. Although the pCR of 4 cycles dual anti-HER2 therapy in PEONY was 39.3%, the reason might be that this study included a relatively large number of locally advanced patients (29). PHEDRA combined pyrotinib with trastuzumab for 4-cycle neoadjuvant treatment, and the result showed a relatively high pCR (41%) (15). Another study also combined lapatinib with trastuzumab for 6-cycle neoadjuvant treatment and achieved a pCR of 41.2% (30). These results indicate that in dual anti-HER2 therapy, regardless of the duration of the treatment or the differences of anti-HER2 drugs combined with trastuzumab, similar pCRs can be obtained. For single anti-HER2 therapy, after excluding Z1041 for subgroup analysis, it was found that the pCR of long-term neoadjuvant trastuzumab treatment was better than that of short-term treatment. The pCR of JBCRG-10 and neoCARH after short-term treatment was around 30–40%, similar to the 38% pCR result in the previous NOAH study (12). After long-term neoadjuvant trastuzumab treatment, the pCR of JBCRG-10 and neoCARH was 55.9% and 62.5% respectively, similar to the pCR of 6-cycle neoadjuvant trastuzumab or lapatinib treatment in NeoALTTO (47% vs. 48%) (31). These results suggest that when using trastuzumab or other single anti-HER2 therapy, prolonging the treatment cycle can, to some extent, help improve the pCR.

Next, a meta-analysis of the safety of the five included studies was carried out. After comparing the incidence of grade 3 and above adverse events between long-term and short-term neoadjuvant trastuzumab treatment, the results showed that the incidence of adverse events in the short-term arm was significantly lower than that in the long-term arm.

Finally, a subgroup analysis was performed according to different HR statuses. Three studies (neoCARH, TBCRC023 and Z1041) discussed the subgroups of long-term and short-term neoadjuvant trastuzumab treatment according to different HR statuses. In the HR negative(−) subgroup, there was no significant difference in pCR between long-term and short-term arm. In the HR positive(+) group, after excluding the Z1041 trial, which had a large impact on the heterogeneity of the results, the pCR of long-term neoadjuvant trastuzumab treatment for HR+/HER2+ breast cancer was significantly better than that of the short-term arm. This is consistent with previous clinical research findings that HR+/HER2+ breast cancer may have relatively lower sensitivity to trastuzumab (32). Wang et al. found that ER is associated with HER2 re-activation and plays a crucial role in trastuzumab resistance, and the combined use of lapatinib to completely block the HER network can provide more stable inhibition (33). Some studies also suggest that the PI3K/AKT signaling pathway involved in the trastuzumab resistance mechanism interacts with the HR signaling pathway (34). When trastuzumab inhibits the HER2 signaling pathway, the HR may activate bypass signaling pathways such as PI3K/AKT, leading to cell proliferation that is not effectively inhibited by trastuzumab, thus reducing the sensitivity to trastuzumab (35). The HR status may also affect the sensitivity to trastuzumab by influencing the activity of related signaling pathways and the expression and function of downstream molecules (36). In general, these studies have confirmed that HR status affects the sensitivity of HER2-positive breast cancer to trastuzumab through various mechanisms. The results of our meta-analysis show that prolonging the treatment duration of trastuzumab or adding another anti-HER2 treatment drug can improve the efficacy of neoadjuvant treatment for HER2-positive breast cancer.

There are still some limitations in this study. First, due to the limited number of relevant studies, the number of included studies is small, and there is significant heterogeneity among the included trials. The source of the heterogeneity of Z1041 has been discussed previously. Second, the included trials lack long-term follow-up data, making it impossible for us to systematically evaluate patients’ survival outcomes. Finally, the pCR criteria used in each study are not uniform. Some studies use bpCR, which does not cover lymph node metastasis, and is likely to overestimate the efficiency, introducing potential bias in data analysis and result comparison.

In conclusion, the results of this meta-analysis suggest that when using trastuzumab alone for neoadjuvant treatment of HER2-positive breast cancer, a longer treatment duration can lead to better efficacy. In dual anti-HER2 therapy, the efficacy of long-term and short-term treatments is similar, and a treatment duration of 4 cycles or even shorter can be considered to reduce drug-related adverse events. At the same time, the addition of anti-HER2 therapy to traditional drugs, such as research on the application of antibody-drug conjugates (ADCs) in neoadjuvant treatment will also become a hot topic. In 2024, the results of a study on the HER2-targeted ADC SHR-A1811 reported at the San Antonio Breast Cancer Symposium (SABCS) showed that the pCR of SHR-A1811 monotherapy was as high as 63%. SHAMROCK is also evaluating the pCR results of 4- or 6-cycle use of T-Dxd in the neoadjuvant treatment stage, and the specific data have not been released yet (37). In future research, it is necessary to focus on conducting large-scale, homogeneous clinical trials, formulating standardized endpoint indicators, and conducting long-term and systematic follow-up, aiming to further clarify the optimal neoadjuvant treatment strategy for HER2-positive breast cancer, and striving to improve the treatment effect while minimizing adverse reactions and achieving the best balance between efficacy and toxicity.

Conclusions

This meta-analysis indicates that when using single anti-HER2 therapy (trastuzumab combined with chemotherapy) in HER2-positive breast cancer, a long-term treatment may bring better efficacy. In dual anti-HER2 therapy, the efficacy of long-term and short-term treatments is similar, and a shorter treatment cycle can be considered to reduce adverse events.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-25/rc

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-25/prf

Funding: This work was supported by the National Natural Science Foundation of China (No. 62476285).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-25/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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