Dual Anti-HER2 Therapy Vs Trastuzumab Alone with Neoadjuvant Anthracycline and Taxane in HER2-Positive Early-Stage Breast Cancer: Real-World Insights

Introduction

Breast cancer continues to pose a significant global health burden, with 2.3 million new cases reported in 2020, constituting 11.7% of all newly diagnosed cancer cases. This malignancy resulted in approximately 685,000 deaths, emphasizing its profound impact.¹ Among these cases, 15–20% are characterized as human epidermal growth factor receptor (HER2)-positive.^2,3 HER2-positive breast cancer often carries a less favorable prognosis when compared to other subtypes.⁴ However, it exhibits heightened sensitivity to cytotoxic chemotherapy, providing patients with an opportunity to achieve a pathologic complete response (pCR) through neoadjuvant chemotherapy (NACT).⁵

Moreover, the combination of agents targeting HER2-activated signaling pathways has shown promise in improving chemosensitivity, leading to an increased rate of pCR.⁶

Improving pathological complete response (pCR) is a critical endpoint in HER2-positive early breast cancer (EBC) because it serves as a robust surrogate marker for long-term outcomes, including survival and recurrence rates. Achieving pCR is associated with significantly better disease-free survival (DFS) and overall survival (OS), particularly in aggressive subtypes such as HER2-positive and triple-negative breast cancer.⁷ pCR reflects the effectiveness of neoadjuvant therapy in eradicating tumor burden, reducing the risk of residual disease and distant metastases, which are key factors influencing recurrence and mortality.

Various clinical trials have validated the effectiveness of HER2-targeted therapies, either alone or in combination, highlighting the enhanced responsiveness of HER2-positive breast cancer to tailored neoadjuvant therapy.^8,9

Trastuzumab is a humanized monoclonal antibody directed against the extracellular domain of HER2.¹⁰ The addition of trastuzumab to NACT resulted in a significant improvement in the pCR rate in HER2-positive breast cancer patients in addition to the improvement in disease-free survival (DFS) and overall survival (OS).^8,9 Hence, trastuzumab stands as a pivotal element in neoadjuvant therapy for HER2-positive early-stage breast cancer (EBC) patients.

Following trastuzumab, multiple HER2-targeting agents, such as pertuzumab, have gained approval, contributing to enhanced efficacy when combined with trastuzumab. Pertuzumab functions by binding to HER2 at a distinct site, thereby preventing HER2 dimerization with other members of the HER family. The approval of pertuzumab for use in conjunction with trastuzumab and docetaxel in neoadjuvant therapy primarily emanated from the Phase II NEOSPHERE trial, with pCR approaching 45.8% with improvements in DFS, too.¹¹

After standard neoadjuvant therapy, the adjuvant treatment strategy can now be tailored based on the achievement of pCR. For patients attaining pCR, the adjuvant anti-HER2 therapy involves administering trastuzumab for the remainder of the one-year total anti-HER2 therapy. Despite achieving pCR, there remains a residual risk of recurrence, especially in individuals with a high tumor burden at the time of diagnosis, as evidenced by a pooled analysis conducted by the German Breast Group (GBG).¹²

Data extrapolated from the adjuvant APHINITY trial suggests that the ongoing use of pertuzumab in the adjuvant setting is particularly beneficial for patients with node-positive disease. After a median follow-up of 74 months, in the node-positive cohort, the 6-year invasive DFS (iDFS) rates were 88% for the pertuzumab arm compared to 83%, for the placebo arm, with an HR of 0.72 (95% CI, 0.59–0.87). No discernible benefit was noted in cases of node-negative (N0) disease. The pertuzumab-associated benefit was found to be independent of hormone receptor (HR) status.¹³ However, when considering the results from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis and the APHINITY trial, which includes two follow-up durations,^13,14 it becomes evident that extended follow-up is crucial in HER2+ early breast cancer, particularly for comprehensively capturing the therapeutic benefits, especially in the HR-positive subgroup. The KATHERINE trial introduced a strategy for patients with residual disease, switching them to Trastuzumab emtansine (T-DM1), resulting in a remarkable 11% improvement in DFS. Notably, only 18.7% of patients received dual anti-HER2 therapy (trastuzumab/pertuzumab), while the majority (80.2%) received trastuzumab as a single agent.¹⁵

While clinical trials provide valuable insights, their applicability to broader patient populations may not fully encompass the diversity encountered in routine practice due to strict eligibility criteria and controlled environments. These factors often exclude patients with comorbidities or those with characteristics outside the trial’s parameters, potentially limiting the generalizability of findings. Real-world data, derived from diverse clinical settings, are essential for validating the efficacy and safety of interventions, offering a more comprehensive understanding of their impact across heterogeneous patient populations.

In this study, we aim to compare pCR with single anti HER2 therapy (trastuzumab) versus dual anti HER2 therapy (trastuzumab and pertuzumab) and its relation to DFS and breast-conserving surgery (BCS) rate in patients receiving chemotherapy with anthracycline and taxanes, based on the National Surgical Adjuvant Breast and Bowel Project (NSABP)-B27 protocol, and to determine if these treatment outcomes differ according to baseline patients’ characteristics in a real-world setting.

Materials and Methods

Study Population and Design

This is a retrospective study that included all consecutive adult female patients (18 years or older) diagnosed with HER2-positive breast cancer who received neoadjuvant therapy at our institution. We included patients with pathologically confirmed cases and comprehensive medical records, which encompassed treatment regimens and follow-up data. HER2 was defined positive as IHC+3 or IHC+2 with positive Fluorescence in Situ Hybridization (FISH), adhering to the guidelines set forth by the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) for HER2 testing in breast cancer. Figure 1 illustrates patients’ flow. Patients with missing or insufficient data on anti-HER2 therapy regimens, dosages, or treatment durations were excluded. Additionally, patients who switched between trastuzumab monotherapy and dual anti-HER2 therapy during the treatment period and those with concurrent malignancies were excluded, too.

Figure 1 Flow diagram of patients included in the study.

Overall survival (OS) was defined as the duration from the initial histological diagnosis of breast cancer to death from any cause or the last recorded medical encounter. Disease-free survival (DFS) was defined as the time from the date of surgery to either the occurrence of relapse or death, whichever came first.

Data Collection

We extracted data concerning patient demographics, clinical characteristics, and treatment regimens from medical records. This included details such as age at diagnosis, prior history of breast cancer, HR status (including estrogen and progesterone receptors), HER2 status by IHC, lymph node involvement at diagnosis, and the type of anti-HER2 therapies administered (either trastuzumab alone or in combination with pertuzumab). We compared the two treatment groups using chi-square tests for categorical variables and independent t-tests for continuous variables where applicable.

Disease-Free Survival Analysis

Disease-free survival (DFS) was defined as the time from surgery until recurrence of breast cancer or death from any cause. To identify factors affecting DFS, we conducted univariable and multivariable Cox proportional hazards regression analyses. The included variables are previous diagnosis of breast cancer, tumor grade, lymphovascular invasion, HR status, HER2 status by IHC, tumor size, lymph node involvement, treatment response, and the type of anti-HER2 treatment. Variables significant in the univariable analysis were included in the multivariable model to adjust for potential confounders and identify independent predictors of DFS.

DFS rates were estimated using the Kaplan–Meier method, with differences between groups assessed using the Log rank test.

Analysis of Surgical Outcomes

To identify predictors influencing the type of surgery, both univariable and multivariable logistic regression models were employed. Variables included age at diagnosis, previous breast cancer history, HR status, HER2 status assessed by IHC, tumor size and lymph node involvement at diagnosis, and anti-HER2 therapies received.

Analysis of Response to Neoadjuvant Treatment Analysis

The response to neoadjuvant treatment, categorized into pCR or residual disease (RD), was analyzed as the dependent variable. Factors considered in the analysis included tumor size, HR status, lymph node involvement, type of anti-HER2 therapy, and HER2 expression by IHC. Similar to the surgical decision analysis, we first conducted univariable logistic regression for each factor to evaluate its association with treatment response. Factors showing significance were then included in a multivariable logistic regression model to determine their independent effects on achieving a pCR versus RD.

For both analyses, odds ratios (OR) with 95% confidence intervals (CI) were calculated. Statistical significance was set at a p-value of <0.05. All statistical analyses were performed using jamovi (The jamovi project, 2022, Version 2.3) and R (R Core Team, 2021, Version 4.1), with R packages retrieved from the MRAN snapshot dated 2022–01-01.

Results

Patient Characteristics

Our study encompassed 484 patients with a median age of 47 (21–80) years and a median follow-up of 35.3 (range, 7.0–94.0) months, of whom a minor portion (n=17, 3.5%) had a previous diagnosis of breast cancer. The majority were HR-positive (n=349, 72.1%), and a significant proportion (n=372, 76.9%) had lymph nodes involvement prior to neoadjuvant therapy. Analysis of neoadjuvant regimens revealed that 171 (35.3%) patients received trastuzumab, while 313 (64.7%) others were given pertuzumab in combination with trastuzumab. Patient characteristics indicate a significant difference in age (48 years vs 46 years, p=0.023), and lymph node involvement (71.9% vs 86%, p=0.001) between the dual anti-HER2 therapy group and the trastuzumab alone group, Table 1.

Table 1 Patient Characteristics by Anti-HER2 Treatment Group

Treatment Response and Predictors

To identify factors predictive of response to neoadjuvant therapy, our analysis included variables such as tumor size, HR status, lymph node involvement, type of anti-HER2 therapy and HER2 expression levels as determined by IHC scoring (+2 vs +3). Through univariable logistic regression analysis, only HR negativity [OR=0.53, 95% CI, 0.35–0.79, p=0.002] and high HER2 expression; HER2 by IHC score of +3 [OR=0.25, 95% CI, 0.09–0.57, p=0.003] emerged as significant predictors of a favorable response to treatment. Further analysis was performed using multivariable logistic regression to adjust for potential confounders upheld the significance of these factors. Hormone receptor-negative status maintained a strong association with treatment response [OR=0.54, 95% CI, 0.36–0.82, p=0.004], and same for HER2 by IHC score of +3 [OR=0.26, 95% CI, 0.09–0.60, p=0.003], Table 2.

Table 2 Response to Neoadjuvant Treatment Based on Tumor Characteristics and Anti-HER2 Received

Type of Surgery

Rates of breast conserving surgery (BCS) were significantly higher among patients with smaller tumors (<50 mm) compared to those with larger ones (≥50 mm); 29.0% compared to 13.0% [OR=0.36, 95% CI, 0.22–0.59, p<0.001], and among patients who received dual anti-HER2 compared to those who received trastuzumab alone; 26.5% compared to 15.2% [OR=0.50, 95% CI, 0.30–0.82, p=0.007]. This significance persisted following multivariable adjustment, confirming the influence of both tumor size and anti-HER2 treatment type on surgical decisions, Table 3.

Table 3 Rate of Breast-Conserving Surgery (BCS) by Patients’ Characteristics and Anti-HER2 Received

Factors Affecting DFS

In univariable analysis, lymphovascular invasion, tumor size, lymph node involvement, and treatment response to neoadjuvant therapy had a significant impact on DFS, Table-4. In multivariable analysis, however, only positive axillary lymph nodes [HR=3.00, 95% CI, 1.06–8.54, p=0.039], Table 4.

Table 4 Univariable and Multivariable Analysis for Disease-Free Survival (DFS)

With a median follow-up of 35.3 (range, 7.0–94.0) months, Kaplan–Meier survival analysis revealed significant differences in 3-year DFS rates among our patient cohort based on pathological response post-neoadjuvant treatment and lymph node involvement at diagnosis. Patients who achieved a pCR exhibited a notably higher 3-year DFS rate of 89.3%, in contrast to those with residual disease, who had a DFS rate of 81.8% (p=0.016). Additionally, patients without lymph node involvement at the time of diagnosis demonstrated a significantly higher 3-year DFS rate of 95.1% compared to those with lymph node involvement, whose DFS rate was 82.3% (p=0.009).

Discussion

The escalating global burden of breast cancer necessitates continual refinement of treatment strategies.¹ In our cohort involving 484 patients with HER2-positive EBC, we aimed to assess pCR and 3-year DFS with neoadjuvant dual anti-HER2 therapy using pertuzumab and trastuzumab in conjunction with anthracycline and taxane-based chemotherapy as used in the neoadjuvant NSABP-B27 protocol.¹⁶ Additionally, we examined the impact of this treatment regimen on surgical outcomes.

The assessment of clinical endpoints is crucial for evaluating the effectiveness and safety of cancer-targeted therapies in clinical trials.^17,18 Overall survival (OS), defined as the time from randomization until death from any cause, has traditionally served as the “gold standard” endpoint in oncology trials, directly reflecting the impact of interventions on patients’ survival.¹⁷ In the specific context of HR+/HER2-breast cancers, clinical endpoints include DFS and pCR. Recognized by the Food and Drug Administration (FDA) as standard endpoints for trials seeking regulatory approval, these measures, including pCR, provide valuable insights.¹⁹ pCR was defined as the absence of residual invasive cancer in the breast and axilla (ypT0/is, ypN0) at surgery after neoadjuvant treatment, and according to various studies this is linked to improved survival.^6,11,20 However, the use of pCR as a reliable surrogate in HR+ disease remains undetermined. A recent study on HER2-breast cancer patients reported an association between pCR and improved OS, yet statistical analysis of this correlation was not conducted.⁷ These observations underscore the evolving landscape of surrogate markers like pCR in predicting long-term outcomes, necessitating further research and statistical scrutiny to establish their reliability in the context of specific breast cancer subtypes.

The median age of our cohort was 47 (21–80) years, with 72.1% exhibiting HR positivity and 76.9% presenting with LN involvement before neoadjuvant therapy. The comparatively younger age of our breast cancer patients, coupled with a higher proportion presenting with locally advanced or metastatic disease, highlights variations from global reports.^21,22 The observed higher 3-year DFS in LN-negative patients (96.39%) contrasts with 82.35% in LN-positive patients (p<0.0021), aligning with trends observed in other studies.^23–25

In the realm of real-world clinical practice, our study investigated neoadjuvant therapy based on dual blockade with pertuzumab and trastuzumab for HER2-positive EBC, achieving a pCR rate of 46.6%. This aligns with results from clinical trials such as NeoSphere (45.8%),¹¹ Tryphaena (46.6–66.2%),^26,27 and real-world data reported by Hall et al (47%).²⁸ However, our pCR rates were lower than those reported in the BERENICE trial (60.7–61.8%); 43% of entire cohort were LN negative,^29,30 and Boér et al (54%),³¹ Medina et al (62.1%),³² and González-Santiago et al (66%).³³ It is important to note that the studies by Boér et al and Medina et al had smaller sample sizes of 82 and 87 patients, respectively (Table 5).

Table 5 Summary of Published Studies with Dual Anti-HER2

Furthermore, González Santiago et al’s cohort had nearly 50% of patients with stage 1 and 2 diseases, and 40% were HR-negative. These differences in patients’ characteristics and study designs may account for the variation in pCR rates. Nevertheless, to the best of our knowledge, this represents the largest cohort study providing real-world data on pCR with neoadjuvant treatment involving pertuzumab and trastuzumab in HER2-positive EBC patients.

The review article by Ischii and et.al emphasized that only the level of HER2 expression, rather than the HR status, predicted efficacy.³⁶ Our analysis, however, found that the variation in HER2 expression level (2+ vs 3+) had a significant impact on efficacy, with rates of 46.2% compared to 17.6% (HR 0.25 [0.09–0.57], p=0.003). Additionally, our study observed considerably higher pCR rates in HR-negative patients (55.6%) compared to HR-positive patients (39.8%, p=0.002), consistent with patterns seen in other studies.^8,15,31

Additionally, our data indicated higher pCR rates with dual anti-HER2 therapy (46.6%) compared to trastuzumab alone (39.8%, p=0.15), with estimated 3-year DFS rates also favoring dual anti-HER2 therapy (86.1%) over trastuzumab alone (83.1%, p=0.37), though not reaching statistical significance.

Comparing our study with NeoSphere, which employed taxane-based neoadjuvant therapy and adjuvant FEC and trastuzumab, both studies exhibited similar outcomes, particularly in DFS. NeoSphere reported an overall DFS rate of 84%, closely mirroring our study’s DFS rate of 86.1%.

Post-surgery, the majority (89.4%) of our patients received adjuvant trastuzumab, while none received pertuzumab or T-DM1. The landscape of anti-HER2 therapy has evolved significantly over the years, witnessing the development and testing of various agents, including pertuzumab, neratinib, and T-DM1. Trastuzumab has historically been the mainstay in adjuvant therapy; however, recent approvals for therapies such as the combination of trastuzumab and pertuzumab and neratinib following trastuzumab signify a paradigm shift in the adjuvant treatment approach for HER2-positive breast cancer.^37,38

Neoadjuvant systemic therapy (NST) is widely utilized in EBC to shrink tumors, increase resection rates, and make patients eligible for b BCS. While the improved rate of conversion from mastectomy to BCS is a significant finding, its implications extend beyond surgical outcomes, directly influencing patient quality of life and overall treatment goals. Breast-conserving surgery is often associated with better aesthetic outcomes, higher patient satisfaction, and improved body image compared to mastectomy. Additionally, preserving breast tissue can have psychological benefits, including reduced emotional distress and improved self-esteem, which are critical for long-term survivorship.

From a clinical perspective, achieving BCS without compromising oncological safety aligns with the broader goals of personalized cancer care. It underscores the potential of dual anti-HER2 therapy not only to control disease but also to enhance surgical options, thereby integrating effective tumor management with patient-centered care priorities. These outcomes reinforce the importance of considering both oncological and quality-of-life measures when evaluating therapeutic strategies. While a prior trial by Boér et al³¹ observed a higher rate of conversion from mastectomy to BCS with the addition of pertuzumab, several subsequent trials did not replicate these findings.^39,40 In our study, we found a significant improvement in the rate of BCS with the addition of pertuzumab, with an odds ratio of 0.50 (95% CI [0.30–0.80], p=0.005) However, factors such as multifocal/multicentric disease and large tumor size contributed to the necessity for mastectomy. This discordance highlights the disparity between high rates of pCR and low rates of BCS.

Limitations

This study has several limitations inherent in its retrospective design. First, the potential for selection bias exists due to the non-randomized treatment allocation, which may have influenced the outcomes. Other is the difference in follow-up durations between the two arms, which could introduce bias into the survival analysis. In our center, trastuzumab was the standard of care as of October 2017, after which we began using a combination of pertuzumab and trastuzumab. As a result, the median follow-up time for trastuzumab was 59.4 months, compared to 26.8 months for the pertuzumab and trastuzumab combination. Truncating the follow-up period at three years helps minimize this bias in calculating the DFS but also limits the assessment of long-term outcomes.

Conclusion

Although dual anti-HER2 therapy has shown significant improvement in pCR compared to trastuzumab alone, our results demonstrated that this benefit did not extend to long-term survival. This finding underscores the importance of switching from trastuzumab to T-DM1 or continuing pertuzumab in the adjuvant setting for patients with residual disease. However, the addition of pertuzumab did improve the rate of conversion from mastectomy to BCS.