# HER2-Targeted Therapy Before Surgery for HER2-Positive Breast Cancer: Advances, Challenges, and What Patients Should Know

This review examines how HER2-targeted therapies have transformed neoadjuvant treatment (treatment given before surgery) for HER2-positive breast cancer, a subtype that accounts for roughly 15–20% of all breast cancers. The authors analyze clinical trial data on monoclonal antibodies such as trastuzumab and pertuzumab. The authors also analyze tyrosine kinase inhibitors such as lapatinib and pyrotinib, and antibody-drug conjugates. These agents substantially raise pathological complete response (pCR) rates when combined with chemotherapy. The review also details treatment-related toxicities, the role of biomarkers such as tumor-infiltrating lymphocytes, and the promise of newer agents such as trastuzumab deruxtecan.

# HER2-Targeted Therapy Before Surgery for HER2-Positive Breast Cancer: Advances, Challenges, and What Patients Should Know

## Table of Contents

- Key Points
- Background: Why HER2-Positive Breast Cancer Matters
- The Biology of HER2 and How It Drives Cancer
- What Is Neoadjuvant Therapy and Why Is It Used?
- Trastuzumab in Neoadjuvant Therapy
- Efficacy and Toxicity Risks of Trastuzumab Plus Chemotherapy
- Cost-Effective Trastuzumab Biosimilars: CT-P6 and SB3
- Lapatinib Combined With Trastuzumab
- Pyrotinib Combination Therapy
- Clinical Implications: What This Means for Patients
- Limitations of the Research
- Recommendations for Patients
- Frequently Asked Questions
- Source Information

## Key Points

- Neoadjuvant therapy is given before surgery to shrink tumors, make surgery more feasible, and assess response to treatment.
- Adding trastuzumab to chemotherapy raised pCR rates from 15.7% to 31.7% in one trial and from 23% to 43% in another.
- Dual HER2 blockade with trastuzumab plus lapatinib raised pCR to 56% versus 46% with trastuzumab alone in a 305-patient trial.
- In the PHEDRA trial of 355 women, adding pyrotinib to standard treatment nearly doubled pCR (41.0% vs 22.0%).
- Biosimilars CT-P6 and SB3 offer similar efficacy and safety to reference trastuzumab at significantly lower cost.

## Background: Why HER2-Positive Breast Cancer Matters

Breast cancer is one of the most common malignant tumors in women worldwide. The global incidence rate reaches as high as 11.6%, with a mortality rate of approximately 6.6%. Conventional treatments such as mastectomy (surgical removal of the breast) and radiotherapy remain standard approaches for early-stage breast cancer. These treatments typically offer favorable outcomes with manageable side effects.

However, conventional treatments may not be equally effective for all patients. This is particularly true for patients whose tumors have specific molecular characteristics. Research has shown that abnormal HER2 expression occurs in about 15–20% of invasive breast cancers. This abnormal expression is closely associated with aggressive tumor behavior, high recurrence rates, and poor clinical prognoses. Therefore, subtyping breast cancer and clarifying its molecular features are crucial for developing more targeted and precise therapeutic strategies.

From the late 1970s to the 1980s, the rapid development of molecular biology techniques significantly advanced the research and identification of epidermal growth factor and its receptor. EGFR (epidermal growth factor receptor) is now classified as a member of the human epidermal growth factor receptor family, specifically HER1. This family also includes HER2, HER3, and HER4.

HER family receptors bind with various ligands (molecules that attach to receptors) to induce homodimerization or heterodimerization. These terms describe how two receptor molecules pair up. This pairing activates downstream tyrosine kinase cascades (a chain of signaling events inside the cell). These signals regulate multiple cellular processes such as proliferation, migration, invasion, and survival. These mechanisms play a central role in the onset and progression of breast cancer.

## The Biology of HER2 and How It Drives Cancer

HER2 is a transmembrane protein (a protein that spans the cell membrane) composed of 1,255 amino acids, with a molecular weight of 185 kDa. It consists of three main parts: an extracellular domain, a transmembrane region, and an intracellular tyrosine kinase domain.

The extracellular domain is divided into four subdomains (labeled I, II, III, and IV). These subdomains interact with epidermal growth factors or other members of the epidermal growth factor receptor family. The transmembrane region anchors HER2 in the cell membrane. The intracellular tyrosine kinase domain (amino acids 720–987) is crucial for signal transduction because of its kinase activity.

Under normal conditions, the expression of HER2 protein is tightly regulated. However, in breast cancer cells, HER2 gene amplification or protein overexpression leads to HER2 overproduction. This overproduction continuously drives rapid proliferation and metastasis of cancer cells, resulting in HER2-positive breast cancer.

Compared to other breast cancer subtypes, this subtype tends to grow rapidly, recur frequently, and metastasize easily. This leads to a lower five-year survival rate and greater invasiveness.

## What Is Neoadjuvant Therapy and Why Is It Used?

Neoadjuvant therapy refers to treatment given before surgery. The goals of neoadjuvant therapy include reducing tumor size, lowering tumor staging, making inoperable tumors operable, and increasing the likelihood of breast-conserving surgery.

Neoadjuvant therapy also serves other important purposes. It allows doctors to assess how well the tumor responds to systemic therapy. This information helps adjust subsequent treatment plans. It also provides prognostic information for patients who achieve complete remission. Finally, it allows evaluation of new therapies.

Pathological complete response (pCR) refers to the absence of residual invasive tumor cells in the resected breast and sampled lymph nodes after neoadjuvant therapy. This is determined by pathological examination. It is important to understand that pCR does not necessarily indicate the complete eradication of tumor cells from the patient's body.

Studies have shown that pCR in breast cancer is significantly associated with the patient's event-free survival (EFS, the time without cancer-related events) and overall survival (OS). This association is particularly strong for HER2-positive breast cancer patients.

Neoadjuvant therapy is also based on pCR as an alternative endpoint. This approach accelerates the adoption of innovative therapies for HER2-positive breast cancer. Before the development of HER2-targeted therapies, treatment for HER2-positive breast cancer primarily relied on chemotherapy, such as taxanes and anthracyclines. However, the non-selectivity of chemotherapy resulted in significant resistance and severe side effects.

In contrast, HER2-targeted therapies have demonstrated significant clinical efficacy. These therapies improve both survival rates and quality of life. For example, the CLEOPATRA trial showed that dual blockade with pertuzumab and trastuzumab increased the median overall survival to 57.1 months. This represented a 37% improvement over the placebo group. Therefore, HER2-targeted therapies have become one of the key regimens for neoadjuvant treatment of HER2-positive breast cancer.

With the advancement of molecular biology and drug development, several HER2-targeted therapies have emerged. These include monoclonal antibodies, tyrosine kinase inhibitors, and antibody-drug conjugates. Trastuzumab is the first HER2-targeted drug and has shown significant efficacy in neoadjuvant therapy. When combined with pertuzumab, the therapeutic effect can be further enhanced.

## Trastuzumab in Neoadjuvant Therapy

Trastuzumab is a recombinant humanized monoclonal antibody (a laboratory-made immune protein) that specifically targets HER2. HER2 is a tyrosine kinase receptor that is overexpressed in approximately 15–20% of breast cancer patients. Overexpression of HER2 is closely associated with high tumor invasiveness, higher recurrence rates, and poor prognosis.

Trastuzumab works by blocking HER2 receptor dimerization (pairing of receptors). This inhibits downstream signaling pathways and reduces cancer cell proliferation and division. Additionally, trastuzumab can mark HER2-positive tumor cells. This marking induces antibody-dependent cellular cytotoxicity (ADCC, a process where immune cells attack marked cancer cells). Trastuzumab also promotes the internalization and degradation of the HER2 receptor. These actions help the immune system recognize and eliminate cancer cells, further weakening proliferation signals.

Although trastuzumab has shown good efficacy in treating HER2-positive breast cancer, monotherapy (treatment with a single drug) still faces issues of insufficient response or resistance in some patients. Therefore, trastuzumab is often combined with traditional chemotherapy drugs, such as taxanes, to further enhance its anti-tumor effect. Whether this combination is needed because of the limitations of trastuzumab's anti-cancer action remains an important topic of clinical and research focus. Alternatively, the combination may be needed because chemotherapy agents alone cannot sufficiently control HER2-positive breast cancer.

When combined with chemotherapy drugs like taxanes, trastuzumab demonstrates more significant efficacy in treating HER2-positive breast cancer. This combination notably extends progression-free survival (PFS, time without cancer progression) and overall survival. It has become one of the standard regimens for HER2-positive breast cancer treatment.

Taxane-based drugs stabilize microtubules to prevent depolymerization. This inhibits mitosis (cell division) and causes cell cycle arrest in the G2/M phase, which ultimately induces apoptosis (programmed cell death). Cyclophosphamide, an alkylating agent, induces cell death by cross-linking DNA and disrupting its structure and function. Doxorubicin, an anthracycline antibiotic, intercalates into DNA and inhibits topoisomerase II. This blocks DNA replication and transcription, leading to cell apoptosis. The antimetabolite 5-FU inhibits thymidylate synthase, preventing DNA synthesis. This halts the cell cycle in the S phase and induces cell death. These chemotherapy drugs act synergistically, enhancing trastuzumab's cytotoxicity against tumor cells and significantly improving the therapeutic effect on HER2-positive breast cancer cells.

In the multicenter, randomized Phase III GeparQuattro trial, 445 patients with stage II–III HER2-positive breast cancer were enrolled. After adding trastuzumab to neoadjuvant chemotherapy (EC combined with taxanes), the pCR rate significantly increased to 31.7%. This was far higher than the 15.7% observed in the standard chemotherapy group. Moreover, no significant differences in toxic reactions were observed between the two groups.

Similarly, in the Phase III NOAH trial, the experimental group received trastuzumab combined with anthracycline and taxane chemotherapy (including doxorubicin, cyclophosphamide, and paclitaxel). The control group received the same chemotherapy regimen without trastuzumab. The pCR rate in the experimental group was 43%, compared to 23% in the control group. Three-year follow-up results showed that the EFS rate in the experimental group was significantly higher than in the control group, at 71% versus 56%.

These trial results strongly support the position of trastuzumab combined with chemotherapy as the standard neoadjuvant treatment for HER2-positive breast cancer. In conclusion, trastuzumab not only significantly increases the pCR rate but also plays a crucial role in improving EFS and reducing the risk of recurrence. This provides a solid foundation for future HER2-positive breast cancer treatment.

## Efficacy and Toxicity Risks of Trastuzumab Plus Chemotherapy

In several single-arm studies using trastuzumab combined with standard chemotherapy drugs as neoadjuvant treatment for HER2-positive breast cancer, high pCR rates were achieved. However, a number of adverse reactions were also observed, which warrant attention.

In a single-arm study conducted by Shinya Tokunaga and colleagues, 29 patients with operable stage I–IIIA HER2-positive breast cancer were included. The patients initially received four cycles of nab-paclitaxel and trastuzumab combination therapy. This was followed by four cycles of the FEC regimen (fluorouracil, epirubicin, and cyclophosphamide).

The results showed a pCR rate of 74.0%. However, a series of toxic reactions were also observed. The most common adverse effect was neuropathy (nerve damage), with an incidence rate of 96.6%. This included a 3.4% incidence of grade 3 neuropathy. Additionally, one patient developed grade 2 interstitial pneumonia (lung inflammation) caused by albumin-bound paclitaxel or trastuzumab.

During FEC treatment, common toxicities included:

- Nausea (79.3%)
- Leukopenia, or low white blood cell count (72.4%)
- Neutropenia, or low neutrophil count (72.4%)
- Anemia, or low red blood cell count (62.1%)

Furthermore, one patient experienced a grade 3 thromboembolic event (a blood clot). No symptomatic cardiac toxicity was observed in the study.

Another study enrolled 43 patients with stage II–III HER2-positive breast cancer and used the same treatment regimen. The results similarly showed risks of hematologic toxicity (blood-related side effects) and neuropathy. One patient unfortunately died due to acute respiratory distress syndrome caused by febrile neutropenia and septic shock.

These findings suggest that although trastuzumab combined with chemotherapy significantly improves pCR rates in HER2-positive breast cancer patients, it is also associated with a higher risk of adverse reactions. These reactions particularly include neurotoxicity and hematologic toxicity. Therefore, close monitoring and proactive management of these potential adverse effects are crucial in clinical practice to ensure patient safety during treatment.

## Cost-Effective Trastuzumab Biosimilars: CT-P6 and SB3

CT-P6 and SB3 are two trastuzumab biosimilars (near-copies of an original biologic drug) used for the treatment of HER2-positive breast cancer. Their efficacy, safety, pharmacokinetics (how the body processes the drug), and immunogenicity (the ability to trigger an immune response) are similar to the reference drug trastuzumab. However, they offer significantly lower costs, providing a more cost-effective treatment option.

In a Phase III equivalence trial led by Justin Stebbing and colleagues, CT-P6 demonstrated comparable efficacy and safety to the reference trastuzumab. The pCR rate for CT-P6 was 46.8%, which was within the equivalence range of the reference drug's 50.4%. The 6-year OS rate for CT-P6 was 96%, higher than the reference drug's 94%. This indicates that CT-P6 provides similar efficacy to the original drug in early HER2-positive breast cancer patients. At the same time, CT-P6 is more cost-effective, helping to improve treatment accessibility and reduce the burden on healthcare systems.

Similarly, SB3 was compared with the reference trastuzumab in a Phase III study. The results showed that SB3 was similar to trastuzumab in terms of efficacy, cardiac safety, and long-term outcomes. After five years of follow-up, the 5-year EFS rate for the SB3 group was 82.8%, and the OS rate was 93.1%. The trastuzumab group had an EFS of 79.7% and an OS of 86.7%. These results further confirm the feasibility of SB3 as a trastuzumab biosimilar.

Trastuzumab combined with chemotherapy has demonstrated significant efficacy in treating HER2-positive breast cancer. This is particularly true for improving the pCR rate and enhancing EFS. However, treatment is also associated with some risks of adverse effects, particularly neurotoxicity and hematologic toxicity. These require close monitoring and active management in clinical practice.

With the introduction of biosimilars, CT-P6 and SB3 provide more cost-effective treatment options. Their efficacy and safety are comparable to the reference trastuzumab. The use of CT-P6 and SB3 not only increases the accessibility of treatment for HER2-positive breast cancer patients but also reduces the economic burden on healthcare systems. This further promotes the widespread clinical use of trastuzumab biosimilars. In the future, with further clinical validation and optimization of these biosimilars, they are expected to offer more widespread and economical treatment options for HER2-positive breast cancer.

## Lapatinib Combined With Trastuzumab

Lapatinib is a small molecule tyrosine kinase inhibitor (TKI). It exerts its effect by inhibiting the tyrosine kinase activity of both HER2 and EGFR. Lapatinib competitively binds to the tyrosine kinase domains of HER2 and EGFR. This binding blocks their phosphorylation processes and inhibits the activation of downstream signaling pathways such as PI3K/Akt and Ras/Raf/MEK/ERK. This leads to the suppression of cancer cell proliferation and the induction of apoptosis.

Unlike trastuzumab, which acts on the extracellular domain of HER2, lapatinib targets the intracellular tyrosine kinase activity. This provides additional internal inhibition of signal transduction. Additionally, lapatinib decreases the number of HER2 receptors on the cell surface. This enhances the sensitivity of cancer cells to the immune system and promotes receptor internalization and degradation.

In the EPHOS-B trial, 257 newly diagnosed HER2-positive breast cancer patients were treated preoperatively. They were randomly assigned to either no treatment, trastuzumab, lapatinib, or a combination of both. The results showed that the combination therapy group had a significantly enhanced Ki67 response. Ki67 is a marker of cell division. A Ki67 reduction of ≥50% was associated with a lower risk of recurrence. Compared to the monotherapy groups, combination therapy significantly improved cancer cell suppression. This indicates the important clinical significance of combining lapatinib with trastuzumab in HER2-positive breast cancer treatment.

The combination of trastuzumab and lapatinib has shown significant efficacy in the treatment of HER2-positive breast cancer. This is particularly true when combined with standard chemotherapy drugs such as paclitaxel or docetaxel to further improve treatment outcomes.

In a Phase III randomized trial led by Lisa A. Carey and colleagues, 305 patients with stage II or III HER2-positive breast cancer were randomly assigned to different treatment groups:

- Weekly paclitaxel combined with trastuzumab and lapatinib (THL group)
- Trastuzumab alone (TH group)
- Lapatinib alone (TL group)

The results showed that in 295 evaluable patients, the pCR rate in the THL group was 56%. This was significantly higher than the 46% in the TH group and 32% in the TL group. Particularly in hormone receptor-negative patients, the pCR rate in the THL group was 79%, compared to 54% in the TH group and 37% in the TL group. These results highlight the importance of hormone receptor status in HER2-positive breast cancer treatment. They also support dual HER2-targeted therapy, especially in hormone receptor-negative patients. After more than seven years of follow-up, the THL group showed significantly better RFS (recurrence-free survival) and OS compared to the TH group. No significant differences were found between the TH and TL groups.

Similarly, in the randomized multicenter Phase III NeoALTTO trial, six-year and ten-year follow-up data further demonstrated the significant efficacy of the combination therapy. This was especially true for improving EFS and OS in hormone receptor-negative breast cancer patients.

In another Phase II randomized Cher-LOB study, 121 patients with HER2-positive stage II to IIIA breast cancer received neoadjuvant chemotherapy based on paclitaxel-anthracycline. This chemotherapy was combined with trastuzumab (Group A), lapatinib (Group B), or trastuzumab plus lapatinib (Group C). The results showed that the pCR rate in Group C was the highest at 44.2%, compared to 25% in both Group A and Group B. After nine years of median follow-up, the combination of trastuzumab and lapatinib showed an improving trend in RFS (HR 0.44). Furthermore, pCR was significantly associated with better RFS (HR 0.12) and OS (HR 0.12). This indicates that dual HER2-targeted therapy provides better prognostic outcomes for HER2-positive breast cancer patients.

## Pyrotinib Combination Therapy

Pyrotinib is an irreversible small-molecule tyrosine kinase inhibitor (TKI) targeting members of the human epidermal growth factor receptor (HER) family, including HER1, HER2, and HER4. By inhibiting the intracellular kinase domains of these receptors, pyrotinib blocks the activation of downstream signaling pathways. These pathways include phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) and mitogen-activated protein kinase (MAPK). This suppresses tumor cell proliferation and promotes apoptosis.

Unlike trastuzumab, which binds to the extracellular domain of HER2, pyrotinib targets the intracellular tyrosine kinase domain. It inhibits receptor signaling from within the cell. The combination of these two agents therefore enables dual blockade of the HER2 signaling pathway, resulting in enhanced anti-tumor activity.

The efficacy of pyrotinib-based dual-targeted therapy has been demonstrated in several clinical trials. In the multicenter, double-blind, phase III PHEDRA trial, 355 women with early or locally advanced HER2-positive breast cancer were randomly assigned. These women received pyrotinib or placebo in combination with trastuzumab and docetaxel. The results showed that the pathological complete response (pCR) rate was significantly higher in the pyrotinib group than in the placebo group (41.0% vs 22.0%). These findings indicate that the addition of pyrotinib can significantly enhance the efficacy of treatment.

## Clinical Implications: What This Means for Patients

The research reviewed here has several important implications for patients with HER2-positive breast cancer. First, neoadjuvant therapy before surgery is now a cornerstone of treatment for this subtype. The goal is to shrink the tumor, make surgery more feasible, and assess how well the cancer responds to treatment.

Second, combining HER2-targeted drugs with chemotherapy significantly improves outcomes. The data show that adding trastuzumab to chemotherapy raises pCR rates from 15.7% to 31.7% in one major trial. In another trial, pCR rates rose from 23% to 43%. These are substantial improvements that directly affect survival.

Third, dual HER2 blockade (using two targeted drugs together) can further improve results. For example, combining lapatinib with trastuzumab raised pCR rates to 56% compared to 46% with trastuzumab alone. In hormone receptor-negative patients, the benefit was even greater, with pCR rates of 79% versus 54%.

Fourth, newer agents such as pyrotinib are expanding the treatment landscape. The PHEDRA trial showed that adding pyrotinib to standard treatment nearly doubled the pCR rate (41.0% vs 22.0%).

Fifth, biosimilars such as CT-P6 and SB3 offer equally effective treatment at lower cost. This improves access to care and reduces the financial burden on patients and healthcare systems.

Finally, patients should be aware that these treatments carry risks of side effects. The most common include neuropathy, hematologic toxicity, nausea, and fatigue. Close monitoring and proactive management are essential to ensure patient safety during treatment.

## Limitations of the Research

This review article summarizes findings from multiple clinical trials, but it has several limitations that patients should understand.

First, the review does not present new experimental data. It synthesizes results from previously published studies. The conclusions depend on the quality and design of those original studies.

Second, many of the trials included different patient populations, treatment regimens, and follow-up durations. This makes direct comparisons between trials difficult.

Third, the review focuses primarily on pCR as a key endpoint. While pCR is strongly associated with survival outcomes, it does not guarantee that a patient is cured. Some patients who achieve pCR may still experience recurrence.

Fourth, the long-term safety data for newer agents such as pyrotinib and antibody-drug conjugates are still emerging. More research is needed to fully understand the risk-benefit profile of these treatments over many years.

Fifth, the review does not address all patient populations equally. For example, the optimal treatment for elderly patients, patients with significant comorbidities, or those with specific genetic backgrounds may differ from the general population.

Finally, the review acknowledges that treatment-related toxicities remain a significant challenge. Neurotoxicity and hematologic toxicity are common and can affect quality of life. Strategies to prevent or manage these side effects are still needed.

## Recommendations for Patients

Based on the findings of this review, patients with HER2-positive breast cancer can consider the following recommendations:

1.
**Discuss neoadjuvant therapy with your care team.** For many patients with HER2-positive breast cancer, starting treatment before surgery can shrink the tumor and improve surgical options. Ask whether this approach is appropriate for your specific situation.
1.
**Understand the role of pCR.** Pathological complete response means no residual invasive cancer cells are found in the breast or lymph nodes after treatment. Achieving pCR is associated with better long-term outcomes, but it does not guarantee a cure.
1.
**Ask about dual HER2-targeted therapy.** If you have hormone receptor-negative breast cancer, dual blockade with trastuzumab plus lapatinib or pertuzumab may offer additional benefit. Discuss the risks and benefits with your oncologist.
1.
**Inquire about biosimilars.** If cost is a concern, ask whether biosimilars such as CT-P6 or SB3 are available. These options have similar efficacy and safety to the original trastuzumab but may be more affordable.
1.
**Monitor for side effects.** Report any new symptoms to your care team promptly. Common side effects include numbness or tingling in the hands and feet (neuropathy), fatigue, nausea, and low blood cell counts. Early management can prevent complications.
1.
**Stay informed about new therapies.** The treatment landscape for HER2-positive breast cancer is rapidly evolving. Newer agents such as pyrotinib and trastuzumab deruxtecan (T-DXd) are showing promise. Ask your oncologist whether any clinical trials or new treatments might be appropriate for you.
1.
**Seek support.** A diagnosis of HER2-positive breast cancer can be overwhelming. Consider joining a support group or speaking with a counselor to help manage the emotional aspects of treatment.

## Frequently Asked Questions

### What is neoadjuvant therapy and why is it used for HER2-positive breast cancer?

Neoadjuvant therapy is treatment given before surgery. For HER2-positive breast cancer, its goals include shrinking the tumor, lowering its stage, making inoperable tumors operable, and increasing the chance of breast-conserving surgery. It also lets doctors see how well the tumor responds to systemic therapy, which can guide later treatment decisions and provide prognostic information.

### How much does adding trastuzumab to chemotherapy improve outcomes before surgery?

In the GeparQuattro trial of 445 patients with stage II–III HER2-positive breast cancer, adding trastuzumab to neoadjuvant chemotherapy raised the pCR rate to 31.7%, compared with 15.7% for chemotherapy alone. In the NOAH trial, pCR was 43% with trastuzumab plus chemotherapy versus 23% without it, and three-year event-free survival was 71% versus 56%.

### What side effects should I watch for during trastuzumab plus chemotherapy?

In a single-arm study of 29 patients, common side effects included neuropathy (96.6%), nausea (79.3%), low white blood cell count (72.4%), low neutrophil count (72.4%), and anemia (62.1%). One patient had a grade 3 blood clot. Another study of 43 patients reported one death from acute respiratory distress syndrome due to febrile neutropenia and septic shock. Close monitoring is important.

### Are biosimilars like CT-P6 and SB3 as effective as the original trastuzumab?

CT-P6 and SB3 are trastuzumab biosimilars with efficacy, safety, pharmacokinetics, and immunogenicity similar to the reference drug, but at significantly lower cost. In a phase III trial, CT-P6 had a pCR rate of 46.8% versus 50.4% for the reference drug, within the equivalence range, and a 6-year overall survival of 96% versus 94%. SB3 also showed similar outcomes.

### What is dual HER2-targeted therapy, and who might benefit from it?

Dual HER2-targeted therapy uses two drugs that block HER2 in different ways, such as trastuzumab plus lapatinib or pertuzumab. In a phase III trial of 305 patients, the pCR rate was 56% with trastuzumab, lapatinib, and paclitaxel, versus 46% with trastuzumab and paclitaxel. In hormone receptor-negative patients, the rate was 79% versus 54%, suggesting greater benefit for this group.

### What is pyrotinib, and how does it change treatment before surgery?

Pyrotinib is an irreversible small-molecule tyrosine kinase inhibitor that targets HER1, HER2, and HER4. In the phase III PHEDRA trial of 355 women with early or locally advanced HER2-positive breast cancer, adding pyrotinib to trastuzumab and docetaxel significantly increased the pCR rate to 41.0%, compared with 22.0% for placebo. This shows pyrotinib can enhance treatment efficacy.

### When should a patient with HER2-positive breast cancer considering neoadjuvant therapy before surgery seek a second opinion?

A second opinion is reasonable when the treatment plan involves choices this evidence leaves open: whether to start HER2-targeted therapy before surgery, whether to use dual blockade such as trastuzumab plus lapatinib or pertuzumab, and whether a biosimilar such as CT-P6 or SB3 is appropriate. Because trials used different regimens, populations, and follow-up, and because pCR does not guarantee a cure, an independent review of pathology and imaging can clarify options. Diagnostic Detectives Network provides independent expert second opinions.

## Source Information

**Original article title:** Focusing on the Advances and Challenges of HER2-Targeted Therapy: Cutting-Edge Breakthroughs in Neoadjuvant Treatment for HER2-Positive Breast Cancer.

**Authors:** Shang A, Xiong Y, Li M, Tang W, Wan K, Deng Z, Mao X, Chen H.

**Publication:** Technology in Cancer Research & Treatment, Volume 25, pages 1–18, 2026

**DOI:** 10.1177/15330338261446455

**Corresponding author:** Haizhu Chen, MD, PhD, Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

**Note:** This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes only and does not replace personalized medical advice. Patients should consult their healthcare providers for guidance on their individual treatment plans.


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