Editor's Note: Over the past two decades, the treatment of HER2-positive breast cancer has undergone a dramatic transformation, evolving from targeted therapy to the era of antibody-drug conjugates (ADCs), with substantial improvements in patient survival and prognosis. Recently, the Northern Breast Cancer Salon was successfully held in Qingdao. During the meeting, Oncology Frontier interviewed Professor Guohong Song of Peking University Cancer Hospital, who provided an in-depth overview of milestone developments in the treatment of HER2-positive breast cancer, individualized treatment strategies involving treatment “escalation” and “de-escalation” in early breast cancer, and the changes and future prospects brought about by ADC therapies.Oncology Frontier: From trastuzumab ushering in the era of targeted therapy to the current incorporation of ADCs into the treatment of both early and advanced breast cancer, the treatment landscape for HER2-positive breast cancer has changed dramatically over the past two decades. Looking back on this journey, which key milestones do you believe have truly changed the lives of patients with HER2-positive breast cancer?
Professor Guohong Song: I have been working in clinical practice for more than 30 years and have personally witnessed the rapid development and evolution of pharmacological treatment for breast cancer. In the treatment of HER2-positive breast cancer, the most challenging and undoubtedly one of the most significant milestone events was the advent of trastuzumab. Trastuzumab significantly reduced the risk of recurrence in patients with early HER2-positive breast cancer while substantially prolonging survival in patients with advanced breast cancer, leading to a major improvement in the overall prognosis of HER2-positive breast cancer.
Following trastuzumab, an increasing number of novel targeted therapies emerged, providing patients with varying degrees of clinical benefit. For example, the introduction of pertuzumab established the dual HER2-targeted regimen of trastuzumab plus pertuzumab (dual HER2 blockade) as an effective treatment approach for both early and advanced HER2-positive breast cancer. Studies such as NeoSphere and PEONY demonstrated that dual HER2 blockade combined with chemotherapy could further increase pathological complete response (pCR) rates and reduce the risk of recurrence in early breast cancer. Meanwhile, CLEOPATRA and PUFFIN showed that, in the first-line treatment of advanced disease, dual HER2 blockade combined with chemotherapy not only prolonged progression-free survival (PFS), but also significantly extended overall survival (OS). In addition, small-molecule tyrosine kinase inhibitors (TKIs), such as pyrotinib, have played an important role in the treatment of advanced HER2-positive breast cancer, further prolonging patient survival.
In recent years, the emergence of antibody-drug conjugates (ADCs) has provided breast cancer patients with additional treatment options. The first ADC used in breast cancer was T-DM1. The EMILIA study showed that among patients with HER2-positive advanced breast cancer who had previously received trastuzumab and a taxane, T-DM1 significantly prolonged both median PFS (9.6 months vs 6.4 months; HR=0.65; P<0.001) and OS (30.9 months vs 25.1 months; HR=0.68; P<0.001) compared with lapatinib plus capecitabine. These findings established T-DM1 as a standard second-line treatment for HER2-positive advanced breast cancer.
The KATHERINE study enrolled patients with HER2-positive early breast cancer who had residual disease following neoadjuvant therapy and compared adjuvant T-DM1 with trastuzumab. The 3-year invasive disease-free survival (iDFS) rate was significantly higher with T-DM1 than with trastuzumab (88.3% vs 77.0%; HR=0.50; P<0.001). The estimated 7-year OS rates were 89.1% and 84.4%, respectively, representing an absolute difference of 4.7% (HR=0.66), which was statistically significant. These findings established T-DM1 as an important adjuvant treatment for HER2-positive early breast cancer, particularly for patients who fail to achieve pCR following neoadjuvant therapy.
The emergence of novel ADCs represented by trastuzumab deruxtecan (T-DXd) has further prolonged survival in patients with advanced breast cancer, while also increasing pCR rates and significantly reducing the risk of recurrence in patients with early breast cancer. T-DXd can be considered a landmark development in the field.
In the neoadjuvant setting, the DB-11 study evaluated the efficacy and safety of T-DXd monotherapy or T-DXd followed by paclitaxel, trastuzumab, and pertuzumab (T-DXd-THP) versus standard therapy with dose-dense doxorubicin and cyclophosphamide followed by THP (ddAC-THP) in patients with high-risk (node-positive [N1-3] or primary tumor stage T3-4), locally advanced, or inflammatory HER2-positive early breast cancer. The results showed that the pCR rate was 67.3% in the T-DXd-THP group, significantly higher than the 56.3% observed with ddAC-THP, representing an absolute difference of 11.2%. Subgroup analyses suggested that neoadjuvant T-DXd-THP achieved favorable pCR rates regardless of hormone receptor (HR) status.
The DB-05 study evaluated the efficacy and safety of T-DXd versus T-DM1 as adjuvant therapy in patients with high-risk HER2-positive early breast cancer who had residual invasive disease after neoadjuvant treatment. The 3-year iDFS rate was 92.4% with T-DXd versus 83.7% with T-DM1, corresponding to an absolute benefit of 8.7% (HR=0.47, 95% CI: 0.34-0.66; P<0.0001) and a 53% reduction in the risk of disease recurrence or death. In advanced HER2-positive breast cancer, data from the DB-03 and DB-09 studies have demonstrated highly impressive efficacy with T-DXd in both the second- and first-line settings.
The continuous evolution of these therapies has indeed increased the cure rate of patients with early HER2-positive breast cancer, while providing patients with advanced disease with longer survival and better quality of life. The ongoing advancement of treatment options has brought substantial benefits to patients, which is deeply encouraging for clinicians and offers renewed hope to patients.
Oncology Frontier: HER2-positive early breast cancer has now entered an era of individualized treatment based on risk stratification. In clinical practice, while pursuing higher pCR rates, how do you determine the appropriate boundary between “treatment intensification” and “de-escalation”? Based on your clinical experience, which patients are suitable for de-escalated treatment, and which patients still require treatment intensification?
Professor Guohong Song: For early breast cancer, our ultimate goal is cure. How to appropriately escalate or de-escalate treatment requires a stratified approach.
First, in the neoadjuvant setting, the current standard regimen for HER2-positive breast cancer is dual HER2 blockade with trastuzumab plus pertuzumab combined with two chemotherapy agents, with the aim of further increasing the pCR rate. De-escalation strategies in the neoadjuvant setting have mainly explored whether single-agent chemotherapy can replace dual-agent chemotherapy while maintaining or improving efficacy and reducing treatment-related toxicity.
For example, the HELEN-006 study conducted by Henan Cancer Hospital showed that single-agent chemotherapy with nab-paclitaxel combined with dual HER2 blockade achieved a significantly higher pCR rate and better safety compared with dual chemotherapy consisting of docetaxel plus carboplatin combined with dual HER2 blockade.
However, not all patients are suitable for single-agent chemotherapy, nor do all patients necessarily require dual chemotherapy. Based on clinical trial data and my own experience, for patients with a high risk of recurrence or more aggressive disease, particularly those with HR-negative/HER2-positive breast cancer, I tend to favor a more intensive regimen, such as dual chemotherapy combined with dual HER2 blockade. For patients with HR-positive/HER2-positive, or “triple-positive,” breast cancer, single-agent chemotherapy combined with dual HER2 blockade can also achieve good outcomes. Of course, this represents my personal perspective and may not encompass every clinical scenario, but it is supported to some extent by available clinical research data. Therefore, when selecting neoadjuvant therapy, I tend to take HR status and other factors into consideration.
In the adjuvant setting, for patients with positive lymph nodes, as well as those with negative lymph nodes but high-risk prognostic factors—such as high Ki-67 expression, HR-negative disease, or grade 3 pathology—I tend to use adjuvant dual HER2 blockade. For patients with node-negative disease and no high-risk factors, adjuvant trastuzumab monotherapy is generally sufficient.
Currently, for patients with non-pCR after neoadjuvant therapy who remain at high risk of recurrence, we also consider adjuvant treatment intensification, meaning that rather than continuing the original regimen, we switch to a more potent treatment. The KATHERINE study and other trials have demonstrated that patients with non-pCR after neoadjuvant therapy can receive adjuvant T-DM1 as an intensified treatment. The DB-05 study further showed that T-DXd can reduce the risk of recurrence more significantly than T-DM1 in these patients, providing additional benefit.
To further reduce the risk of recurrence in high-risk patients, clinical studies are also exploring adjuvant intensification strategies following neoadjuvant therapy for patients with extremely high-risk HER2-positive breast cancer, such as those with positive lymph nodes, large tumors, or more advanced disease. The ExteNET study showed that, in the intention-to-treat population, neratinib significantly reduced the risk of recurrence in patients with early HER2-positive breast cancer, with particularly pronounced benefits among high-risk patients with non-pCR and those with node-positive disease. Based on these findings, neratinib has been recommended by numerous authoritative guidelines in China and internationally as an adjuvant intensification strategy.
In clinical practice, I also consider neratinib for high-risk patients in an effort to achieve sustained benefit. Of course, the level of evidence supporting this strategy is not the highest, but it can be considered for high-risk populations in clinical practice. Overall, treatment escalation and de-escalation must be individualized according to disease stage, tumor aggressiveness, and risk level rather than applied uniformly to all patients.
Oncology Frontier: With the introduction of ADCs into the treatment of early HER2-positive breast cancer, patients now have a much broader range of treatment options. Based on evidence from key studies such as DB-05 and DB-11, what fundamental changes do you believe ADCs will bring to the clinical management of early HER2-positive breast cancer? How might treatment paradigms evolve in the future?
Professor Guohong Song: The development of ADCs is indeed changing the treatment paradigm for breast cancer.
Taking neoadjuvant therapy as an example, the DB-11 study showed that T-DXd-THP produced a statistically significant and clinically meaningful improvement in pCR compared with ddAC-THP. As we discussed during the earlier debate session, the optimal selection of neoadjuvant therapy remains an important question. The increase in pCR observed with T-DXd-THP—whether it is primarily attributable to T-DXd itself or to the subsequent contribution of THP—is not yet completely clear.
Furthermore, after using such a highly potent drug in the neoadjuvant setting, how should subsequent adjuvant therapy be designed? How should patients who achieve pCR be managed, and how should those who fail to achieve pCR be treated? These questions have generated considerable discussion, but there are currently no definitive answers.
Therefore, experts have different opinions regarding whether such a highly potent regimen should be used in the neoadjuvant setting. At present, for patients with more advanced disease and extremely high risk, more experts tend to favor the intensified T-DXd-THP regimen. For patients with standard-risk disease, conventional chemotherapy combined with dual HER2 blockade remains a relatively standard option.
On the other hand, for adjuvant intensification in patients with non-pCR after neoadjuvant therapy, the DB-05 study has provided important evidence. Compared with T-DM1, T-DXd significantly improved iDFS.
Personally, I find this study particularly compelling because it first uses neoadjuvant therapy to identify patients who are less sensitive to treatment and therefore have a poorer prognosis, and then provides these patients with more intensive adjuvant therapy. Therefore, I tend to favor conventional treatment in the neoadjuvant setting, followed by identification of patients at high risk or those who are less responsive to therapy, and then use T-DXd for adjuvant intensification. In this way, we can more precisely reduce the risk of recurrence and metastasis and increase the likelihood of cure.
This strategy allows us to more specifically select patients who are likely to benefit, while maintaining efficacy and reducing unnecessary toxicity, ultimately achieving a balance between treatment efficacy and safety throughout the patient’s entire treatment journey.
Professor Guohong Song
Peking University Cancer Hospital
