Editor's Note: In recent years, the field of breast cancer treatment has witnessed a series of innovative research developments, particularly in the treatment of HER2+ early breast cancer (EBC). Strategies such as "de-escalation," "chemotherapy-free," and "precision treatment" have become hot topics. At the 7th Oncology Precision Diagnosis and Treatment Conference and the 10th Breast Cancer Individualized Treatment Conference (2024 COMB), Oncology Frontier invited Dr. Tao Sun from Liaoning Cancer Hospital to delve into the latest developments and future directions in the treatment of HER2+ EBC.Oncology Frontier: In recent years, “de-escalation” has become a hot topic in HER2+ EBC. The APT study was the first to explore the feasibility of single-target therapy for small-tumor breast cancer patients. How do you view this treatment strategy?
Dr. Tao Sun: In recent years, the field of breast cancer treatment has been pursuing the concept of adaptive therapy: intensified treatment for high-risk recurrence populations and reduced treatment for low-risk recurrence populations. For HER2-positive patients—who originally had a poor prognosis but have seen improved overall survival due to iterative advancements in anti-HER2 targeted therapies—the question has arisen whether some patients have been overtreated. This is the feasibility that the APT study explored for single-target therapy in low-risk, small-tumor patients.
The APT study’s results indicated that in low-risk, specific conditions—namely, HER2+ EBC patients with tumor diameters less than or equal to 3 cm and negative lymph nodes—a single-target therapy regimen combining paclitaxel and trastuzumab achieved encouraging results, with a 10-year invasive disease-free survival (IDFS) rate of 91.3% (95% CI: 88.3-94.4). This suggests that most patients can maintain long-term disease-free survival after treatment. This study not only demonstrated the feasibility of single-target therapy in small-tumor breast cancer patients but also showed its safety and efficacy, which is significant for reducing treatment burden and improving patients’ quality of life.
Secondly, from a clinical practice perspective, the “de-escalation” treatment strategy embodies the principles of individualized treatment. Different patients have different biological characteristics and disease severity, so treatment plans should be tailored to the patient’s specific situation. For patients with smaller tumor burdens and better prognoses, single-target therapy or simplified treatment regimens may be more appropriate, helping to reduce unnecessary treatment toxicity and improve patient tolerance and quality of life. The study also preliminarily identified the HER2DX genomic tool as a potential prognostic predictor, with the HER2DX risk score (0-100, higher scores indicate higher recurrence risk) used to predict long-term recurrence risk. Patients with high HER2DX scores or Luminal B subtypes may have an increased risk of recurrence, but this finding still requires further validation.
However, we must also recognize that single-target therapy is not suitable for all HER2+ EBC patients. For patients with larger tumor burdens and poorer prognoses, more aggressive treatment strategies, such as dual-target therapy combined with chemotherapy, are still necessary to further improve efficacy and prognosis. Therefore, while the APT study provides new ideas and directions for treatment, it also requires us to conduct individualized assessments and treatment decisions based on the specific circumstances of each patient in clinical practice. Additionally, we must continue to explore new treatment methods and approaches to continuously optimize HER2+ EBC treatment strategies and improve patient survival and quality of life.
Oncology Frontier: The ADAPT and PHERGain studies discussed the feasibility of chemotherapy-free strategies, but researchers used PET CT to evaluate pathological responses and guide treatment. How do you view the chemotherapy-free strategy in HER2+ EBC?
Dr. Tao Sun: The chemotherapy-free strategy is a hot topic in the current field of breast cancer treatment, and studies such as ADAPT and PHERGain, through innovative clinical trial designs, have provided us with valuable data and insights. The background and significance of the chemotherapy-free strategy lie in reducing treatment toxicity. While chemotherapy has been an effective traditional treatment method, it often comes with significant toxicity, impacting patients’ quality of life. The chemotherapy-free strategy aims to reduce unnecessary chemotherapy by adopting precision treatment while retaining effective anti-HER2 targeted therapies, thereby lessening the treatment burden on patients.
With a deeper understanding of the biological characteristics of breast cancer, individualized treatment has become a trend. In studies like ADAPT and PHERGain, PET CT was used to guide treatment decisions and help doctors adjust treatment plans in a timely manner. Research has shown that PET CT response may be a good surrogate marker for pathological complete response (pCR). This means that by using PET CT for evaluation, doctors can preliminarily assess treatment efficacy without invasive surgery, guiding the chemotherapy-free strategy. Besides PET CT, MRI-based assessments are also being explored in the TRAIN-3 study to evaluate radiological complete response (rCR) and pCR as a basis for chemotherapy exemption.
Oncology Frontier: Circulating tumor DNA (ctDNA) is a novel form of liquid biopsy, and its use is gradually expanding in the treatment of breast cancer patients. Do you see a promising future for its application in HER2+ breast cancer?
Dr. Tao Sun: ctDNA, as a novel liquid biopsy method, is gradually being applied from advanced breast cancer to early-stage breast cancer, with different clinical applications in various scenarios. First, in advanced breast cancer, ctDNA serves as a non-invasive liquid biopsy to identify actionable mutations that can guide targeted therapy, such as ESR1 mutations and PIK3CA mutations, particularly when tissue samples are unavailable. Initially, retrospective analyses found that ESR1 mutations frequently occurred in advanced-stage patients after AI treatment, leading to AI resistance, while fulvestrant remained unaffected. Therefore, the prospective PADA-1 study aimed to explore the efficacy of switching to fulvestrant plus palbociclib versus continuing AI plus palbociclib in HR+/HER2- mBC patients with ESR1 mutations detected in circulating blood during first-line AI plus palbociclib treatment.
At the 2020 ASCO meeting, it was first reported that PFS was significantly worse in patients with baseline ESR1 mutations who received CDK4/6i plus AI as first-line therapy compared to non-mutant patients (11 months vs. 26.7 months), consistent with previous studies suggesting a poorer prognosis with ESR1 mutations. The second phase, reported at the 2021 SABCS, showed that patients who developed ESR1 mutations during treatment and switched to fulvestrant plus palbociclib had better PFS than those who continued AI plus palbociclib (11.9 months vs. 5.7 months). PADA-1 is the first clinical trial to demonstrate the clinical benefit of ctDNA-based ESR1 mutation detection in optimizing treatment plans, particularly for guiding specific mutation-targeted therapy. Similar mutation monitoring can also be considered for guiding PI3K inhibitor selection based on PIK3CA mutations, enabling more precise treatment stratification.
Beyond guiding the identification of specific actionable mutations for targeted therapy, ctDNA also has another clinical application scenario: reflecting tumor burden. This includes minimal residual disease (MRD) in the absence of macroscopic tumors and serving as a dynamic assessment tool for evaluating the efficacy of neoadjuvant therapy or advanced treatments. MRD has been studied not only in breast cancer but also in lung and colorectal cancers, where it has been shown to detect residual disease earlier than imaging, with MRD-positive patients having significantly worse prognoses than MRD-negative patients. Therefore, in addition to baseline tumor pathological characteristics, dynamic MRD monitoring can assist in prognostic assessment for early breast cancer, particularly for early detection of MRD positivity, which could enable earlier intervention.
The 2021 SABCS reported the cTRAK TN study, which monitored MRD positivity in relatively high-risk TNBC (non-pCR after neoadjuvant therapy, post-surgery >T2 or N+). Patients were randomly assigned 2:1 to one year of pembrolizumab immunotherapy versus surveillance, with MRD positivity monitored at baseline and every 3 months up to 12 months, yielding a 27.3% MRD positivity rate. Among the 32 patients assigned to the treatment group, 23 (71.9%) experienced metastatic recurrence concurrent with ctDNA positivity, and among the non-recurrent patients, four refused treatment due to COVID-19, with only five receiving pembrolizumab. Of the five, four experienced recurrence, and one is still in treatment.
Although this study was the first prospective exploration of MRD-guided adjuvant immunotherapy in TNBC, the small number of patients in the treatment group precluded an assessment of pembrolizumab’s efficacy. Subsequent findings suggest that ctDNA should be monitored as early as possible, ideally within a 6-week window post-adjuvant radiotherapy and chemotherapy, with more frequent monitoring during peak recurrence periods, and using MRD monitoring schemes with higher sensitivity based on more monitoring loci. Therefore, it is evident that ctDNA holds great promise in the clinical application of breast cancer, as it can guide treatment based on mutation detection, dynamically monitor treatment efficacy, and predict breast cancer prognosis earlier, potentially allowing for earlier intervention to reduce recurrence risk. Of course, this also depends on the clinical application of more novel targeted therapies, more sensitive and standardized ctDNA detection methods, and the cost-effectiveness of such testing.
Dr. Tao Sun Director of the Department of Breast Oncology, Liaoning Cancer Hospital, Ph.D. Supervisor Expert with State Council Special Allowance, Second-Level Professor Distinguished Young Physician of Liaoning Standing Committee Member, Breast Cancer Committee, Chinese Society of Clinical Oncology (CSCO) Vice Chairman, Tumor Cardiology Committee, Chinese Society of Clinical Oncology (CSCO) Vice Chairman, Tumor Biomarker Committee, Chinese Anti-Cancer Association Vice Chairman, Tumor Heterogeneity and Individualized Therapy Committee, Chinese Anti-Cancer Association Deputy Director, Breast Disease Professional Committee, China Medical Education Association Standing Committee Member, Multiple and Unknown Primary Tumors Committee, Chinese Anti-Cancer Association Member, Breast Cancer Committee, Chinese Anti-Cancer Association Vice Chairman, Precision Medicine and Tumor MDT Committee, Chinese Research Hospital Association Chairman, Tumor Biomarker Committee, Liaoning Anti-Cancer Association Chairman (Elect), Chemotherapy Committee, Liaoning Anti-Cancer Association
