In recent years, the field of breast cancer treatment has seen a series of innovative research advancements, 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 Precision Diagnosis and Treatment of Tumors and the 10th Individualized Treatment of Breast Cancer Conference (2024 COMB), Oncology Frontier invited Dr. Tao Sun from Liaoning Cancer Hospital to discuss the latest developments and future directions in HER2+ EBC treatment.01 Oncology Frontier: In recent years, “de-escalation” has become a hot topic in the discussion of HER2+ EBC. The APT study first discussed 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 treatment: providing intensive treatment for high-risk recurrence groups and reducing treatment for low-risk recurrence groups. For the HER2-positive population, which originally had a poor prognosis, continuous iteration of anti-HER2 targeted drugs has improved overall survival. There is also consideration of whether some patients have received overly intensive treatment, which is the feasibility of single-target therapy for small tumor low-risk patients discussed in the APT study.
The results of the APT study indicate that in specific low-risk conditions, namely HER2+ EBC patients with tumors 3 cm or less in diameter and negative lymph nodes, the single-target treatment regimen of paclitaxel combined with trastuzumab achieved encouraging efficacy. The 10-year IDFS survival rate was 91.3% (95% CI: 88.3-94.4), indicating that most patients could maintain long-term disease-free survival after treatment. This study not only proves the feasibility of single-target therapy in small tumor breast cancer patients but also shows its good safety and efficacy, which is significant for reducing patients’ treatment burden and improving their quality of life.
From a clinical practice perspective, the “de-escalation” treatment strategy embodies the principle of individualized treatment. Different patients have different biological characteristics and disease severity; thus, personalized treatment plans should be formulated based on the patient’s specific condition during treatment. For patients with smaller tumor loads and better prognoses, adopting 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) predicting long-term recurrence risk. Patients with high HER2DX scores or the Luminal B subtype may have increased recurrence risk, but this finding still needs further validation.
However, it is also necessary to 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 needed to further improve efficacy and prognosis. Therefore, I believe the APT study provides us with new treatment ideas and directions, but in clinical practice, we need to conduct individualized assessments and treatment decisions based on the patient’s specific situation. Meanwhile, we should continue to explore new treatment methods and means to continuously optimize the treatment strategies for HER2+ EBC and improve patient survival and quality of life.
02 Oncology Frontier: The ADAPT and PHERGain studies discussed the feasibility of chemotherapy-free strategies, but researchers used PET CT to evaluate pathological response and guide treatment. How do you view the chemotherapy-free strategy for HER2+ EBC?
Dr. Tao Sun: The chemotherapy-free strategy is a hot topic in the current field of breast cancer treatment, and studies like ADAPT and PHERGain, through innovative clinical trial designs, have provided valuable data and insights. The background and significance of the chemotherapy-free strategy are to reduce treatment toxicity. While chemotherapy, as a traditional treatment method, is effective, it often comes with high toxicity reactions, impacting patients’ quality of life. The chemotherapy-free strategy aims to reduce unnecessary chemotherapy through precision treatment while retaining effective anti-HER2 targeted therapy, thereby reducing patients’ treatment burden.
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 is used to guide treatment decisions, helping doctors adjust treatment plans promptly. The studies show that the response on PET CT might be a good surrogate marker for pathological complete response (pCR). This means that through PET CT evaluation, doctors can preliminarily judge the treatment effect without invasive surgery, guiding the chemotherapy-free strategy. Besides PET CT, MRI-based evaluation in the TRAIN-3 study explored the possibility of chemotherapy omission based on radiographic complete response (rCR) and pCR.
Feasibility and effectiveness: The results of studies like ADAPT and PHERGain show that for some HER2+ EBC patients, the chemotherapy-free strategy is feasible and effective. These studies, through precise evaluation of patients’ treatment responses, successfully liberated some patients from chemotherapy while maintaining good treatment efficacy. The MD Anderson center further explored direct surgery exemption for low-risk patients, achieving a 3-year ipsilateral breast tumor-free survival rate of 100%. In the future, we can expect more explorations regarding biomarkers, drug combinations, and treatment timing to achieve more precise individualized treatment.
03 Oncology Frontier: Circulating tumor DNA (ctDNA) is a new type of liquid biopsy gradually being applied in breast cancer treatment. How do you view its application prospects in HER2+ breast cancer patients?
Dr. Tao Sun: ctDNA, as a new liquid biopsy method, has gradually expanded from use in advanced breast cancer to early breast cancer, focusing on different clinical scenarios with varying applications. Firstly, ctDNA in advanced breast cancer is used as a non-invasive liquid biopsy when tissue is not obtainable, to identify driver mutations that could guide targeted therapy, such as ESR1 mutations and PIK3CA mutations. Initially, retrospective analyses found that ESR1 mutations often exist after advanced AI treatment, leading to AI resistance, whereas fulvestrant remains unaffected. Therefore, the PADA-1 study aimed to explore the efficacy of switching to fulvestrant + palbociclib vs. continuing AI + palbociclib treatment in HR+/HER2- mBC patients with detected ESR1 mutations during first-line AI + palbociclib treatment.
The first report at the 2020 ASCO showed that AI-sensitive patients with baseline ESR1 mutations had significantly shorter PFS with first-line CDK4/6i + AI treatment compared to non-mutated patients (11 months vs. 26.7 months), similar to previous studies, indicating that ESR1 mutation is a poorer prognostic factor. The second phase reported at the 2021 SABCS showed that switching to fulvestrant + palbociclib for patients with ESR1 mutations during treatment had superior PFS compared to continuing AI + palbociclib (11.9 months vs. 5.7 months). PADA-1 is the first clinical trial proving that circulating ESR1 detection has clinical value in optimizing treatment regimens, focusing on specific mutation-driven therapeutic guidance. Similar mutation monitoring can also be considered for PIK3CA mutations to guide the selection of PI3K inhibitors, enabling more precise treatment classification.
Besides guiding targeted therapy through driver gene identification, ctDNA also has another clinical application scenario, reflecting tumor burden. This includes minimal residual disease (MRD) in a tumor-free state and dynamic evaluation of treatment efficacy in neoadjuvant and advanced settings. MRD exists not only in breast cancer but also in lung cancer and colorectal cancer, with studies confirming it can detect residual disease earlier than imaging. Patients with MRD positivity have significantly worse prognoses than those with MRD negativity. Therefore, in addition to baseline tumor pathological features, dynamic MRD detection can assist in early breast cancer prognosis, especially as it shows MRD positivity earlier than imaging, allowing for potential early intervention.
The 2021 SABCS reported the cTRAK TN trial attempting to monitor MRD positivity in clinically high-risk TNBC (non-pCR post-neoadjuvant, direct surgery > T2, or N+ presence), with 2:1 randomization to pembrolizumab immunotherapy for one year vs. observation. MRD positivity rates at baseline and every 3 months up to 12 months were 27.3%, with 32 patients in the treatment group. Due to the study’s use of 1-2 mutation points for monitoring, leading to poor sensitivity, 23 patients (71.9%) showed metastatic disease at ctDNA+; among non-relapsed patients, 4 refused treatment due to COVID-19, and only 5 received pembrolizumab, with 4 relapsed and 1 still in treatment.
Although this study is the first prospective exploration of MRD-guided adjuvant immunotherapy in TNBC in the breast cancer field, the treatment group had too few patients to evaluate pembrolizumab’s efficacy. Subsequent results suggest that ctDNA should be monitored early, ideally within a 6-week window post-adjuvant radiochemotherapy, using higher sensitivity MRD monitoring schemes with more monitoring points. More intensive monitoring should be conducted during peak recurrence periods. Therefore, ctDNA has great potential in breast cancer’s clinical application scenarios: guiding drug use through mutation detection, dynamically evaluating treatment efficacy, and early monitoring of breast cancer prognosis, potentially allowing for early intervention to reduce recurrence risk. However, this also relies on the clinical application of more new targeted drugs and more sensitive and standardized ctDNA detection, considering the pharmacoeconomic benefits of detection costs.
Dr. Tao Sun
Director of the Department of Breast Oncology at Liaoning Cancer Hospital, Doctoral Advisor Expert receiving special government allowances from the State Council, Secondary Professor Famous Young Doctor of Liaoning Standing Committee Member of the Breast Cancer Expert Committee of the Chinese Society of Clinical Oncology (CSCO) Vice Chairman of the Tumor Cardiology Expert Committee of CSCO Vice Chairman of the Tumor Marker Expert Committee of the Chinese Anti-Cancer Association Vice Chairman of the Tumor Heterogeneity and Individualized Treatment Expert Committee of the Chinese Anti-Cancer Association Deputy Director of the Breast Disease Professional Committee of the Chinese Medical Education Association Standing Committee Member of the Multiple and Unknown Primary Tumors Expert Committee of the Chinese Anti-Cancer Association Member of the Breast Cancer Expert Committee of the Chinese Anti-Cancer Association Vice Chairman of the Precision Medicine and Tumor MDT Expert Committee of the Chinese Research Hospital Association Chairman of the Tumor Marker Expert Committee of the Liaoning Anti-Cancer Association Chairman (Designate) of the Chemotherapy Expert Committee of the Liaoning Anti-Cancer Association
