丨 9th East China Breast Cancer Salon**
Editor’s Note: The treatment paradigm for breast cancer brain metastases (BCBM) is undergoing major conceptual shifts. With advances in radiotherapy technology and continuous evolution of targeted therapeutics, survival for patients with BCBM has markedly improved—some patients can now achieve long-term survival even with persistent intracranial disease. At the 2025 2nd Innovative Anticancer Drug Clinical Research Forum & 9th East China Breast Cancer Salon, Professor Jiayi Chen from Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, delivered a lecture on “Integrated Strategies for Systemic Therapy and Radiotherapy in Breast Cancer.” Following her presentation, Oncology Frontier invited Professor Chen to discuss mechanisms of synergy between radiotherapy and targeted agents, individualized treatment selection for patients with brain metastases, and future directions—as well as challenges—for combined-modality therapy.01
Oncology Frontier: The prognosis for patients with breast cancer brain metastases remains suboptimal. What opportunities and challenges exist in combining radiotherapy with systemic therapy for these patients?
Professor Jiayi Chen:
Brain metastases remain one of the major challenges in breast cancer management. Broadly, patients can be divided into two categories: HER2-positive and HER2-negative brain metastases. Although the treatment strategies differ between these groups, both face unique opportunities and challenges. With evolving therapeutic approaches, the integration of radiotherapy and systemic agents may gradually reshape the treatment landscape.
For HER2-positive BCBM, targeted therapies provide significant benefit. From early monoclonal antibodies and tyrosine kinase inhibitors (TKIs) to the widely used antibody–drug conjugates (ADCs), these agents have consistently improved antitumor activity and survival outcomes. Evidence shows that combining radiotherapy with anti-HER2 agents yields substantial efficacy with manageable safety. Early data suggested a potential increase in intracranial edema when T-DM1 was used alongside stereotactic radiotherapy; however, emerging evidence with next-generation ADCs indicates a more favorable safety profile. Nevertheless, further clinical studies are needed. A key ongoing challenge is that once patients progress on both ADCs and TKIs, subsequent treatments must rely on novel mechanisms to overcome resistance.
From a radiotherapy perspective, the evolution in local treatment strategies has been dramatic: – from whole brain radiation therapy (WBRT), – to hippocampal avoidance WBRT, – to stereotactic body radiotherapy (SBRT) capable of targeting multiple lesions—even up to 20.
One of the most significant shifts is that patients with BCBM can now undergo multiple courses of focal radiotherapy across their disease trajectory. This allows radiation oncologists to treat only the isolated intracranial lesions that progress during systemic therapy, enabling patients to remain on systemic regimens that are otherwise controlling extracranial disease—thereby maximizing duration of benefit.
In HER2-negative BCBM, major challenges persist. Due to the lack of agents with strong blood-brain barrier penetration, systemic therapy alone often yields limited control. Thus, radiotherapy and surgery remain essential first-line strategies. Recent exploration of treatment combinations—such as CDK4/6 inhibitors in HR+ disease and TROP2-targeted ADCs combined with radiotherapy—offers new hope for these patients. In parallel, advances in radiotherapy allow repeated, stage-specific interventions for progressive lesions.
Overall, outcomes for BCBM have improved markedly, with a median survival approaching 18 months. HER2-positive patients benefit the most: multiple studies report survival exceeding 24 months, and a subset achieves long-term survival.
Given these gains, clinical thinking must shift: brain metastasis should no longer be viewed solely as a terminal event, but rather as a manageable chronic disease stage requiring long-term, multidisciplinary care. Through individualized, full-course management, we aim not only to prolong survival but also to improve quality of life.
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Oncology Frontier: Does the sequencing of CDK4/6 inhibitors and radiotherapy influence efficacy or toxicity?
Professor Jiayi Chen:
In current clinical practice, CDK4/6 inhibitors are used mainly for HR+/HER2– high-risk early breast cancer, particularly in patients with axillary lymph node involvement. Postoperative adjuvant radiotherapy is also indicated in high-risk disease, especially in cases with N2 or greater nodal burden.
Notably, in both pivotal studies of CDK4/6 inhibitors for adjuvant therapy—MonarchE and NATALEE—patients were required to complete adjuvant radiotherapy and wait at least 14 days before initiating CDK4/6 inhibitor treatment.
There is growing interest in evaluating the safety of concurrent radiotherapy and CDK4/6 inhibition in high-risk patients. Mechanistically, concurrent treatment may increase hematologic toxicities such as neutropenia and in-field radiotoxicities such as dermatitis or esophagitis. However, the true incidence and clinical manageability of these effects require further prospective evaluation.
More importantly, if toxicities are confirmed to be manageable, concurrent treatment may potentially exploit synergy: radiotherapy-induced DNA damage combined with G1 arrest induced by CDK4/6 inhibition might amplify antitumor activity.
As targeted therapy rapidly evolves, this question has become a key area of shared interest for both radiation oncologists and medical oncologists.
Professor Jiayi Chen
Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
