HER2-positive intracranial metastases

• Stereotactic radiosurgery for HER2-positive breast cancer brain metastases: prognostic factors and the evolving role of anti-HER2 therapies
• Gene signatures associated with brain-topical proliferative activity in breast cancer
• Advances in Targeted Therapy for Brain Metastases in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer: A Focus on ADCs and TKIs
• Efficacy and safety of trastuzumab deruxtecan in HER2-positive breast cancer patients with brain metastases after failure of pyrotinib-based therapy
• Breast Cancer Brain Metastases: A Neurosurgical Point of View From a Single-Center Experience
• Excellent Response to Trastuzumab Deruxtecan of a Large Medullary Metastasis from Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: A Case Report
• Factors associated with local failure after stereotactic radiation to the surgical bed of patients with a single breast cancer metastasis
• Treatment Outcome of Brain Metastases from Breast Cancer Following Gamma Knife Radiosurgery: A Retrospective Study in Vietnam

### Epidemiology of HER2-Positive Intracranial Metastases

HER2-positive intracranial metastases are a significant complication in HER2-positive breast cancer (HER2+ BC), with increasing incidence due to longer survival and improved systemic treatments.

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### 1. Incidence & Prevalence - Overall Risk:

1. 30–50% of HER2+ breast cancer patients will develop brain metastases (BM) at some point in their disease course.

- Higher Risk in Advanced Disease:

1. Among metastatic HER2+ BC patients, brain metastases occur in up to 50%.

- Leptomeningeal Disease (LMD) Risk:

1. 5–10% of HER2+ BC patients with CNS involvement develop leptomeningeal metastases, a poor prognostic factor.

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### 2. Comparison to Other Breast Cancer Subtypes - HER2+ BC has a higher rate of brain metastases compared to hormone receptor-positive/HER2-negative and triple-negative breast cancer (TNBC). - CNS metastases by subtype:

1. HER2-positive: 30-50%
2. Triple-negative: 40-50% (similar risk but shorter survival)
3. Hormone receptor-positive/HER2-negative: 10-15%

- HER2+ brain metastases occur later in the disease course compared to TNBC but earlier than in HR+/HER2-negative disease.

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### 3. Risk Factors for Developing Brain Metastases in HER2+ BC - Young Age:

1. Patients <50 years old have a higher risk of CNS involvement.

- Visceral Metastases (Lung, Liver):

1. Higher burden of extracranial disease is associated with increased CNS spread.

- Prolonged Survival with Systemic Therapy:

1. Improved HER2-targeted treatments (trastuzumab, pertuzumab, T-DXd, tucatinib) have extended systemic disease control, allowing brain metastases to emerge as a common site of progression.

- Blood-Brain Barrier (BBB) Challenge:

1. Many HER2-targeted therapies have limited CNS penetration, allowing brain metastases to develop despite systemic disease control.

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### 4. Median Time to Brain Metastases Development - Typically 2–3 years after initial HER2+ breast cancer diagnosis. - After systemic metastases: Brain metastases may develop within 12-24 months.

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### 5. Survival Outcomes - HER2+ Brain Metastases Median Survival:

1. 9–24 months, depending on treatment response.

- Leptomeningeal Disease (LMD) Survival:

1. 3–6 months, significantly worse prognosis.

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### Key Trends - Increasing incidence due to prolonged survival with HER2-targeted therapies. - More effective CNS-active treatments (tucatinib, trastuzumab-deruxtecan) are improving outcomes. - Brain metastases often occur in controlled extracranial disease, highlighting the need for early CNS screening in metastatic HER2+ patients.

### Conclusion HER2-positive intracranial metastases remain a major clinical challenge, but advances in targeted therapies and radiotherapy have improved survival. Early detection and CNS-specific treatment strategies are essential for optimizing outcomes.

see HER2-positive brain metastases.

### Classification of HER2-Positive Intracranial Metastases HER2-positive intracranial metastases can be classified based on disease extent, response to treatment, and location within the central nervous system (CNS). The classification helps guide treatment decisions and prognosis assessment.

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### 1. Based on Number and Extent of Metastases - Oligometastatic Disease:

1. ≤4 brain metastases (typically ≤3 cm in size)
2. Better prognosis, suitable for stereotactic radiosurgery (SRS)

- Multifocal Brain Metastases:

1. >4 brain metastases
2. Often requires systemic therapy + whole-brain radiotherapy (WBRT) or SRS if feasible

- Leptomeningeal Disease (LMD):

1. Tumor cells infiltrate the cerebrospinal fluid (CSF) and meninges
2. Worst prognosis, often requiring intrathecal therapy (trastuzumab, chemotherapy), WBRT, or palliative care

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### 2. Based on Response to HER2-Targeted Therapies - Therapy-Responsive Metastases:

1. Controlled with trastuzumab, tucatinib, trastuzumab-deruxtecan (T-DXd), or neratinib
2. Considered stable disease, manageable with maintenance therapy

- Progressive CNS Metastases:

1. Worsening disease despite targeted therapy
2. May require radiotherapy, switching systemic therapy, or experimental options

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### 3. Based on Radiological and Anatomical Features - Parenchymal Brain Metastases:

1. Located within brain tissue (most common, ~30-50% of HER2+ breast cancer patients develop these)

- Leptomeningeal Metastases:

1. Spread within the meninges and cerebrospinal fluid

- Combined Parenchymal & Leptomeningeal Disease:

1. Poor prognosis, often requiring a multimodal approach

- Brainstem/Cerebellar Metastases:

1. More challenging due to critical location
2. Requires stereotactic approaches to minimize neurological damage

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### 4. Based on Clinical Presentation - Asymptomatic Metastases:

1. Detected via screening MRI, common in HER2+ breast cancer

- Symptomatic Metastases:

1. Neurological deficits (headache, seizures, cognitive decline, ataxia, focal weakness)
2. Requires urgent intervention (radiation, surgery, or systemic therapy adjustment)

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### Clinical Implications of Classification - Oligometastatic and therapy-responsive disease → Better prognosis, more aggressive interventions possible - Multifocal or leptomeningeal disease → Worse prognosis, often palliative treatment required - Parenchymal vs. leptomeningeal involvement → Different treatment approaches (WBRT/SRS vs. intrathecal therapy)

This classification helps in selecting personalized treatment strategies to optimize survival and quality of life in HER2-positive breast cancer patients with CNS involvement.

HER2-positive intracranial metastases treatment

The prognosis for HER2-positive intracranial metastases varies depending on several factors, including the number and size of metastases, treatment response, and extracranial disease. However, compared to HER2-negative cases, patients with HER2-positive breast cancer brain metastases (BCBM) tend to have a better prognosis due to advances in targeted therapies.

1. Systemic Disease Control: Patients with well-controlled extracranial disease tend to survive better.

2. Number of Brain Metastases: Fewer metastases (<4) generally correlate with better prognosis.

3. Performance Status: Higher Karnofsky Performance Status (KPS) is associated with improved survival.

4. Treatment Response: Sensitivity to HER2-targeted therapies (trastuzumab, tucatinib, and neratinib) significantly improves outcomes.

5. Radiotherapy Approach: Stereotactic radiosurgery (SRS) is associated with longer survival compared to whole-brain radiotherapy (WBRT).

6. Presence of Leptomeningeal Disease: This worsens prognosis significantly.

- Median overall survival (OS): Ranges between 9 to 24 months, with some long-term survivors in the era of modern HER2-targeted therapies. - Better prognosis with:

1. Tucatinib-based regimens (HER2CLIMB trial): OS ~ 18 months for patients with active brain metastases.
2. SRS + systemic therapy: OS > 15 months in some studies.
3. Combination of trastuzumab-deruxtecan (T-DXd) and SRS: Promising results in recent trials.

While HER2-positive intracranial metastases remain a serious complication, targeted therapies and advanced radiation techniques have significantly improved survival and quality of life in recent years. Prognosis is better than HER2-negative cases, especially in patients with limited brain metastases and controlled extracranial disease.

A 64-year-old female patient was diagnosed with HER2-positive invasive ductal carcinoma of the right breast. She achieved a complete pathological response following neoadjuvant chemotherapy, mastectomy, and adjuvant trastuzumab. However, two years after treatment completion, she developed axillary lymphadenopathy and a solitary cerebellar metastasis. This case highlights the importance of long-term follow-up and the role of targeted therapies in HER2-positive breast cancer with central nervous system involvement.

- Medical History: Chronic bronchitis, former smoker, previous mammoplasty, inguinal hernia repair, and urinary incontinence surgery.

- Family History: Mother had ovarian cancer; father had laryngeal and lung cancer.

#### 2.2 Initial Diagnosis and Treatment

- Primary Tumor: Right breast, 9 cm lesion with microcalcifications extending to the nipple. - Biopsy (Core Needle Biopsy, 14G):

1. Invasive ductal carcinoma, Grade II (2,3,2).
2. Immunohistochemistry:
   1. ER: 0% (negative)
   2. PR: 0% (negative)
   3. HER2: 3+ (positive)
   4. Ki-67: 25% (high proliferation index)

- Neoadjuvant Chemotherapy: CTHP (Carboplatin, Docetaxel, Trastuzumab, Pertuzumab) for 6 cycles, achieving a complete pathological response (pCR, RCB 0).

- Surgery (12/2022): Right mastectomy with sentinel lymph node biopsy (negative for malignancy, ypT0 snN0).

- Adjuvant Therapy: Trastuzumab SC, completed.

- Reconstructive Surgery: Expander placement (May 2024), final implant replacement (October 2024).

#### 2.3 Follow-Up and Recurrence - 11/2023: Mammogram of the left breast (BIRADS 2, no evidence of malignancy). - 02/2025: The CT scan showed suspicious left axillary lymphadenopathy (1.4 cm) but no distant metastases. - 03/2025: Brain MRI revealed a solitary 3.8 x 3.1 x 3.6 cm cerebellar lesion with perilesional edema and partial compression of the 4th ventricle, suggesting metastasis.

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### 3. Discussion This case illustrates the natural course of HER2-positive breast cancer with an initial favorable response to neoadjuvant chemotherapy but late recurrence in the CNS.

- CNS Metastases in HER2-Positive Disease: The brain is a common metastatic site due to the inability of trastuzumab to penetrate the blood-brain barrier effectively. - Management Considerations:

1. The axillary lymphadenopathy requires biopsy confirmation and, if positive, consideration of additional systemic or local therapy.
2. The cerebellar metastasis may be amenable to stereotactic radiosurgery (SRS) or surgical resection, depending on symptoms and tumor accessibility.
3. Tucatinib-based therapy (Tucatinib + Trastuzumab + Capecitabine) should be considered, given its proven CNS efficacy in HER2-positive patients.

This case underscores the importance of long-term surveillance in HER2-positive breast cancer patients and highlights the need for personalized treatment approaches for CNS metastases. The patient’s management will require a multidisciplinary approach, including oncology, neurosurgery, and radiation oncology teams.

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### 5. Future Directions - Further Imaging: Serial MRI scans to monitor disease progression. - Biopsy of Axillary Adenopathy: To confirm metastatic involvement. - CNS-Directed Therapy: Consider SRS, surgery, or targeted systemic treatment. - Clinical Trial Enrollment: Evaluation for novel HER2-directed CNS therapies.