What is the best course of action for a patient with metastatic breast cancer on Enhertu (trastuzumab deruxtecan) and Methotrexate for brain metastasis, presenting with shortness of breath and an elevated D-Dimer level?

Immediate Evaluation for Drug-Induced Interstitial Lung Disease/Pneumonitis

This patient requires urgent evaluation for Enhertu-associated interstitial lung disease (ILD)/pneumonitis, which is a potentially life-threatening complication that must be ruled out before considering other diagnoses like pulmonary embolism.

Critical First Steps

Hold Enhertu immediately pending evaluation, as ILD/pneumonitis is a known serious adverse event that can be fatal if treatment continues 1, 2, 3.

Diagnostic Workup Priority

• Obtain high-resolution chest CT immediately to evaluate for ground-glass opacities, interstitial infiltrates, or other patterns consistent with drug-induced pneumonitis 1, 2, 3
• Assess oxygen saturation and arterial blood gas to determine severity of respiratory compromise 1, 2
• Perform pulmonary function tests if patient is stable enough 2
• Consider CT pulmonary angiography (CTPA) to evaluate for pulmonary embolism given the elevated D-dimer, but only after ILD/pneumonitis is assessed, as both conditions can coexist 2, 3

Why Enhertu-Associated ILD/Pneumonitis is the Primary Concern

Enhertu (trastuzumab deruxtecan) carries a significant risk of ILD/pneumonitis, with rates ranging from 9.5% to 31% in real-world studies, including fatal cases 1, 2, 3. This is a black box warning for this medication.

• The median time to onset is typically within the first few months of treatment, but can occur at any time 1, 2
• Shortness of breath is the cardinal presenting symptom 1, 2, 3
• Early detection and immediate drug discontinuation are critical to prevent progression to severe or fatal pneumonitis 1, 2

Differential Diagnosis Considerations

While the elevated D-dimer (6.42) raises concern for pulmonary embolism, do not anchor on PE as the sole diagnosis:

• Cancer patients on chemotherapy have chronically elevated D-dimers from tumor burden, inflammation, and hypercoagulability 2, 3
• Enhertu-associated pneumonitis can also cause elevated D-dimers through inflammatory processes 2
• The presence of brain metastases increases thrombotic risk, but this does not exclude drug-induced lung toxicity 4

Management Algorithm

If ILD/Pneumonitis is Confirmed:

Grade 1 (asymptomatic):

• Hold Enhertu until resolution 1, 2
• Consider resuming at reduced dose after complete resolution 1

Grade 2 (symptomatic but not requiring oxygen):

• Permanently discontinue Enhertu 1, 2
• Initiate corticosteroids (prednisone 0.5-1 mg/kg/day) 2
• Monitor closely with serial imaging 2

Grade 3-4 (severe, requiring oxygen or life-threatening):

• Permanently discontinue Enhertu 1, 2
• Initiate high-dose corticosteroids immediately (methylprednisolone 1-2 mg/kg/day IV) 2
• Consider ICU admission for respiratory support 2
• Infectious workup to rule out superimposed pneumonia 2

If PE is Confirmed (with or without ILD):

• Initiate therapeutic anticoagulation per standard protocols 2
• Do not resume Enhertu if any grade of ILD/pneumonitis is present 1, 2

Alternative HER2-Targeted Therapy Options

If Enhertu must be permanently discontinued due to ILD/pneumonitis, consider:

Tucatinib + capecitabine + trastuzumab (HER2CLIMB regimen):

• This is the preferred alternative for HER2-positive metastatic breast cancer with brain metastases 4
• Demonstrated significant CNS activity with HR 0.32 for CNS progression-free survival 5
• Does not carry the same pneumonitis risk as Enhertu 4

Other options include:

• Neratinib plus capecitabine 4
• Lapatinib plus capecitabine 4
• T-DM1 (ado-trastuzumab emtansine) if not previously used 4

Regarding Methotrexate for Brain Metastases

Methotrexate is not standard therapy for parenchymal brain metastases in HER2-positive breast cancer 4. The evidence-based approaches are:

• Stereotactic radiosurgery (SRS) for limited metastases 4
• Whole-brain radiotherapy with memantine and hippocampal avoidance for extensive disease 4
• Systemic HER2-targeted therapy with CNS penetration (tucatinib-based regimen or Enhertu) 4, 5

Methotrexate may be appropriate only for leptomeningeal disease, not parenchymal brain metastases 4.

Common Pitfalls to Avoid

• Do not attribute all dyspnea to PE without ruling out drug-induced pneumonitis first - this delay can be fatal 1, 2
• Do not continue Enhertu while "monitoring" respiratory symptoms - immediate discontinuation is required for any suspected ILD 1, 2
• Do not assume elevated D-dimer equals PE in cancer patients - it is often chronically elevated 2, 3
• Do not restart Enhertu after Grade ≥2 pneumonitis - permanent discontinuation is mandatory 1, 2