In an adult with HER2‑positive breast cancer and residual invasive disease after neoadjuvant chemotherapy and surgery, what is the recommended adjuvant regimen, dosing, and monitoring for trastuzumab deruxtecan (Enhertu)?

Trastuzumab Deruxtecan in Residual HER2-Positive Breast Cancer

Trastuzumab deruxtecan (T-DXd) is NOT currently approved or recommended for adjuvant treatment of residual HER2-positive breast cancer after neoadjuvant therapy; trastuzumab emtansine (T-DM1) remains the established standard of care for this indication. 1, 2

Current Standard of Care: T-DM1, Not T-DXd

Established Adjuvant Regimen for Residual Disease

• Administer trastuzumab emtansine (T-DM1) 3.6 mg/kg intravenously every 3 weeks for exactly 14 cycles in patients with any residual invasive disease (non-pCR) after completing neoadjuvant chemotherapy plus HER2-targeted therapy. 1, 3, 2
• T-DM1 reduces the risk of invasive disease-free survival events by 50% (HR 0.50) compared to continuing trastuzumab alone, representing a category 1, level A recommendation. 1, 2
• This applies to all patients with residual disease regardless of extent—including those with node-negative disease and residual tumors <1 cm. 1

Concurrent Endocrine Therapy for HR-Positive Disease

• Initiate letrozole (or another aromatase inhibitor for postmenopausal patients) concurrently with T-DM1 and continue for a total duration of 5-10 years as appropriate for adjuvant endocrine therapy. 1, 2
• Endocrine therapy is a category 1 recommendation for all hormone receptor-positive disease. 1, 3

Why T-DXd Is NOT the Current Standard

Regulatory Status

• The FDA label for trastuzumab deruxtecan (Enhertu) does not include an indication for adjuvant treatment of early breast cancer with residual disease. 4
• FDA-approved indications for T-DXd are limited to metastatic/unresectable HER2-positive breast cancer, HER2-low metastatic breast cancer, and other advanced malignancies—not the adjuvant setting. 4

Guideline Recommendations

• NCCN 2024 guidelines explicitly recommend T-DM1 (not T-DXd) for 14 cycles as the adjuvant therapy for patients with residual invasive disease after neoadjuvant therapy. 1
• The 2021 Cancer Treatment Reviews consensus and 2023 St. Gallen guidelines both establish T-DM1 as the standard based on the KATHERINE trial, with no mention of T-DXd in this setting. 1

Emerging Evidence (Not Yet Practice-Changing)

• The DESTINY-Breast05 trial (published 2025) demonstrated that T-DXd 5.4 mg/kg every 3 weeks resulted in superior invasive disease-free survival compared to T-DM1 (HR 0.47; 3-year iDFS 92.4% vs 83.7%, p<0.001) in patients with high-risk residual disease. 5
• However, this trial has not yet resulted in FDA approval or guideline incorporation for adjuvant use, and T-DXd carries a significantly higher risk of interstitial lung disease (9.6% vs 1.6% with T-DM1), including two fatal cases. 5
• The ARIADNE trial is currently investigating T-DXd in the neoadjuvant (not adjuvant) setting, with results pending. 6

Monitoring Requirements for T-DM1

Cardiac Surveillance

• Assess left ventricular ejection fraction (LVEF) at baseline, every 3 months during HER2-targeted therapy, and after completion of treatment. 3, 2, 4
• T-DM1 must never be given concurrently with anthracyclines due to cardiotoxicity risk. 2

Hematologic and Hepatic Monitoring

• Monitor complete blood counts regularly for thrombocytopenia (occurs in ~50% of patients) and neutropenia. 1
• Check liver enzymes (AST/ALT) periodically, as elevations occur in approximately 50% and 45% of patients, respectively. 1

Management of Toxicity

• Discontinuation rates due to adverse events are 18% with T-DM1 versus 2.1% with trastuzumab alone. 1
• If T-DM1 is discontinued for toxicity, complete up to 1 year of HER2-directed therapy with trastuzumab ± pertuzumab (pertuzumab if node-positive at initial staging). 1, 3

Critical Pitfalls to Avoid

Do Not Use T-DXd Off-Label in the Adjuvant Setting

• T-DXd lacks regulatory approval and guideline support for adjuvant treatment of residual disease; using it outside of a clinical trial represents off-label use without established safety or efficacy in this population. 1, 4
• The 9.6% incidence of interstitial lung disease with T-DXd (including fatal cases) requires careful risk-benefit consideration that has not been validated in the adjuvant setting. 5

Do Not Continue Trastuzumab Alone

• Continuing trastuzumab monotherapy in patients with residual disease represents a missed opportunity for a 50% reduction in recurrence risk that T-DM1 provides. 2

Do Not Re-Biopsy to Reassess HER2 Status

• Systemic therapy choice should be based on HER2 and hormone receptor status at initial presentation, not on residual disease characteristics, as exploratory analyses show benefit regardless of changes in receptor status. 1

Ensure Adequate Neoadjuvant Exposure

• Patients must have completed ≥6 cycles (16 weeks) of neoadjuvant chemotherapy containing ≥9 weeks of taxane-based therapy and 9 weeks of trastuzumab to be eligible for the T-DM1 strategy validated in KATHERINE. 1

Completion of HER2-Targeted Therapy for pCR

If Pathologic Complete Response Is Achieved

• Complete up to 1 year total of trastuzumab therapy (including neoadjuvant cycles), which may be given concurrently with radiation and endocrine therapy. 1, 3
• If the patient was node-positive at initial staging, continue trastuzumab plus pertuzumab to complete 1 year of dual HER2 blockade. 1, 3
• This represents a category 1 recommendation for patients achieving pCR. 1