What is the next step in treatment for a patient with HER2 (Human Epidermal growth factor Receptor 2) positive metastatic breast cancer, who has a history of carcinoma of the breast with residual invasive disease post-mastectomy, and has been previously treated with 10 cycles of trastuzumab (Trastuzumab) and Neoadjuvant Chemotherapy (NACT)?

Treatment for HER2-Positive Metastatic Breast Cancer After Trastuzumab Failure

You should initiate trastuzumab deruxtecan (T-DXd) 5.4 mg/kg IV every 3 weeks as second-line therapy, as this represents the current standard of care for HER2-positive metastatic breast cancer that has progressed after prior trastuzumab-based treatment. 1

Rationale for T-DXd as Preferred Second-Line Therapy

• The 2022 ASCO guideline update provides a strong recommendation (high evidence quality) that if a patient's HER2-positive advanced breast cancer has progressed during or after first-line HER2-targeted therapy and the patient has not received T-DXd, clinicians should recommend T-DXd as second-line treatment 1

• T-DXd demonstrated superior progression-free survival compared to T-DM1 in the DESTINY-Breast03 trial, with median PFS of 28.8 months versus 6.8 months (HR 0.28; 95% CI 0.22-0.37; P<0.001) 2

• This patient's clinical scenario—receiving 10 cycles of trastuzumab post-mastectomy followed by metastatic recurrence—indicates trastuzumab resistance, making T-DXd the evidence-based choice 1

Treatment Algorithm Based on Prior Exposure

Since this patient completed trastuzumab-based adjuvant treatment ≤12 months before developing metastatic disease, you should follow second-line HER2-targeted therapy recommendations rather than restarting first-line therapy 1

Key decision point: The timing of recurrence determines treatment sequencing:

• ≤12 months after completing adjuvant trastuzumab = treat as second-line (use T-DXd) 1
• >12 months after completing adjuvant trastuzumab = treat as first-line (use trastuzumab + pertuzumab + taxane) 1

Alternative if T-DXd is Unavailable or Contraindicated

If T-DXd cannot be used (e.g., pre-existing interstitial lung disease), then T-DM1 3.6 mg/kg IV every 3 weeks should be offered as the alternative second-line option 1, 2, 3

The FDA label for T-DM1 specifically indicates its use for patients with HER2-positive metastatic breast cancer who previously received trastuzumab and a taxane, and who either received prior therapy for metastatic disease or developed disease recurrence during or within six months of completing adjuvant therapy 3

Treatment Duration and Monitoring

• Continue T-DXd until disease progression or unacceptable toxicity 1, 2
• Do not stop HER2-targeted therapy when/if chemotherapy is discontinued—the HER2-targeted agent should continue indefinitely until progression 1

Third-Line Planning for Future Progression

When planning ahead for potential third-line therapy after T-DXd progression:

• Tucatinib + trastuzumab + capecitabine is the preferred third-line regimen, particularly if CNS metastases develop, as this combination increases 1-year PFS/OS in heavily pre-treated patients with metastatic disease and CNS involvement 1, 4

• Alternative third-line options include lapatinib + capecitabine, or other combinations of chemotherapy with trastuzumab 1

Special Consideration: Hormone Receptor Status

If this patient's tumor is hormone receptor-positive (ER+ or PR+), you have two strategic options, though HER2-targeted therapy plus chemotherapy remains preferred 1:

1. Standard approach: T-DXd alone (preferred for most patients) 1
2. Selected cases only: Endocrine therapy plus trastuzumab or lapatinib may be considered in highly selected patients with low disease burden, significant comorbidities, or long disease-free interval 1

However, the ASCO guideline emphasizes that the majority of patients should receive chemotherapy plus HER2-targeted therapy regardless of hormone receptor status 1

Critical Safety Monitoring for T-DXd

• Contraindication: Do not use T-DXd in patients with pre-existing interstitial lung disease 2
• Monitor closely for interstitial lung disease/pneumonitis during treatment, as this is a serious potential adverse effect 2
• Assess cardiac function before and during treatment, as with all HER2-targeted therapies 3

Common Pitfall to Avoid

Do not restart first-line therapy (trastuzumab + pertuzumab + taxane) in this patient, as the recurrence occurred during or shortly after completing trastuzumab-based adjuvant therapy, indicating trastuzumab resistance 1. The evidence clearly directs you to second-line therapy with T-DXd in this scenario.