What is the next best treatment option for a patient with stage 4 (Stage IV) breast cancer who is HER2-positive (Human Epidermal growth factor Receptor 2-positive) and hormone receptor-positive, and has progressed on Trastuzumab (Herceptin) and Paclitaxel (Taxol), as well as TCH (Docetaxel, Carboplatin, and Trastuzumab)?

Second-Line Treatment for HER2-Positive Stage IV Breast Cancer After Progression on Trastuzumab and Taxane-Based Therapy

Trastuzumab deruxtecan (T-DXd) is the preferred second-line therapy for this patient who has progressed on trastuzumab and paclitaxel-based regimens. 1

Treatment Algorithm for Second-Line Therapy

Primary Recommendation: Trastuzumab Deruxtecan

• T-DXd 5.4 mg/kg IV every 3 weeks should be initiated as the standard second-line treatment after progression on trastuzumab and taxane therapy, based on Level I, Grade A evidence from ESMO guidelines 1
• This recommendation is supported by the DESTINY-BREAST03 trial, which demonstrated median PFS of 28.8 months with T-DXd versus 6.8 months with T-DM1 (HR 0.28; 95% CI 0.22-0.37; P<0.001) 2, 3
• T-DXd showed a trend toward improved overall survival compared to T-DM1, establishing it as the preferred agent in this setting 3

Alternative Second-Line Option: T-DM1

• T-DM1 should only be used when T-DXd is unavailable or contraindicated (particularly in patients with pre-existing interstitial lung disease) 1, 2
• T-DM1 remains a Level I, Grade A evidence-based option with ESMO-MCBS score of 4 1

Special Consideration for Brain Metastases

• For patients with brain metastases, tucatinib + capecitabine + trastuzumab or T-DXd may be used in the second-line setting 1
• This represents a Level II, Grade A recommendation for selected patients with CNS involvement 1

Critical Principle: Continue HER2 Blockade

• Continued HER2 blockade beyond disease progression is considered standard clinical practice 1, 2
• Multiple studies demonstrate benefit from continuing HER2-targeted therapy after progression on trastuzumab-containing regimens 2
• If anti-HER2 therapies are exhausted or unavailable, sequential trastuzumab-based strategies in combination with different chemotherapy partners should be considered 1

Third-Line and Beyond Treatment Options

If T-DXd Was Used Second-Line:

• Tucatinib + capecitabine + trastuzumab is the preferred third-line regimen following second-line T-DXd (Level I, Grade A; ESMO-MCBS score: 3) 1, 2
• T-DM1 remains an option if not previously used (Level I, Grade A; ESMO-MCBS score: 4) 1

If T-DM1 Was Used Second-Line:

• Tucatinib + capecitabine + trastuzumab 1
• T-DXd (Level III, Grade A; ESMO-MCBS score: 2) 1
• Lapatinib-based combinations (preferably with capecitabine or trastuzumab) 1

Later-Line Options:

• Lapatinib + capecitabine improves time to progression (8.4 months vs 4.4 months with capecitabine alone; HR 0.49; P<0.001) 2
• Lapatinib + trastuzumab (without chemotherapy) shows improved PFS (12 weeks vs 8.1 weeks; P=0.008) and OS benefit (median 14 months vs 9.5 months; HR 0.74; P=0.026) 2
• Neratinib + capecitabine (Level I, Grade C; FDA approved, not EMA approved) 1
• Margetuximab (Level I, Grade B; ESMO-MCBS score: 2; FDA approved, not EMA approved) 1

Hormone Receptor-Positive Disease Considerations

Since this patient is hormone receptor-positive:

• After completing chemotherapy in second-line, consider adding endocrine therapy to continued HER2-targeted therapy 1
• For premenopausal women, ovarian function suppression should also be added 1
• This maintenance strategy is reasonable although not studied in randomized trials 1

Critical Safety Monitoring

Cardiac Monitoring:

• Assess LVEF prior to initiation and every 12 weeks during treatment 4
• Withhold T-DXd and trastuzumab for at least 3 weeks if LVEF decreases to <40% or 40-45% with ≥10-point fall below baseline 4
• Resume therapy when LVEF recovers to >45% or 40-45% with <10-point fall from baseline 4

Pulmonary Monitoring for T-DXd:

• T-DXd is contraindicated in patients with pre-existing interstitial lung disease 2
• Monitor closely for signs of interstitial lung disease/pneumonitis during treatment 2, 3

Common Pitfalls to Avoid

• Do not discontinue HER2-targeted therapy after chemotherapy completion—continue until disease progression or unacceptable toxicity 1, 5
• Do not use T-DM1 as preferred second-line when T-DXd is available, as T-DXd demonstrates superior outcomes 1, 2, 3
• Do not delay re-biopsy of accessible metastatic lesions to confirm HER2 status, as receptor status can change during disease progression 5
• Do not use single-agent endocrine therapy without HER2-targeted therapy in HER2-positive disease, even if hormone receptor-positive, unless cardiac contraindications exist 1