What are the treatment options for a female adult patient with HER2-positive (human epidermal growth factor receptor 2-positive) breast cancer, previously treated with trastuzumab (Herceptin, trastuzumab) and other standard therapies?

Treatment Options for HER2-Positive Breast Cancer After Trastuzumab

For patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and standard therapies, trastuzumab deruxtecan (T-DXd) is the preferred second-line treatment, demonstrating superior progression-free survival compared to trastuzumab emtansine (T-DM1), with a median PFS of 16.4 months and objective response rate of 79.7%. 1, 2

Treatment Sequencing Algorithm

Second-Line Treatment (After Progression on Trastuzumab + Pertuzumab + Taxane)

• Trastuzumab deruxtecan (T-DXd) 5.4 mg/kg IV every 3 weeks is the standard of care based on DESTINY-Breast03 trial results showing median PFS of 28.8 months versus 6.8 months with T-DM1 (HR 0.28; 95% CI 0.22-0.37; P<0.001). 1, 2

• T-DM1 should only be used when T-DXd is unavailable or contraindicated (e.g., patients with pre-existing interstitial lung disease). 1

• The 12-month survival rate is 94.1% with T-DXd versus 85.9% with T-DM1, though overall survival data remain immature. 2

Third-Line Treatment (After Progression on T-DXd)

The tucatinib + trastuzumab + capecitabine combination is the preferred third-line regimen following second-line T-DXd, as recommended by Austrian, Canadian, French, and Italian guidelines. 1

• This combination is FDA-approved after at least two prior anti-HER2 regimens and shows particular efficacy in patients with brain metastases. 1, 3

• Real-world data demonstrate median overall survival of 13-14 months with tucatinib-based therapy post-T-DXd. 1

• A 2024 consensus of 80 European breast cancer experts (98% agreement) supports the sequence: trastuzumab/pertuzumab → T-DXd → tucatinib/trastuzumab/capecitabine. 1

Alternative Third-Line Options

If tucatinib is unavailable or the patient has not received certain agents:

• T-DM1 if not previously administered 1
• Neratinib + capecitabine after two or more prior anti-HER2 regimens (FDA-approved) 4
• Lapatinib + capecitabine 1
• Pertuzumab if not previously received (limited evidence) 1

Fourth-Line and Beyond

• Lapatinib + chemotherapy combinations 1
• For hormone receptor-positive disease: endocrine therapy + HER2-targeted therapy or endocrine therapy alone 1
• Margetuximab + chemotherapy (FDA-approved but not EMA-approved) 1

Critical Safety Considerations for T-DXd

Interstitial lung disease (ILD)/pneumonitis is the most significant toxicity requiring vigilant monitoring:

• ILD occurs in 10.5-13.6% of patients receiving T-DXd 5, 2
• Grade 1-2 ILD: 10.9% of patients 6
• Grade 5 (fatal) ILD: 2.2% of patients 6
• T-DXd is contraindicated in patients with pre-existing interstitial lung disease 1

Other common adverse events with T-DXd:

• Neutropenia (grade ≥3 in 20.7%) 6
• Anemia (grade ≥3 in 8.7%) 6
• Nausea (grade ≥3 in 7.6%) 6
• Overall grade ≥3 adverse events: 45.1% 2

Special Population: Hormone Receptor-Positive/HER2-Positive Disease

For patients with both HR-positive and HER2-positive disease:

• Standard first-line therapy (trastuzumab + pertuzumab + taxane) remains preferred 1, 7
• Endocrine therapy + HER2-targeted therapy may be considered in highly selected patients with low disease burden, significant comorbidities, or long disease-free interval 1, 7
• Endocrine therapy should be added after chemotherapy completion or at progression 7

Treatment Duration

• HER2-targeted therapy should continue until disease progression or unacceptable toxicity, not just until chemotherapy completion 1, 7
• Chemotherapy duration: 4-6 months or until maximal response 1, 7

Emerging First-Line Data

Very recent evidence (2025) shows trastuzumab deruxtecan + pertuzumab as first-line therapy demonstrates superior efficacy to standard THP:

• Median PFS: 40.7 months versus 26.9 months (HR 0.56; 95% CI 0.44-0.71; P<0.00001) 8
• Objective response rate: 85.1% versus 78.6% 8
• This may change future first-line recommendations pending guideline updates 8

Common Pitfalls to Avoid

• Do not discontinue HER2-targeted therapy when chemotherapy ends—continue until progression 1, 7
• Do not use T-DXd in patients with pre-existing interstitial lung disease—use T-DM1 instead 1
• Do not fail to monitor for pulmonary symptoms—ILD can be fatal if not detected early 5, 6, 2
• Re-biopsy accessible metastatic lesions to confirm HER2 status, as receptor status can change during disease progression 7