What are the next steps for a patient with HER2-positive breast cancer that has progressed after Taxane (T), Carboplatin (C), and Herceptin (H) (Trastuzumab) chemotherapy?

Management of HER2-Positive Breast Cancer After TCH Progression

For HER2-positive metastatic breast cancer that has progressed after first-line TCH (taxane, carboplatin, trastuzumab), trastuzumab deruxtecan (T-Dxd) is the preferred second-line treatment. 1

Second-Line Treatment Algorithm

Primary Recommendation: Trastuzumab Deruxtecan

• Trastuzumab deruxtecan should be offered as the standard second-line therapy after progression on taxane and trastuzumab-based regimens 1
• This recommendation is supported by high-quality evidence from ASCO guidelines (2022) and ESMO guidelines (2021), both designating T-Dxd as the preferred option in this setting 1
• T-Dxd demonstrates superior efficacy compared to T-DM1 in the second-line setting based on the most recent evidence 1

Alternative if T-Dxd Unavailable: T-DM1

• If trastuzumab deruxtecan is not available, T-DM1 (trastuzumab emtansine) remains an acceptable second-line option 1
• T-DM1 has established efficacy after progression on taxane and trastuzumab with high-quality evidence (ESMO-MCBS score: 4) 1

Special Consideration: Brain Metastases

• For patients with brain metastases, tucatinib plus capecitabine plus trastuzumab or trastuzumab deruxtecan may be prioritized in the second-line setting 1
• This combination has demonstrated specific activity in CNS disease based on the HER2CLIMB trial 1

Timing Considerations Based on Prior Adjuvant Therapy

Recent Adjuvant Completion (≤12 months)

• If the patient completed trastuzumab-based adjuvant treatment ≤12 months before recurrence, follow second-line therapy recommendations immediately 1, 2
• Do not restart first-line therapy; proceed directly to T-Dxd or T-DM1 1, 2

Distant Adjuvant Completion (>12 months)

• If recurrence occurs >12 months after completing adjuvant trastuzumab, restarting first-line therapy (pertuzumab, trastuzumab, taxane) is appropriate 1, 2
• This represents a treatment-free interval sufficient to consider the disease as newly recurrent rather than refractory 1

Hormone Receptor Status Considerations

HR-Positive Disease

• For hormone receptor-positive, HER2-positive disease, continue HER2-targeted therapy as the backbone 1
• Endocrine therapy may be added to HER2-targeted agents in selected cases with non-visceral or asymptomatic visceral disease 1
• However, HER2-targeted therapy plus chemotherapy remains the preferred approach for most patients with progressive disease 1

HR-Negative Disease

• For hormone receptor-negative disease, HER2-targeted therapy with chemotherapy is the standard approach 1
• No role for endocrine therapy in this population 1

Third-Line and Beyond Treatment Options

After Second-Line Progression

• The most active third-line options include tucatinib-capecitabine-trastuzumab, trastuzumab deruxtecan (if not used second-line), or T-DM1 (if not used second-line) 1
• Choice depends on prior second-line therapy, patient characteristics, toxicity profile, and drug availability 1

Later-Line Options

• Lapatinib-based combinations (with capecitabine, trastuzumab, or endocrine therapy) represent evidence-based options in later lines 1
• Neratinib and margetuximab are FDA-approved options for heavily pretreated patients, though not EMA-approved 1

Critical Principle: Continued HER2 Blockade

Continue anti-HER2 therapy beyond progression as the standard of care for HER2-positive disease 1

• Even after exhausting multiple HER2-targeted agents, trastuzumab should be continued with subsequent chemotherapy lines 1
• This principle is supported by evidence showing continued benefit from HER2 blockade even in resistant disease 1

Common Pitfalls to Avoid

Do Not Stop HER2-Targeted Therapy

• Never discontinue all HER2-targeted therapy when disease progresses 1
• Continue HER2 blockade with subsequent lines of chemotherapy, even if switching the specific HER2-targeted agent 1

Do Not Skip T-Dxd in Second-Line

• Do not proceed to third-line options without offering T-Dxd if the patient has not received it 1
• T-Dxd represents the highest quality evidence for second-line therapy and should not be bypassed 1

Avoid Anthracyclines with Trastuzumab

• Never combine trastuzumab with anthracyclines concurrently due to 27% cardiac dysfunction risk 2, 3
• If anthracyclines are necessary, allow up to 7 months washout after stopping trastuzumab due to its long half-life 3

Monitor Cardiac Function

• Evaluate left ventricular ejection fraction (LVEF) every 3 months during HER2-targeted therapy 2, 3
• Permanently discontinue trastuzumab if congestive heart failure develops or persistent LVEF decline occurs 2, 3

Emerging Considerations

Immunotherapy Combinations

• Pembrolizumab plus trastuzumab has shown objective responses in PD-L1-positive, trastuzumab-resistant HER2-positive advanced breast cancer 1
• This remains investigational but represents a potential future option for refractory disease 1

Novel HER2-Targeted Agents

• Several novel HER2-targeted conjugates are in development, including trastuzumab duocarmazine 1
• These agents may provide additional options for patients who have exhausted standard therapies 1