What is the primary treatment recommendation for patients with Her2/neu (human epidermal growth factor receptor 2) positive breast cancer?

Primary Treatment for HER2-Positive Breast Cancer

For patients with HER2-positive advanced breast cancer, the recommended first-line treatment is the combination of trastuzumab, pertuzumab, and a taxane, unless contraindicated. 1, 2

First-Line Treatment

• The combination of trastuzumab, pertuzumab, and a taxane is the standard first-line treatment for HER2-positive advanced breast cancer, supported by high-quality evidence 1, 2
• Pertuzumab (PERJETA) is FDA-approved for use in combination with trastuzumab and docetaxel for treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease 3
• Chemotherapy should continue for approximately 4-6 months or until maximal response, while HER2-targeted therapy should be continued until disease progression or unacceptable toxicity 1
• For patients who completed trastuzumab-based adjuvant treatment more than 12 months before recurrence, first-line HER2-targeted therapy recommendations should be followed 2
• For patients who completed trastuzumab-based adjuvant treatment less than or equal to 12 months before recurrence, second-line HER2-targeted therapy recommendations should be followed 2

Second-Line Treatment

• If disease progresses during or after first-line HER2-targeted therapy, trastuzumab emtansine (T-DM1) is recommended as second-line treatment 1
• T-DM1 (KADCYLA) is FDA-approved for patients with HER2-positive metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination 4
• Recent evidence suggests trastuzumab deruxtecan (T-DXd) may be preferred over T-DM1 in the second-line setting based on improved progression-free survival 5

Third-Line and Beyond Treatment

• For progression after second-line therapy, if the patient has not received T-DM1, it should be offered 1
• If the patient has not received pertuzumab, it may be considered, though evidence for this approach is limited 1
• For patients who have already received both pertuzumab and T-DM1, third-line options include lapatinib plus capecitabine, other chemotherapy combinations with trastuzumab, lapatinib plus trastuzumab, or hormonal therapy (in hormone receptor-positive disease) 1

Special Considerations for Hormone Receptor-Positive and HER2-Positive Disease

• For patients with both hormone receptor-positive and HER2-positive disease, clinicians may recommend one of the following approaches:
  • HER2-targeted therapy plus chemotherapy (strongest evidence) 1
  • Endocrine therapy plus trastuzumab or lapatinib (in selected cases) 1
  • Endocrine therapy alone (only in selected cases with low disease burden, significant comorbidities, or long disease-free interval) 1
• When starting with HER2-targeted therapy plus chemotherapy, endocrine therapy may be added when chemotherapy ends 2

Common Pitfalls and Caveats

• Failure to re-biopsy accessible metastatic lesions to confirm HER2 status, as receptor status can change during disease progression 6
• Discontinuing HER2-targeted therapy prematurely after chemotherapy completion instead of continuing until disease progression 2, 6
• Using trastuzumab in combination with anthracyclines outside of clinical trials due to high risk of cardiac toxicity 6
• Inadequate cardiac monitoring before and during trastuzumab therapy due to risk of cardiotoxicity 6
• For patients with HER2-positive disease who have cardiac contraindications to trastuzumab-based regimens, treatment should be evaluated on a case-by-case basis 1

Emerging Therapies

• Newer HER2-targeted therapies including tucatinib, neratinib, and margetuximab are showing promise in later-line settings, particularly for patients with brain metastases 7, 8
• T-DXd has demonstrated significant efficacy in the second-line setting and may become the preferred agent in this setting based on recent clinical trial results 5