What is the recommended treatment approach for patients with HER2 (Human Epidermal growth factor Receptor 2) positive breast cancer?

HER2-Positive Breast Cancer: Treatment Implications and Management

HER2-positive breast cancer, representing approximately 15-20% of all breast cancers, requires aggressive HER2-targeted therapy combined with chemotherapy to improve survival and quality of life, with specific treatment sequences depending on disease stage and prior therapy exposure. 1, 2

Prognostic Significance

HER2-positive breast cancer historically conferred a poor prognosis with aggressive behavior and high recurrence rates. 2, 3 However, the development of HER2-targeted therapies has fundamentally transformed this disease into one with significantly improved outcomes, including median survival approaching 5 years in metastatic disease. 3

First-Line Treatment for Advanced/Metastatic Disease

The standard first-line regimen is trastuzumab + pertuzumab + taxane (docetaxel or paclitaxel), which should be used unless contraindications to taxanes exist. 1, 4

• Chemotherapy should continue for 4-6 months or until maximal response, depending on toxicity and absence of progression. 1
• HER2-targeted therapy (trastuzumab + pertuzumab) must continue beyond chemotherapy completion until disease progression or unacceptable toxicity. 1, 4
• A critical pitfall is discontinuing HER2-targeted therapy when chemotherapy ends—this is incorrect and reduces efficacy. 4

Special Consideration for Adjuvant Treatment Recurrence

The timing of recurrence after adjuvant trastuzumab determines treatment approach:

• If recurrence occurs >12 months after completing trastuzumab-based adjuvant therapy: Use first-line therapy (trastuzumab + pertuzumab + taxane). 1, 4
• If recurrence occurs ≤12 months after completing trastuzumab-based adjuvant therapy: Skip to second-line therapy recommendations. 1, 4

Second-Line Treatment

Trastuzumab deruxtecan (T-DXd) is now the preferred second-line therapy after progression on first-line HER2-targeted treatment. 4, 2, 5

• The DESTINY-BREAST03 trial demonstrated T-DXd significantly improved progression-free survival compared to T-DM1 (trastuzumab emtansine), with a trend toward improved overall survival. 2
• If T-DXd is unavailable, trastuzumab emtansine (T-DM1) should be offered as second-line treatment. 1, 4

Third-Line and Beyond

For patients who have not received T-DM1 in earlier lines, it should be offered. 1, 4

For patients who have already received both pertuzumab and T-DM1, third-line options include: 1

• Lapatinib + capecitabine
• Tucatinib + trastuzumab + capecitabine (particularly valuable for CNS metastases)
• Other chemotherapy combinations with trastuzumab
• Lapatinib + trastuzumab

The tucatinib-based regimen is particularly important as it demonstrates survival benefits in patients with and without CNS involvement. 5

Hormone Receptor-Positive and HER2-Positive Disease

For patients with dual-positive (ER+/PR+ and HER2+) disease, treatment options depend on clinical scenario: 1

Preferred approach: HER2-targeted therapy + chemotherapy (strongest evidence). 1

Alternative for selected patients:

• Endocrine therapy + trastuzumab or lapatinib (moderate evidence). 1
• Endocrine therapy alone only in highly selected cases with low disease burden, significant comorbidities contradicting HER2-targeted therapy (such as congestive heart failure), or long disease-free interval. 1

When starting with HER2-targeted therapy plus chemotherapy, endocrine therapy may be added when chemotherapy ends or when cancer progresses. 1

Critical Safety Monitoring

Cardiac function must be evaluated prior to and during treatment, as HER2-targeted therapy can cause left ventricular dysfunction and congestive heart failure. 1, 6, 7

• Patients with clinical congestive heart failure or significantly compromised left ventricular ejection fraction should be evaluated case-by-case. 1
• T-DM1 carries additional risks including hepatotoxicity requiring liver function monitoring before each dose. 7

Infusion-related reactions and hypersensitivity can occur with all HER2-targeted antibodies. 6, 7

• Monitor during and after infusion; slow or interrupt infusion if significant reactions occur.
• Permanently discontinue for life-threatening reactions.

Brain Metastases Considerations

Brain metastases occur in up to 50% of patients with HER2-positive metastatic breast cancer. 1

For patients with active brain metastases, tucatinib + trastuzumab + capecitabine represents a particularly suitable option given its CNS penetration. 2, 5

Common Pitfalls to Avoid

• Stopping HER2-targeted therapy when chemotherapy is completed—HER2-targeted agents must continue until progression. 1, 4
• Omitting pertuzumab from first-line regimen—the triple combination (trastuzumab + pertuzumab + taxane) is the evidence-based standard with high-quality evidence. 1, 4
• Failing to re-biopsy accessible metastatic lesions—HER2 status can change during disease progression. 4
• Using inappropriate treatment sequencing after adjuvant therapy—timing of recurrence dictates whether to use first-line or second-line recommendations. 1, 4

Embryo-Fetal Toxicity Warning

All HER2-targeted therapies can cause embryo-fetal death and birth defects. 6, 7

Patients must be counseled about these risks and the need for effective contraception during and after treatment.