What is the primary treatment for estrogen receptor (ER) negative, progesterone receptor (PR) negative, human epidermal growth factor receptor 2 (HER2) positive breast cancer?

Treatment of ER-Negative, PR-Negative, HER2-Positive Breast Cancer

For ER-negative, PR-negative, HER2-positive breast cancer, the primary treatment is HER2-targeted therapy combined with chemotherapy—specifically trastuzumab, pertuzumab, and a taxane as first-line therapy for metastatic disease, or neoadjuvant/adjuvant therapy for early-stage disease. 1

First-Line Treatment for Metastatic Disease

Clinicians should recommend the combination of trastuzumab, pertuzumab, and a taxane for first-line treatment, unless the patient has a contraindication to taxanes. 1 This triple combination represents the evidence-based standard with high-quality evidence and strong recommendation strength. 1

• The taxane component should be either docetaxel (75-100 mg/m² every 3 weeks) or weekly paclitaxel (80 mg/m² for 12 weeks). 2
• Chemotherapy should continue for approximately 4-6 months or until maximal response, depending on toxicity and in the absence of progression. 1
• When chemotherapy is stopped, clinicians must continue HER2-targeted therapy; no further change in the regimen is needed until progression or unacceptable toxicities. 1

Early-Stage Disease (Neoadjuvant/Adjuvant Setting)

For locally advanced or high-risk early-stage disease (such as T3N1M0), the treatment algorithm follows a structured approach:

• Neoadjuvant chemotherapy with trastuzumab, pertuzumab, and a taxane for 3-6 cycles, followed by surgery. 2
• After surgery, postmastectomy radiation therapy is mandatory for locally advanced presentations (can be given concurrently with HER2-targeted therapy). 2
• Continue trastuzumab plus pertuzumab to complete one year of HER2-targeted therapy from the start of neoadjuvant treatment. 2, 3

Critical Pitfall to Avoid:

Do not stop HER2-targeted therapy when chemotherapy is completed—HER2-targeted therapy must continue for the full year in the adjuvant setting. 2, 3

Second-Line Treatment After Progression

If HER2-positive breast cancer has progressed during or after first-line HER2-targeted therapy, clinicians should recommend trastuzumab emtansine (T-DM1) as second-line treatment. 1 This recommendation is based on high-quality evidence with strong recommendation strength. 1

Third-Line and Beyond

If disease has progressed during or after second-line or greater HER2-targeted therapy, clinicians should recommend third-line or greater HER2-targeted therapy-based treatment. 1 Options include:

• Trastuzumab deruxtecan (T-DXd) if not previously administered 1
• Tucatinib plus trastuzumab plus capecitabine, particularly for patients with brain metastases (52% reduction in risk of disease progression or death, p < 0.001) 1
• Pertuzumab if not previously received 1

Treatment Sequencing Considerations:

For patients with predominantly CNS disease, current guidance suggests tucatinib, trastuzumab, and capecitabine combination could follow disease progression, with T-DXd potentially used after this combination. 1 In contrast, T-DXd may be initially preferred in patients with predominantly extracranial disease despite the presence of brain metastases. 1

Duration and Monitoring

• Assess left ventricular ejection fraction (LVEF) prior to initiation and at regular intervals during treatment due to risk of cardiomyopathy, particularly with anthracycline-containing regimens. 3
• Verify pregnancy status of females of reproductive potential prior to initiation due to embryo-fetal toxicity risks. 3
• HER2-targeted therapy can continue until time of progression or unacceptable toxicities. 1

Recurrence After Adjuvant Therapy

The timing of recurrence determines treatment approach:

• If a patient finished trastuzumab-based adjuvant treatment ≤12 months before recurrence, follow second-line HER2-targeted therapy-based treatment recommendations. 1
• If a patient finished trastuzumab-based adjuvant treatment >12 months before recurrence, follow first-line HER2-targeted therapy-based treatment recommendations. 1

Key Contraindications

HER2-targeted therapy is recommended for all patients with HER2-positive disease except for those with clinical congestive heart failure or significantly compromised left ventricular ejection fraction, who should be evaluated on a case-by-case basis. 1, 3 Patients with uncontrolled hypertension (diastolic >100 mm Hg or systolic >200 mm Hg) require careful evaluation. 3

Why Endocrine Therapy Is NOT Recommended

Unlike hormone receptor-positive/HER2-positive disease where endocrine therapy may be considered in selected cases, ER-negative/PR-negative/HER2-positive breast cancer lacks hormone receptor expression, making endocrine therapy ineffective and inappropriate. 1 The absence of estrogen and progesterone receptors means these tumors will not respond to hormonal manipulation, and treatment must focus exclusively on HER2-targeted therapy combined with chemotherapy.