What does a HER2 (Human Epidermal growth factor Receptor 2) 2+ score mean in breast cancer and how is it treated?

HER2 2+ in Breast Cancer: Definition and Treatment

A HER2 2+ score by immunohistochemistry (IHC) is an equivocal result that requires reflex testing with in situ hybridization (ISH) to determine true HER2 status—only if ISH shows gene amplification is the cancer classified as HER2-positive and eligible for HER2-targeted therapy. 1

What HER2 2+ Means

HER2 2+ is NOT a diagnosis by itself—it is an intermediate, indeterminate result that mandates further testing. 1

• HER2-positive breast cancer is definitively defined as either:

  • IHC 3+, OR
  • IHC 2+ WITH positive ISH (showing ERBB2 gene amplification) 1

• The 2+ score indicates equivocal HER2 protein expression on the tumor cell surface 1

• Without ISH confirmation, you cannot determine if the patient has HER2-positive disease and therefore cannot make treatment decisions 1

• If ISH is negative (no gene amplification), the tumor is classified as HER2-negative despite the 2+ IHC score 1

• If ISH is positive (gene amplification present), the tumor is HER2-positive and should be treated as such 1

Treatment Approach (When HER2 2+ with Positive ISH = HER2-Positive Disease)

First-Line Treatment for Metastatic/Advanced Disease

The standard first-line treatment is trastuzumab + pertuzumab + taxane (docetaxel or paclitaxel) for patients who are chemotherapy candidates. 1, 2

• Chemotherapy should continue for 4-6 months or until maximal response 2

• HER2-targeted therapy (trastuzumab + pertuzumab) must continue until disease progression or unacceptable toxicity—do NOT stop when chemotherapy ends 2

• For hormone receptor-positive/HER2-positive disease, after completing chemotherapy, maintenance should consist of trastuzumab + pertuzumab + endocrine therapy 1

• For hormone receptor-negative/HER2-positive disease, maintenance is trastuzumab + pertuzumab alone 1

Second-Line Treatment

Trastuzumab deruxtecan (T-DXd) is the preferred second-line agent based on the most recent evidence 2

• If T-DXd is unavailable, trastuzumab emtansine (T-DM1) should be offered 2

Third-Line and Beyond

Treatment sequencing becomes more complex, but options include: 2

• T-DM1 if not previously received 2
• Pertuzumab-containing regimens if not previously used (though evidence is limited) 2
• Lapatinib + capecitabine 2
• Other chemotherapy combinations with trastuzumab 2
• Lapatinib + trastuzumab 2
• Hormonal therapy (only in hormone receptor-positive disease) 2

Adjuvant Treatment for Early-Stage Disease

For high-risk early breast cancer (e.g., T3N1M0 HER2-positive): 3

• Neoadjuvant chemotherapy with trastuzumab + pertuzumab + taxane for 3-6 cycles 3
• Followed by surgery and radiation therapy 3
• If pathologic complete response is achieved: continue trastuzumab + pertuzumab to complete one year of HER2-targeted therapy 3
• If residual disease remains: switch to trastuzumab deruxtecan as adjuvant therapy 3

Critical Considerations

Prior Adjuvant Therapy Influences Treatment Selection

• If disease recurs >12 months after completing trastuzumab-based adjuvant therapy: follow first-line metastatic treatment recommendations 2

• If disease recurs ≤12 months after completing adjuvant therapy: follow second-line treatment recommendations (drug rechallenge is not appropriate) 2

Hormone Receptor Status Matters

For patients with both hormone receptor-positive AND HER2-positive disease, treatment options include: 2

• HER2-targeted therapy + chemotherapy (strongest evidence, preferred approach) 2
• Endocrine therapy + trastuzumab or lapatinib (selected cases only) 2
• Endocrine therapy alone (only in highly selected cases with low disease burden, significant comorbidities, or long disease-free interval) 2

Common Pitfalls to Avoid

Do not treat HER2 2+ as HER2-positive without ISH confirmation—this is the single most critical error. 1

Do not discontinue HER2-targeted therapy when chemotherapy ends—it must continue until disease progression. 2

Do not fail to re-biopsy accessible metastatic lesions, as HER2 status can change during disease progression. 2

Do not omit pertuzumab from first-line regimens—the combination of trastuzumab + pertuzumab + taxane is the evidence-based standard. 3