What does it mean to have estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2 (HER2) negative breast cancer?

Understanding ER-Positive/HER2-Negative Breast Cancer

Estrogen receptor-positive (ER+) and HER2-negative breast cancer means the tumor cells have receptors that bind to estrogen (which fuels their growth) but lack overexpression of the HER2 protein—this is the most common breast cancer subtype, representing approximately 70% of all cases, and is highly responsive to hormone-blocking therapies. 1

What These Markers Mean Biologically

Estrogen Receptor Positive (ER+)

• ER+ tumors have cancer cells with nuclear receptors that bind estrogen, which stimulates tumor growth. 1
• Tumors with 1-100% of cells showing ER staining by immunohistochemistry are considered ER-positive and eligible for endocrine therapy. 1
• Important caveat: ER-low-positive tumors (1-10% staining) are heterogeneous and often behave more like ER-negative cancers, requiring individualized assessment of endocrine therapy benefits. 1

HER2-Negative Status

• HER2-negative means the tumor lacks overexpression of the HER2 protein (IHC score 0,1+, or 2+ without gene amplification), distinguishing it from the more aggressive HER2-positive subtype. 1
• Approximately 80-85% of breast cancers are HER2-negative. 1
• Two-thirds of hormone receptor-positive tumors exhibit HER2-low expression (IHC 1+ or 2+/ISH not amplified), which may have emerging therapeutic implications with newer antibody-drug conjugates. 1

Clinical Implications for Treatment

Primary Treatment Strategy

ER+/HER2-negative breast cancer is treated primarily with endocrine (hormone) therapy rather than HER2-targeted agents, making it fundamentally different from HER2-positive disease. 1

Endocrine Therapy Options

• Tamoxifen decreases annual odds of recurrence by 41% and death by 31% in ER-positive breast cancer, regardless of age, menopausal status, or lymph node involvement. 1
• For postmenopausal women, aromatase inhibitors (letrozole, anastrozole, exemestane) are preferred over tamoxifen. 2
• For premenopausal women, tamoxifen is standard, with ovarian function suppression plus aromatase inhibitor considered for high-risk patients. 1, 2
• Endocrine therapy should be given for 5-10 years in the adjuvant setting. 1, 2

Role of Chemotherapy

• Chemotherapy decisions should be guided by genomic testing (21-gene recurrence score/Oncotype DX) or clinical-pathologic features, as high recurrence scores gain less benefit from endocrine therapy alone. 1, 2
• When both chemotherapy and endocrine therapy are indicated, chemotherapy should be given first, followed by sequential endocrine therapy. 1

Prognosis and Behavior

Generally Favorable Outlook

• ER+/HER2-negative breast cancer typically has a more favorable prognosis than ER-negative or HER2-positive subtypes, with excellent response rates to endocrine therapy. 3, 4, 5
• The favorable toxicity profile of endocrine therapies allows for prolonged treatment with manageable side effects. 1

Long-Term Considerations

• Endocrine resistance can develop over time in the metastatic setting, requiring sequential endocrine therapies or combination with targeted agents like CDK4/6 inhibitors. 3, 4, 5
• The risk of recurrence extends for many years, necessitating prolonged endocrine therapy and surveillance. 6

Critical Pitfalls to Avoid

• Never prescribe estrogen hormone replacement therapy (HRT) to patients with ER+ breast cancer, as it is absolutely contraindicated due to risk of cancer recurrence. 6
• Do not assume all ER-positive tumors behave identically—ER-low-positive (1-10%) tumors may behave like ER-negative disease and require different treatment considerations. 1
• HER2-negative status does not eliminate the need for endocrine therapy—the ER-positive status is the primary driver of treatment decisions. 1
• Menopausal status must be accurately assessed before selecting endocrine therapy, as aromatase inhibitors can stimulate ovarian function in premenopausal women. 1