HER2-positive breast cancer

Definition

• Breast cancer with amplification of the HER2 gene and/or overexpression of the HER2 protein, a transmembrane tyrosine kinase receptor of the HER family of growth factor receptors (HER1–4).

Classification

Molecular subtypes

• Luminal A: A Luminal A carcinoma is hormone receptor-positive, HER2-negative, well-differentiated with a low Ki-67.
• Luminal B: A Luminal B carcinoma is hormone receptor-positive with a high Ki-67 or poorer grade, HER2 negative or positive.
• Triple-negative: In triple-negative breast cancer: oestrogen receptor, progesterone receptor, and HER2 are all negative.

• HER2-positive tumours may be hormone receptor-positive (luminal B subtype) or hormone receptor-negative; the latter form the HER2-positive (HER2-enriched) subtype.
• HER2-low denotes tumours with an immunohistochemical score of 1+ or 2+ without amplification on in situ hybridisation; they contain some HER2 protein but not enough to be classified as HER2-positive.
• HER2-low is a heterogeneous group, and whether it constitutes a distinct entity remains controversial.

Occurrence & epidemiology

Epidemiology

• About 15–20% of breast cancers are HER2-positive, about 40–60% are HER2-low, and 20–45% show no HER2 expression (score 0).

Aetiopathogenesis

Aetiology and pathogenesis

• The HER2 gene lies on chromosome 17 (band q21); tumour tissue may have up to 25–50 gene copies, up to a 40- to 100-fold increase in protein and up to 2 million receptors on the cell surface.
• HER2 itself binds no ligand but is activated by homo- or heterodimerisation with the ligand-bound receptors HER1, HER3 and HER4, mainly switching on the MAPK and PI3K signalling pathways.
• These pathways promote cell proliferation, invasion and angiogenesis and protect cells against apoptosis.

Clinical features

More facts from the study questions

• The Elston and Ellis grading system is an established system for assessing the aggressiveness of breast carcinoma.
• It is based on the histological evaluation of three criteria: tubule formation, nuclear pleomorphism and mitotic rate.
• The definition of triple-negative breast carcinoma is the lack of expression of all three relevant receptors.
• It is oestrogen receptor-negative, progesterone receptor-negative and HER2-negative.
• HER2 status is primarily determined by immunohistochemistry (IHC).
• Invasive lobular carcinoma is characterised by diffuse growth and is difficult to delineate.

• HER2 positivity gives the tumour a more aggressive behaviour, with higher recurrence rates and shorter disease-free and overall survival.
• HER2-positive carcinomas tend to grow quickly, faster than tumours with less HER2 (HER2-negative or HER2-low).

Diagnosis

• HER2 status is determined on tumour tissue; only immunohistochemistry for protein expression and in situ hybridisation for gene status are clinically validated.
• A tumour is HER2-positive with an immunohistochemical score of 3+ or a score of 2+ with amplification demonstrated by in situ hybridisation; 2+ without amplification, 1+ and 0 count as HER2-negative.
• Pre-analytical and analytical factors such as tissue fixation, processing, staining technique and scoring criteria largely determine the reliability of the result.

Keep learning in the app

Further reading (selection)

1. HER2 expression in breast cancer: evidence gaps and challenges (NPJ Precis Oncol 2025, PubMed Central)
2. HER2/PI3K/AKT pathway in HER2-positive breast cancer: A review (Medicine (Baltimore) 2024, PubMed Central)
3. National Cancer Institute: Breast Cancer Biomarkers
4. DocCheck Flexikon, Mammakarzinom

Cross-references