What is HER2?
HER2 (human epidermal growth factor receptor 2) is a transmembrane tyrosine kinase receptor encoded by the ERBB2 oncogene that, when amplified or overexpressed, drives aggressive tumor growth and serves as a critical therapeutic target in multiple cancers. 1
Molecular Biology
HER2 is a member of the epidermal growth factor receptor (EGFR) family, which includes four structurally related receptors (HER1/EGFR, HER2, HER3, and HER4) that regulate normal cell growth and differentiation 1
The ERBB2 gene is located on chromosome 17q12 and encodes a 185-kd glycoprotein with tyrosine kinase activity 1, 2
Unlike other HER family members, HER2 has no known direct ligand but functions as the preferred dimerization partner for other HER receptors 3
HER2-containing heterodimers generate significantly stronger intracellular signals than other HER receptor combinations, leading to enhanced cell proliferation, survival, migration, and invasion when overexpressed 3, 4
Clinical Significance
Prevalence and Prognosis
HER2 amplification/overexpression occurs in approximately 15-20% of breast cancers, making it one of the most important molecular subtypes 1
Prior to HER2-targeted therapies, HER2-positive breast cancer was associated with significantly worse prognosis compared to HER2-negative disease, with higher rates of recurrence and mortality 1
HER2 overexpression also occurs in 10-30% of gastric/gastroesophageal cancers and has been identified in ovarian, endometrial, bladder, lung, colon, and head and neck cancers 5
Diagnostic Criteria
HER2-positive breast cancer is defined as having an immunohistochemistry (IHC) score of 3+ OR an IHC score of 2+ with positive in situ hybridization (ISH) 1
Specific thresholds include: IHC 3+ (uniform, intense membrane staining of ≥30% of invasive tumor cells), FISH result of >6 HER2 gene copies per nucleus, or FISH ratio (HER2 gene signals to chromosome 17 signals) of >2.2 1
HER2-negative is defined as: IHC 0 or 1+, FISH result of <4.0 HER2 gene copies per nucleus, or FISH ratio of <1.8 1
Therapeutic Implications
Impact on Survival
The introduction of HER2-targeted therapies has dramatically transformed outcomes, with the HERA trial demonstrating 12-year overall survival of 79% with adjuvant trastuzumab versus 73% with observation (6.5% absolute benefit) 1
In metastatic disease, the CLEOPATRA trial showed 8-year overall survival of 37% with trastuzumab, pertuzumab, and docetaxel versus 23% with trastuzumab and docetaxel alone 1
Available Therapies
Multiple HER2-targeted agents are now available, including monoclonal antibodies (trastuzumab, pertuzumab, margetuximab), tyrosine kinase inhibitors (lapatinib, neratinib, tucatinib), and antibody-drug conjugates (trastuzumab emtansine, trastuzumab deruxtecan) 1
Recent advances include trastuzumab deruxtecan for HER2-low breast cancer (IHC 1+ or 2+ without amplification), expanding treatment options beyond traditional HER2-positive disease 1, 6
Testing Requirements
ASCO/College of American Pathologists guidelines mandate that HER2 should be evaluated in every invasive breast cancer, either at diagnosis or recurrence, to guide therapy 2
Testing should be performed in CAP-accredited laboratories with 95% concordance with validated tests for positive and negative values 1
Both IHC and FISH/ISH methods are acceptable, though FISH demonstrates greater reproducibility and less dependence on tissue fixation variables 1
Common Pitfalls
Distinguishing IHC 0 from 1+ has become clinically critical with the approval of trastuzumab deruxtecan for HER2-low disease, though this distinction shows high interobserver variability 1, 7
HER2 status can be heterogeneous within tumors and may differ between primary and metastatic sites, necessitating retesting at recurrence when clinically appropriate 1
Approximately 50% of patients with HER2-positive breast cancer develop brain metastases over the course of their disease, requiring specific management considerations 1