HER2 positive breast cancer is defined by overexpression of human epidermal growth factor receptor 2 (HER2/neu, the product of the ERBB2 gene), accounting for 15-20% of all breast cancers. HER2 is a member of the EGFR family, a tyrosine kinase receptor on tumor cell surfaces responsible for transmitting growth, proliferation, and survival signals. Overexpression usually arises from ERBB2 gene amplification. HER2 positivity is established by IHC 3+ (strong uniform membrane staining in more than 10% of tumor cells) or IHC 2+ confirmed by ISH (in situ hybridization) showing ERBB2 amplification. Tumors with IHC 0/1+ or IHC 2+/ISH-negative are classed as HER2-negative, although a separate HER2-low category (IHC 1+ or IHC 2+/ISH-) has emerged in recent years.
HER2 positive tumors were historically marked by aggressive behavior, early relapse, brain metastasis risk, and poor prognosis. The 1998 approval of trastuzumab (Herceptin) revolutionized HER2+ breast cancer care, and modern management is unimaginable without anti-HER2 therapy. Available agents include: (1) Trastuzumab — humanized IgG1 antibody binding HER2 subdomain IV; (2) Pertuzumab — binds HER2 subdomain II and, with trastuzumab, blocks HER2/HER3 heterodimerization; (3) T-DM1 (ado-trastuzumab emtansine) — antibody-drug conjugate (ADC) carrying emtansine (DM1) payload; (4) T-DXd (trastuzumab deruxtecan) — more potent ADC with deruxtecan (topoisomerase I inhibitor) payload; (5) Lapatinib — small-molecule TKI; (6) Neratinib — irreversible pan-HER TKI; (7) Tucatinib — HER2-specific TKI with blood-brain barrier penetration.
Treatment approach: (1) Early stage — for locally advanced HER2+ disease, neoadjuvant chemotherapy plus trastuzumab and pertuzumab (TCHP — docetaxel + carboplatin + trastuzumab + pertuzumab). Pathologic complete response (pCR) is prognostic; in patients with residual disease, adjuvant T-DM1 (KATHERINE trial) reduces recurrence risk. Patients achieving pCR complete trastuzumab with or without pertuzumab. Total anti-HER2 therapy duration is 1 year. (2) Metastatic — first line is docetaxel plus trastuzumab and pertuzumab (CLEOPATRA). Second line is trastuzumab deruxtecan (DESTINY-Breast03 — superior to T-DM1). Third line and beyond: T-DM1; tucatinib + trastuzumab + capecitabine (HER2CLIMB — effective in brain metastasis); lapatinib + capecitabine; neratinib + capecitabine; margetuximab. For brain metastases, tucatinib and T-DXd are active. In HR+/HER2+ disease, endocrine therapy combinations with anti-HER2 agents are feasible.