A HER2-enriched (HER2+, ER-, PR-) invasive breast carcinoma is diagnosed. HER2 overexpression is confirmed by FISH showing gene amplification. What is the mechanism of action of trastuzumab (Herceptin)?

• A Competitive inhibition of HER2 kinase domain, blocking downstream MAPK and PI3K/AKT signaling
• B Small molecule inhibitor blocking HER2 and EGFR tyrosine kinases intracellularly
• C Monoclonal antibody binding domain IV of HER2 extracellular domain, preventing receptor dimerization and inducing ADCC ✓
• D Anti-HER2 antibody conjugated to cytotoxin DM1, acting primarily as an antibody-drug conjugate

Explanation

Trastuzumab is a recombinant humanized monoclonal antibody (IgG1) that binds domain IV of the HER2 extracellular domain. Its mechanisms include blocking receptor homodimerization/heterodimerization (preventing downstream oncogenic signaling), inducing antibody-dependent cell-mediated cytotoxicity (ADCC) via Fc receptors on NK cells, and downregulating HER2 surface expression. Pertuzumab blocks domain II (dimerization domain). The kinase inhibitors lapatinib and neratinib block the intracellular TK domain; T-DM1 (ado-trastuzumab emtansine) is the antibody-drug conjugate.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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