pertuzumab

**Mechanism of action** - Recombinant humanized IgG1 monoclonal antibody against HER2 (ErbB2), a receptor tyrosine kinase. - Binds the extracellular dimerization domain (subdomain II) of HER2. Trastuzumab binds subdomain IV, a different epitope. - Prevents ligand-activated HER2 heterodimerization with other HER family members (HER3 > EGFR/HER1, HER4). The HER2–HER3 dimer is the most potent mitogenic signaling pair. - This inhibits downstream PI3K/AKT and RAS/MAPK signaling, which reduces proliferation and survival. - It also mediates antibody-dependent cell-mediated cytotoxicity (ADCC). - Pertuzumab and trastuzumab have complementary, synergistic effects. Dual HER2 blockade is more effective than either drug alone.

**Indications** - HER2-positive metastatic breast cancer, first line: pertuzumab + trastuzumab + docetaxel (CLEOPATRA trial showed improved PFS and OS). - Neoadjuvant treatment of HER2+ early breast cancer that is locally advanced, inflammatory, or high-risk (>2 cm or node-positive). The NeoSphere and TRYPHAENA trials support this use, which increases pathologic complete response (pCR). - Adjuvant treatment of HER2+ early breast cancer at high risk of recurrence (APHINITY trial showed modest benefit, mostly in node-positive disease). - A fixed-dose subcutaneous combination of pertuzumab, trastuzumab, and hyaluronidase (Phesgo) is also available.

**Adverse effects (high-yield)** - **Cardiotoxicity:** decreased LVEF and heart failure. Trastuzumab-type toxicity is type II (non-anthracycline-like): usually reversible and not dose-dependent. Monitor LVEF at baseline and periodically. Risk rises with concurrent anthracyclines. - **Embryo-fetal toxicity:** oligohydramnios, pulmonary hypoplasia, skeletal abnormalities, and fetal death. Pregnancy testing and contraception are required. - Diarrhea (common), neutropenia/febrile neutropenia (with chemotherapy), rash, fatigue, and alopecia. - Infusion and hypersensitivity reactions.

**Clinical pearls for boards** - HER2 is overexpressed or amplified in about 15–20% of breast cancers. Testing is by IHC (3+ is positive) or FISH (amplification). HER2+ disease is more aggressive, and these agents improve outcomes. - Pertuzumab is not effective as monotherapy. It is always given with trastuzumab and chemotherapy. - Name pattern: "-mab" = monoclonal antibody; "-zu-" = humanized. - Related HER2-directed drugs: - Trastuzumab: binds subdomain IV and causes ADCC. - Ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan: antibody-drug conjugates. - Lapatinib, neratinib, and tucatinib: small-molecule tyrosine kinase inhibitors (-tinib). - Mnemonic: Pertuzumab "Prevents Pairing" (dimerization) of HER2 with partner receptors.