A patient with HER2-positive breast cancer is treated with trastuzumab (Herceptin). Despite initial response, the tumor becomes resistant. Pertuzumab is added, and it provides benefit despite the same resistance because it:

• A Binds the extracellular domain IV of HER2 (same as trastuzumab) with higher affinity
• B Inhibits HER2 intracellular tyrosine kinase domain that remains active when trastuzumab is bound
• C Blocks HER2 nuclear translocation preventing transcriptional activation of resistance genes
• D Binds extracellular domain II of HER2, preventing HER2 heterodimerization with HER3 and HER1 ✓

Explanation

Trastuzumab binds domain IV of HER2's extracellular region, primarily inhibiting HER2 signaling and mediating ADCC. Pertuzumab binds a different epitope — domain II — which is the dimerization arm. By blocking domain II, pertuzumab prevents HER2 from forming heterodimers with HER3 (the most potent signaling pair) and HER1, thereby blocking ligand-activated HER3:HER2 signaling that often mediates trastuzumab resistance. The combination (dual HER2 blockade) provides superior outcomes in HER2+ breast cancer (CLEOPATRA trial).

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.