Trastuzumab deruxtecan (T-DXd) demonstrates antitumor activity against HER2-low breast cancer (IHC 1+ or 2+/ISH-negative), unlike trastuzumab. Which pharmacological property of T-DXd best explains this expanded activity?
- A T-DXd binds HER2 with 100-fold higher affinity than trastuzumab
- B The membrane-permeable payload enables bystander killing of neighboring cells regardless of HER2 expression ✓
- C T-DXd inhibits HER2 dimerization more potently than trastuzumab
- D T-DXd activates complement-mediated cytotoxicity, which trastuzumab cannot
Correct answer: B. The membrane-permeable payload enables bystander killing of neighboring cells regardless of HER2 expression
Explanation
T-DXd's deruxtecan payload (a topoisomerase I inhibitor) is membrane-permeable. After intracellular release in HER2-expressing cells, it diffuses to neighboring tumor cells regardless of HER2 expression, enabling bystander killing. This explains activity in HER2-low disease. Affinity and dimerization inhibition are not the distinguishing features.
Reference: DeVita, Hellman, and Rosenberg's Cancer: Principles and Practice of Oncology, 12th ed.
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Written and medically reviewed by the StethoPrep medical team.