Before starting cetuximab in metastatic colorectal cancer, tumour tissue must be tested for KRAS mutation status. Cetuximab is ineffective in KRAS-mutant tumours because:

• A KRAS-mutant tumours downregulate EGFR expression entirely
• B KRAS mutations induce PD-L1 expression, causing immune escape
• C KRAS mutations accelerate cetuximab clearance from plasma
• D Constitutively active KRAS drives proliferation downstream of EGFR, bypassing receptor blockade ✓

Explanation

Cetuximab blocks the extracellular domain of EGFR, preventing ligand-driven RAS-RAF-MAPK signalling. A activating KRAS mutation keeps this pathway switched on independent of the receptor, so blocking EGFR upstream achieves nothing. This is the classic example of an oncogene addiction bypassing targeted therapy, and it is why anti-EGFR antibodies are restricted to RAS wild-type disease. EGFR expression is retained in KRAS-mutant tumours, which kills option A.

Reference: Harrison's Principles of Internal Medicine, 21st ed.

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Written and medically reviewed by the StethoPrep medical team.