They are the same protein. CEA (Carcinoembryonic Antigen) is the historical clinical name. CEACAM5 is the official HUGO gene nomenclature. CD66e is the cluster of differentiation designation. In therapeutic development, CEACAM5 is preferred because it clearly distinguishes the target from other CEACAM family members (CEACAM1/CD66a, CEACAM6/CD66c, etc.).

CEACAM5 and CEACAM6 share ~90% sequence homology in their N-terminal IgV domains. CEACAM6 is expressed on normal granulocytes, lung epithelium, and other tissues. An anti-CEA therapeutic antibody that cross-reacts with CEACAM6 may cause on-target off-tumor toxicity — particularly pulmonary toxicity, which has been observed in early anti-CEA ADC clinical trials. Testing candidates against a panel of CEACAM family members (CEACAM5, CEACAM1, CEACAM6, CEACAM8) is standard practice in lead selection.

Normal serum CEA is typically <5 ng/mL in non-smokers and <10 ng/mL in smokers. Elevated CEA is most commonly associated with colorectal cancer but can also be elevated in gastric, pancreatic, lung, breast, and ovarian cancers. CEA is not recommended as a primary screening test due to limited sensitivity and specificity, but is widely used for post-surgical recurrence monitoring — a rising CEA trend after curative resection often precedes radiographic detection of recurrence by several months.

CEA/CEACAM5 has seven extracellular domains: one N-terminal IgV-like domain (A1) and six IgC2-like domains (B1-A3-B2-A3-B3-A3). Most therapeutic anti-CEA antibodies target the A1B1 region (N-terminal domains) because this region is exposed on the tumor cell surface and provides CEACAM5-selective epitopes. The membrane-proximal domains (B3-A3) are more conserved across CEACAM family members and pose higher cross-reactivity risk.

For FFPE sections, use an anti-CEA monoclonal antibody with heat-induced epitope retrieval (citrate pH 6.0 is most commonly used for CEA). CEA staining is typically apical/membranous and cytoplasmic in adenocarcinomas. Include normal colon tissue as a positive control (apical brush border staining). For differential diagnosis, combine CEA with CK20 and CDX2 to confirm colorectal origin of metastatic adenocarcinoma.