Carcinoembryonic antigen is the preferred biomarker for in vivo colorectal cancer targeting

Abstract

Background: Colorectal cancer-specific biomarkers have been used as molecular targets for fluorescent intra-operative imaging, targeted PET/MRI, and selective cytotoxic drug delivery yet the selection of biomarkers used is rarely evidence-based. We evaluated sensitivities and specificites of four of the most commonly used markers: carcinoembryonic antigen (CEA), tumour-associated glycoprotein-72 (TAG-72), folate receptor-α (FRα) and Epithelial growth factor receptor (EGFR).

Methods: Marker expression was evaluated semi-quantitatively in matched mucosal and colorectal cancer tissues from 280 patients using immunohistochemistry (scores of 0-15). Matched positive and negative lymph nodes from 18 patients were also examined.

Results: Markers were more highly expressed in tumour tissue than in matched normal tissue in 98.8%, 79.0%, 37.1% and 32.8% of cases for CEA, TAG-72, FRα and EGFR, respectively. Carcinoembryonic antigen showed the greatest differential expression, with tumours scoring a mean of 10.8 points higher than normal tissues (95% CI 10.31-11.21, P<0.001). Similarly, CEA showed the greatest differential expression between positive and negative lymph nodes. Receiver operating characteristic analyses showed CEA to have the best sensitivity (93.7%) and specificity (96.1%) for colorectal cancer detection.

Conclusion: Carcinoembryonic antigen has the greatest potential to allow highly specific tumour imaging and drug delivery; future translational research should aim to exploit this.

Figure 1

Representative tissue microarray cores of normal colorectal tissue (top row) and colorectal tumours (bottom row) showing immuno-reactivity as labelled. The normal tissue cores shown demonstrate the median score for that antigen in normal colorectal tissues (CEA=1; TAG-72=2; EGFR=0; FRα=0). The tumour cores shown demonstrate the median positive score for that antigen in colorectal tumours (CEA=15; TAG-72=10; EGFR=2; FRα=1). Scale bar=100 μm.

Figure 2

Expression levels of CEA, TAG-72, EGFR or FRα in normal colorectal tissue (left) and in colorectal tumours (right). Expression levels were determined in 280 matched normal and tumour tissues by immunohistochemistry using semi-quantitative scores of 0–15. The scores for each marker are arranged independently in ascending order to demonstrate the distributions across the cohort.

Figure 3

Carcinoembryonic antigen shows the most consistent overexpression in tumour tissues and the greatest differential expression between matched normal and tumour tissues. Left: Expression scores for normal tissues were subtracted from those for matched tumour tissues to quantify the degree of tumour overexpression for each case. Overexpression scores for each marker are arranged in ascending order to demonstrate the distributions across the cohort (left). Minus scores reflect cases where tumour expression was lower than expression in the matched normal tissue. Mean overexpression scores (central marker) with 95% confidence intervals (error bars) are also shown (right).

Figure 4

Expression levels of CEA, TAG-72, EGFR or FRα in lymph nodes, containing colorectal tumour deposits (‘positive' right) and in matched lymph nodes lacking tumour cells (‘negative' left). Expression levels were determined by immunohistochemistry using scores of 0–15 in 18 cases. The scores for each marker are arranged independently in ascending order to demonstrate the distributions across the cohort (note: datapoints are linked by lines to aid interpretation of the distributions not to imply adjacent datapoints are directly related).