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Carbohydrate antigen 19-9 (CA 19-9) is also known as cancer antigen 19-9, sialyl Lewis a antigen (sLea). It is the most commonly used serum tumor marker, especially in the diagnosis and monitoring of pancreatic cancer treatment.
CA 19-9 was discovered as early as 1979 in the colorectal cancer cell line SW1116, and subsequently in the sera of patients with colon and pancreatic cancers, and was later found to be a component of glycoproteins and mucins as well. CA 19-9 is normally synthesized by normal human pancreatic and bile duct cells, as well as gastric, colonic, endometrial, and salivary epithelial cells, is present in small amounts in serum, is overexpressed in several benign gastrointestinal disorders (pancreatitis, pancreatic cysts, benign cholestatic diseases, etc.), and its plasma levels are dramatically increased during oncologic diseases.
Figure 1. Clinical uses of carbohydrate antigen 19-9 based on organ involvement
(Source: Lee T, et al. 2020)
Structurally, the CA 19-9 antigen is a tetrasaccharide carbohydrate known as sialyl Lewis a (belonging to the Lewis family of blood group antigens) with a transmembrane protein backbone and extensively glycosylated extracellular oligosaccharide chains with the sequence Neu5Aca2,3Galb1,3 (Fuca1,4) GlcNAc. Sialyl Lewis a is synthesized by glycosyltransferases, which sequentially bind monosaccharide precursors to N- and O-linked glycans. The Lewis blood grouping system consists of a group of fucosylated glycosphingolipids that are synthesized by exocrine epithelial cells and subsequently adsorbed to the surface of red blood cells to form the Lewis phenotype, which thus circulates in body fluids as an erythrocyte antigen. The Lewis antigen system is based on the expression of genes of members of the fucosyltransferase family, which catalyzes the addition of α-fucose residues to precursor polysaccharides in the final step of Lewis antigen biosynthesis. Enzymes with α 1 → 3 fucosyltransferase and α 1 → 4 fucosyltransferase activities encoded by the Le or FUT3 genes add an α-fucose residue to the subterminal position of the precursor oligosaccharide substrate, converting it to the Lea antigen.
Figure 2. Biosynthesis and structures of CA 19-9 and other Lewis-type antigens
(Source: Luo G, et al. 2021)
There have been many studies on the diagnostic sensitivity and specificity of CA 19-9. Researchers have compared serum CA 19-9 levels in patients with pancreatic cancer to different control groups to assess the diagnostic accuracy of CA 19-9 in pancreatic cancer, and in all of these studies, 37kU/l was used as the threshold for CA 19-9, at which the overall mean sensitivity of CA 19-9 for pancreatic cancer was 81% and the mean specificity was 90%. An increase in the cut-off point significantly improves specificity, but progressively decreases sensitivity. One researcher analyzed data from 1990 to 2005 and showed that CA 19-9 had a median sensitivity of 79% and a median specificity of 82% for pancreatic cancer. CA 19-9 sensitivity varies with pancreatic cancer stage. In addition, the sensitivity of CA 19-9 varies in different types of cancer, 70% in hepatobiliary cancer, 40-50% in gastric cancer, 30-50% in hepatocellular carcinoma, 30% in colorectal cancer and 15% in breast cancer.
Important interfering situations need to be carefully evaluated for CA 19-9 clinical testing, as these interfering factors can make this tumor marker difficult to use in clinical practice. In addition, there are limitations in the diagnostic application of CA 19-9. For example, patients with fucosyltransferase deficiency are unable to detect CA 19-9 because they are unable to synthesize the CA 19-9 epitope. False-negative CA 19-9 serum levels occur in these patients even in the presence of advanced pancreatic cancer. Secondly, CA 19-9 serum levels are not only elevated in malignant diseases, but sometimes patients with benign diseases also show elevated CA 19-9 serum levels, for example, elevated CA 19-9 serum levels have been reported in patients with ovarian cysts, heart failure, and rheumatoid arthritis. Obstructive jaundice may also show false-positive elevations due to obstruction of biliary excretion. From this perspective, CA 19-9 is not considered a strictly cancer-specific marker, and clinicians must use CA 19-9 with caution when evaluating patients with other benign diseases for cancer, combining it with a variety of other tests. In addition, there is a lack of standardization of commercially available assays for CA 19-9, and although different assays have similar diagnostic accuracy, the differences in the results therein cannot be directly analyzed and compared, which means that patients must be continuously monitored for changes in CA 19-9 levels using the same assay.
CA 19-9 can be detected at elevated expression levels in several types of adenocarcinomas, such as cholangiocarcinoma, gastric cancer, colorectal cancer, and hepatocellular carcinoma. Early-onset or small-diameter pancreatic cancer lacks CA 19-9 sensitivity, and only 50% of patients with pancreatic cancer less than 3 cm in diameter have elevated CA 19-9 levels, making it difficult to use CA 19-9 as a marker for early diagnosis of pancreatic cancer. In addition, there was a poor correlation between the degree of tumor cell differentiation and serum CA 19-9 levels. Poorly differentiated pancreatic cancers appear to express less CA 19-9 than moderately or well-differentiated cancers. These limitations serve as a reminder that CA 19-9 should be used with caution, and that its use in a worst-case situation may aid in the diagnosis but does not replace histologic evidence of pancreatic cancer.
Table 1. Roles of CA19-9 in pancreatic cancer
| Role | Main applications or functions |
| Biomarker | Strategies for improving CA 19-9 diagnostic accuracy: 1）Lewis and Secretor genotype-dependent cut-off values 2）Combination with other biomarkers such as glycans, microRNAs, thrombospondin-1/2, etc. 3）CA19-9-targeted molecular imaging 4）Ratio of sLea /dLea 5）Strategies for Lewis-negative cancer (CA 19-9 secretion in Lewis (-) patients; DU-PAN-2; sLex ; CEA and CA125) |
| Predictor | 1）Evaluating the efficacy of neoadjuvant therapy 2）Assessing resectability 3）Postoperative CA 19-9 for evaluating prognosis 4）Predicting response to adjuvant chemotherapy 5）Evaluating the efficacy of systemic chemotherapy 6）Normal baseline CA 19-9 for evaluating long-term survival |
| Promoter | 1）Glycosylating proteins 2）Binding to E-selectin 3）Promoting angiogenesis 4）Modulating the immunologic response |
(Source: Luo G, et al. 2021)
CA 19-9 as a screening and diagnostic biomarker for pancreatic cancer
CA 19-9, when used as a screening tool for pancreatic cancer in asymptomatic populations, has a low positive predictive value and has no role as a screening marker, despite its good sensitivity and specificity. In addition, when screening high-risk populations, serum CA 19-9 levels remain normal in many patients with existing manifestations of pre-invasive pancreatic lesions on imaging. For these reasons, CA 19-9 should no longer be used for screening asymptomatic subjects.
Early detection of pancreatic cancer is important for differential diagnosis and timely treatment, and the use of CA 19-9 in the diagnosis of pancreatic cancer and diagnostic thresholds have been widely evaluated. Levels above 37kU/l were determined to be the most accurate for identifying pancreatic cancer and benign pancreatic disease (sensitivity and specificity 77% and 87%, respectively). Elevated CA 19-9 can indicate the likelihood of pancreatic cancer in patients with suspected symptoms of pancreatic cancer. Based on evidence of the poor sensitivity of early-stage lesions, the European Group on Tumor Marker guidelines confirm the limited value of CA 19-9 in the diagnosis of pancreatic cancer, especially for early-stage disease. The National Academy of Clinical Biochemistry also does not recommend measuring CA 19-9 in the diagnosis of pancreatic cancer, but believes that this marker can be used to aid in the diagnosis, and in combination with other assays can guide further invasive testing.
CA 19-9 serum levels as a prognostic biomarker in patients with pancreatic cancer
Measurement of serum CA 19-9 levels provides important prognostic information and stratifies patients (survival groups) and determines the resectability of pancreatic cancer. Preoperative serum CA 19-9 levels are a useful and independent indicator for assessing the resectability of pancreatic cancer, and a multifactorial survival prediction analysis performed by investigators on 117 patients with pancreatic cancer who underwent surgical resection showed the prognostic value of preoperative CA 19-9 levels in relation to anatomic findings of the peripancreatic tissue margins, and confirmed that higher preCA 19-9 corresponded to a poorer prognosis. Both postoperative CA 19-9 decline and CA 19-9 values less than 200U/mL were strong independent predictors of survival.
In conclusion, studies have shown that CA 19-9 plays a role in predicting the prognosis of patients with pancreatic cancer. Preoperatively CA 19-9 correlates with disease stage, with a median serum level of <100U/ml correlating with resectability, whereas a level of >100U/ml suggests advanced or metastatic pancreatic cancer. A return to normal or a downward trend in postoperative CA 19-9 serum levels is associated with prolonged survival, whereas elevated or non-decreasing CA 19-9 levels after pancreatectomy indicate residual disease or occult metastases and portend a shorter survival period.
CA 19-9 serum levels as a biomarker for chemotherapy response in pancreatic cancer patients
CA 19-9 can be used to assess the efficacy of chemotherapy for advanced pancreatic cancer, and monitoring CA 19-9 appears to be helpful in identifying patients whose tumors show progressive growth and metastasis despite this treatment. Changes in CA 19-9 levels were found to correlate with disease progression and were statistically significant. CA 19-9 is a prognostic and predictive biomarker in patients with advanced pancreatic cancer receiving gemcitabine-containing chemotherapy. Continuous monitoring of CA 19-9 is also recommended in the follow-up of potentially curable post-surgical patients, but CA 19-9 should not be used to determine disease recurrence without the support of accurate imaging assessment techniques.
References
| Target | Cat. No. | Product Name | Size | Species | Application | Detection Sample | |
| CA 19-9 | DEIA-BJ50 | Mouse CA199(Gastrointestinalcancer Marker-CA199) ELISA Kit | 96T | Mouse | Quantitative | Serum, plasma, tissue homogenates, other biological fluids | Inquiry |
| DEIA514 | Human CA19-9 ELISA Kit | 96T | Human | Quantitative | Serum and plasma | Inquiry | |
| DEIA2243 | Human CA19-9(CarbohydRate antigen19-9) ELISA Kit | 96T | Human | Quantitative | Serum, plasma, tissue homogenates and other biological fluids | Inquiry | |
| DEIA5268 | Human CA19-9 ELISA kit | 96T | Human | Quantitative | Serum, plasma, cell culture supernatants | Inquiry | |
| DEIACL11 | CDSimple™ CA 19-9 Chemiluminescent ELISA Kit | 96T, 192T | Quantitative | Serum | Inquiry |
| Target | Cat. No. | Product Name | Expression System | Tag/Conjugate | Application | |
| CA 19-9 | DAG-T1002 | Human CA 19-9 | N/A | Unconjugated | WB | Inquiry |
| DAG-WT2643 | CA 19-9 control | N/A | Unconjugated | Immunoassays | Inquiry | |
| DAGA-768 | CA 19-9 antigen (partially pure) | Human ascites fluids | Unconjugated | N/A | Inquiry | |
| DAGA-765 | CA 19-9 antigen (Control grade) | Human colon adenocarcinoma cells | Unconjugated | Control | Inquiry |
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