Conclusion: A dual-threshold model for measuring the pancreatic tumor marker serum carbohydrate antigen 19-9 (CA19-9) identified patients with pancreatic cancer who had low CA19-9 levels but had high-risk disease due to genetic mutations that impaired their ability to produce this biomarker.
Journal in which the study was published: clinical cancer researchJournal of the American Association for Cancer Research (AACR)
author: Yung-Yeh Su, MD, PhD, research assistant and attending physician at the National Institutes of Health, National Cheng Kung University Hospital, and Kaohsiung Medical University Hospital, Taiwan, and senior author of this study
background: Pancreatic ductal adenocarcinoma is a highly lethal cancer, with approximately 80% of cases identified at an advanced stage and a 5-year survival rate of 13.7%. Physicians commonly use CA19-9 levels to assess pancreatic cancer patients’ risk, guide treatment decisions, and monitor treatment response.
Levels of CA19-9 (also known as sialyl Lewis antigen A) correlate with the stage and prognosis of pancreatic cancer, with higher levels indicating more advanced disease and poorer prognosis. Currently, CA19-9 levels below 37 units/mL are considered normal and have a prognosis of standard-risk disease if pancreatic cancer has been diagnosed.
However, approximately 10% of pancreatic cancer patients do not have elevated CA19-9 levels, even in the presence of advanced disease. The Lewis antigen-negative status of these CA19-9 “non-producer” patients is due to a genetic polymorphism in the FUT3 gene that impairs the fucosyltransferase (FUT) activity required for CA19-9 production.
“If CA19-9 levels are in the normal range, clinicians who do not have access to patient genotyping will not be able to distinguish between patients who are Lewis antigen negative and have advanced disease, and those who have truly low tumor burden,” Professor Hsu said.
How the study was conducted: To establish a CA19-9 cutoff that captures Lewis antigen-negative patients and better predicts their prognosis, Su and his coauthors examined the relationship between genotypically determined Lewis antigen status, CA19-9 levels, and prognosis. They used whole exome sequencing to determine the FUT2/FUT3 genotypes of 615 pancreatic cancer patients from National Cheng Kung University Hospital and Kaohsiung Medical University Hospital in Taiwan. Participants were stratified by FUT genotype into four groups ranging from FUT3 null (CA19-9 non-producer/Lewis antigen negative) to FUT high.
The authors designated half of the study population as a training cohort to determine whether combining FUT2/FUT3 genotype and CA19-9 levels could help define a new CA19-9 threshold for identifying non-producer (Lewis antigen negative) patients, thereby reducing misconceptions and improving prognostic assessment.
result: This process identified a CA19-9 level of 7 units/mL or less as a new cutoff for identifying pancreatic cancer patients with a Lewis antigen-negative genotype. Validation of the cutoff in the remaining study participants showed that this CA19-9 cutoff had 87.9% accuracy in identifying Lewis antigen-negative patients.
The study also found that Lewis antigen-negative patients with CA19-9 levels below 7 units/mL experienced outcomes similar to those with CA19-9 levels above 200 units/mL. By considering overall survival (OS) based on CA19-9 levels, the authors determined that patients in the middle two tiers had the longest OS. Patients with CA19-9 levels between 7 units/mL and 37 units/mL had a median OS of 23.2 months, while those with CA19-9 levels between 37 units/mL and more than 200 units/mL had a median OS of 22 months.
In contrast, patients with CA19-9 levels ≤7 units/mL had a median OS of 13.5 months, which was comparable to the median OS of 12.8 months seen in patients with CA19-9 levels >200 units/mL, suggesting that CA19-9 levels ≤7 units/mL may be a prognosis for high-risk disease.
Author’s comment: “These data show that the conventional normal range for CA19-9 below 37 cannot distinguish between true low tumor burden and Lewis-negative status,” said Su.
To compensate for the lack of routine genotyping in clinical practice, Su and his co-authors proposed that by using a dual-threshold CA19-9 model to identify high-risk Lewis antigen-negative patients with a cutoff of 7 units/mL or less, their clinical outcomes would likely be comparable to those of patients with CA19-9 levels >200 units/mL.
“Using a CA19-9 cutoff value of 7, we achieved approximately 88% accuracy in identifying Lewis antigen-negative patients who have a poor prognosis despite having ‘normal’ or very low CA19-9 values,” Su said. “Using this cutoff is a practical surrogate for identifying these patients without the need for genotyping, thereby improving patient risk stratification and preventing underestimation of disease severity.”
Research limitations: Limitations of this study include the fact that the study was conducted entirely in Taiwan, meaning that the impact of the findings on populations outside of East Asia remains unclear. A further limitation is that CA19-9 assays may vary between laboratories. As a next step, an international validation study is planned.
sauce:
American Association for Cancer Research
Reference magazines:
Yes, C.-M.others. (2026). New CA19-9 cutoff value identifies Lewis antigen status and refines prognostic stratification in PDAC. Clinical cancer research. DOI: 10.1158/1078-0432.CCR-25-4564. https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-25-4564/785321/A-New-CA19-9-Cutoff-Value-Identize-Lewis-Antigen
