A New CA19-9 Cutoff Value Identifies Lewis Antigen Status and Refines Prognostic Stratification in PDAC

Carbohydrate antigen 19-9 (CA19-9) has limited utility in the ∼10% of patients with pancreatic ductal adenocarcinoma (PDAC) who are Lewis-negative CA19-9 "nonproducers" (FUT3-null). This study aims to define the prognosis of FUT3-null PDAC and establish a CA19-9 cutoff that can help identify this subgroup in clinical practice.

Germline whole-exome sequencing was performed in a multicenter cohort of 615 patients with PDAC to determine FUT2/FUT3 genotypes. Receiver operating characteristic (ROC) analysis identified the optimal CA19-9 cutoff for FUT3-null status. Maximally selected rank statistics were used to derive CA19-9 cutoffs that best stratified overall survival (OS) in a training set (n = 307) and were tested in a validation set (n = 308).

FUT3-null patients had similar demographics except for a lower median baseline CA19-9 level (2.4 vs. 496 U/mL in FUT3-intact patients) and a comparable median OS (13.5 months) to FUT3-intact patients with CA19-9 >200 U/mL (12.9 months). ROC analysis identified 7 U/mL as the optimal CA19-9 cutoff for FUT3-null (positive predictive value 95.1%; accuracy 87.9%). Using CA19-9 cutoffs of 7 and 200 U/mL (without genotyping), patients were stratified into four prognostic groups: >7 to 37 U/mL (median OS, 23.2 months), >37 to 200 U/mL (median OS, 22 months), >200 U/mL (median OS, 12.8 months), and ≤7 U/mL (likely FUT3-null; median OS, 13.5 months; P < 0.001). Findings were consistent in multivariable Cox models.

CA19-9 nonproducers whose outcomes are comparable with those with CA19-9 >200 U/mL represent a high-risk subgroup. CA19-9 ≤7 U/mL is a practical surrogate for identifying these patients. When genotyping is unavailable, a dual-threshold model (≤7 and >200 U/mL) improves risk stratification.