The Diagnostic Value of the CA19-9 and Bilirubin Ratio in Patients with Pancreatic Cancer, Distal Bile Duct Cancer and Benign Periampullary Diseases, a Novel Approach

Abstract

Distinction of pancreatic ductal adenocarcinoma (PDAC) in the head of the pancreas, distal cholangiocarcinoma (dCCA), and benign periampullary conditions, is complex as they often share similar clinical symptoms. However, these diseases require specific management strategies, urging improvement of non-invasive tools for accurate diagnosis. Recent evidence has shown that the ratio between CA19-9 and bilirubin levels supports diagnostic distinction of benign or malignant hepatopancreaticobiliary diseases. Here, we investigate the diagnostic value of this ratio in PDAC, dCCA and benign diseases of the periampullary region in a novel fashion. To address this aim, we enrolled 265 patients with hepatopancreaticobiliary diseases and constructed four logistic regression models on a subset of patients (n = 232) based on CA19-9, bilirubin and the ratio of both values: CA19-9/(bilirubin−1). Non-linearity was investigated using restricted cubic splines and a final model, the ‘Model Ratio’, based on these three variables was fitted using multivariable fractional polynomials. The performance of this model was consistently superior in terms of discrimination and calibration compared to models based on CA19-9 combined with bilirubin and CA19-9 or bilirubin alone. The ‘Model Ratio’ accurately distinguished between malignant and benign disease (AUC [95% CI], 0.91 [0.86–0.95]), PDAC and benign disease (AUC 0.91 [0.87–0.96]) and PDAC and dCCA (AUC 0.83 [0.74–0.92]) which was confirmed by internal validation using 1000 bootstrap replicates. These findings provide a foundation to improve minimally-invasive diagnostic procedures, ultimately ameliorating effective therapy for PDAC and dCCA.

Oncogenic KRAS-Induced Protein Signature in the Tumor Secretome Identifies Laminin-C2 and Pentraxin-3 as Useful Biomarkers for the Early Diagnosis of Pancreatic Cancer

“…CA19-9 is the only serological tumor biomarker approved by the FDA for pancreatic cancer, which is far from ideal. CA19-9 may give false positive results in benign pancreaticobiliary diseases, and is not expressed in about 10% of the Caucasian population [ 11 , 12 , 13 , 14 , 15 ]. Considering the levels of CA19-9 in our cohort of 200 patients, 58 cases (29%) had CA19-9 levels below the standard cutoff value of 37 U/mL.…”

“…CA19-9 is the only serological tumor marker approved by the FDA and used routinely for the detection and monitoring of PDAC progression; it has 79–81% sensitivity and 82–90% specificity for the diagnosis of PDAC [ 11 , 12 , 13 ]. However, CA19-9 also gives false positive results in benign pancreaticobiliary diseases [ 14 , 15 ]. Several studies reported a number of non-invasive diagnostic and/or prognostic markers of pancreatic cancer that have been tested alone or in combination, such as: CA125, CEA, CEACAM1, MUC1, MIC1/GDF15, REG3A/PAP1, PKM2 and AXL, as well as auto-antibodies, fecal microbiome signatures and myeloid-derived suppressor cells [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ].…”

Adjusting CA19-9 values with clinical stage and bilirubin to better predict survival of resectable pancreatic cancer patients: 5-year-follow-up of a single center

“…Many studies have been undertaken in order to identify the best serum biomarkers for predicting the prognosis of pancreatic ductal adenocarcinoma (PDAC) patients. Previous research has shown that carbohydrate antigen 19-9 (CA19-9) is a biomarker for recurrence and survival (4). Bilirubin, on the other hand, has an effect on the level of CA19-9.…”

“…Researchers use a variety of adjustment formulae to optimize the indicators to increase the prediction accuracy of CA19-9. The clinical stage of the patient can indicate the size of the tumor and may suggest the degree of biliary obstruction (4). In the light of this hypothesis, we expect that adjusting CA19-9 values with clinical staging and bilirubin provides a better accurate prognostic expectation than CA19-9 alone.…”

Novel Strategies to Address Critical Challenges in Pancreatic Cancer

“…Patients with PDAC in the pancreatic head may only present with complaints of jaundice at advanced tumour stages. Furthermore, as described by Boyd et al, current diagnostic strategies seem to be unable to accurately differentiate PDAC from distal cholangiocarcinoma and malignant from benign disease in the pancreatic head [ 4 ]. The only validated biomarker that is currently used in the clinic is carbohydrate antigen 19-9 (CA19-9).…”