Serum CA19-9 Is Significantly Upregulated up to 2 Years before Diagnosis with Pancreatic Cancer: Implications for Early Disease Detection

Abstract

Purpose Biomarkers for the early detection of pancreatic cancer are urgently needed. The primary objective of this study was to evaluate whether increased levels of serum CA19-9, CA125, CEACAM1 and REG3A are present prior to clinical presentation of pancreatic cancer and to assess the performance of combined markers for early detection and prognosis. Experimental Design This nested case control study within UKCTOCS included 118 single- and 143 serial-serum samples from 154 post-menopausal women who were subsequently diagnosed with pancreatic cancer and 304 matched non-cancer controls. Samples were split randomly into independent training and test sets. CA19-9, CA125, CEACAM1 and REG3A were measured using ELISA and/or CLIA. Performance of markers to detect cancers at different times prior to diagnosis and for prognosis was evaluated. Results At 95% specificity, CA19-9 (>37 U/mL) had a sensitivity of 68% up to 1 year, and 53% up to 2 yrs before diagnosis. Combining CA19-9 and CA125 improved sensitivity as CA125 was elevated (>30 U/mL) in ~20% of CA19-9-negative cases. CEACAM1 and REG3A were late markers adding little in combined models. Average lead times of 20-23 months were estimated for test-positive cases. Pre-diagnostic levels of CA19-9 and CA125 were associated with poor overall survival (HR 2.69 and 3.15, respectively). Conclusions CA19-9 and CA125 have encouraging sensitivity for detecting pre-clinical pancreatic cancer and both markers can be used as prognostic tools. This work challenges the prevailing view that CA19-9 is up-regulated late in the course of pancreatic cancer development.

Sequential Validation of Blood-Based Protein Biomarker Candidates for Early-Stage Pancreatic Cancer

“…Carbohydrate antigen 19-9 (CA19-9) has shown potential as a diagnostic biomarker for both preclinical and early-stage PDAC (5,6). However, CA19-9 performance characteristics as a PDAC biomarker are limited as its accuracy varies with disease stage (7).…”

The clinical utility of CA125/MUC16 in pancreatic cancer: A consensus of diagnostic, prognostic and predictive updates by the Chinese Study Group for Pancreatic Cancer (CSPAC)

“…In particular, the data support the hypothesis that CA125/MUC16 plays an oncogenic and metastasis-predictive role in the progression of PC, and correlates with the metastatic tumor burden. Although the most commonly used cut-off value of CA125 is 30-35 U/ml (5,37), data indicate that a lower level of CA125 may have a significant diagnostic or predictive value for pC (34,38). In some cases, a second or third cut-off value (concentrations less or more than 35 U/ml CA125) is recommended (55-57).…”

“…However, recent studies have reported that CA19-9 and CA125 can be detected up to 1-2 years prior to diagnosis, and that the combination of CA19-9 and CA125 can improve the diagnostic sensitivity, as elevated CA125 levels are not only observed in CA19-9-positive cases, but also in approximately 20% of CA19-9-negative cases. Moreover, their preclinical levels (the cut-off value of CA125 is 30 U/ml, Table II) also correlate with prognosis, which demonstrate its value for the preclinical evaluation of pC (34). CA19-9 is a classical serum biomarker commonly used in pancreatic ductal adenocarcinoma (pDAC).…”

“…In these patients, serum levels of CA125 provide a valuable contribution in the diagnosis of differentiating malignant and benign pancreatic diseases (33). The sensitivity and specificity for serum CA125 are 41.7-70.3 and 75.1-96.3% (Table II), respectively (34,36). However, CA125 also has a rare diagnostic value in cases where CA19-9 is not elevated, particularly in those patients who are negative for Lewis antigen (34).…”

“…The sensitivity and specificity for serum CA125 are 41.7-70.3 and 75.1-96.3% (Table II), respectively (34,36). However, CA125 also has a rare diagnostic value in cases where CA19-9 is not elevated, particularly in those patients who are negative for Lewis antigen (34). The most commonly used cut-off value of CA125 is approximately 30-35 U/ml (5,37); however, other studies have reported that a lower level of CA125 may also have significance for diagnosis (7,9,34,38).…”