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 before 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 the UKCTOCS included 118 single and 143 serial serum samples from 154 postmenopausal women who were subsequently diagnosed with pancreatic cancer and 304 matched noncancer 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 before 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 years before diagnosis. Combining CA19-9 and CA125 improved sensitivity as CA125 was elevated (>30 U/mL) in approximately 20% of CA19-9-negative cases. CEACAM1 and REG3A were late markers adding little in combined models. Average lead times of 20 to 23 months were estimated for test-positive cases. Prediagnostic 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 preclinical pancreatic cancer, and both markers can be used as prognostic tools. This work challenges the prevailing view that CA19-9 is upregulated late in the course of pancreatic cancer development.

Figure 1

Box and whisker plots showing serum levels of CA19-9, CA125, CEACAM1 and REG3A for all case and control discovery set samples. Whisker limits represent the 5^th and 95^th percentiles, the box limits represent interquartile range, the horizontal line the median and the cross the mean. Case and control groups were compared using the Mann-Whitney test; P values are shown above the plots.

Figure 2

Box and whisker plots showing serum levels of CA19-9, CA125, CEACAM1 and REG3A for case control discovery samples grouped into different time to diagnosis groups. Whisker limits represent the 5^th and 95^th percentiles, the box limits represent interquartile range, the horizontal line the median and the cross the mean. Case and control groups were compared using the Mann-Whitney test; P values are shown above the plots.

Figure 3

Survival curves for CA19-9 and CA125 using time from sample collection to death due to pancreatic cancer.