Serum Carboxypeptidase Activity and Genotype-Stratified CA19-9 to Detect Early-Stage Pancreatic Cancer

Abstract

Background and aims: Serum diagnostic markers of early-stage pancreatic ductal adenocarcinoma (PDAC) are needed, especially for stage I disease. As tumors grow and cause pancreatic atrophy, markers derived from pancreatic parenchyma such as serum carboxypeptidase A (CPA) activity lose diagnostic performance. We evaluated, with CA19-9, serum CPA as a marker of early pancreatic cancer.

Methods: Serum CPA activity levels were measured in 345 controls undergoing pancreatic surveillance, divided into 2 sets, set 1 being used to establish a reference range. Variants within the CPA1 locus were sought for their association with pancreatic CPA1 expression to determine if such variants associated with serum CPA levels. A total of 190 patients with resectable PDAC were evaluated.

Results: Among controls, those having 1 or more minor alleles of CPA1 variants rs6955723 or rs2284682 had significantly higher serum CPA levels than did those without (P = .001). None of the PDAC cases with pancreatic atrophy had an elevated CPA. Among 122 PDAC cases without atrophy, defining serum CPA diagnostic cutoffs by a subject's CPA1 variants yielded a diagnostic sensitivity of 18% at 99% specificity (95% confidence interval [CI], 11.7-26) (vs 11.1% sensitivity using a uniform diagnostic cutoff); combining CPA with variant-stratified CA19-9 yielded a sensitivity of 68.0% (95% CI, 59.0-76.2) vs 63.1% (95% CI, 53.9- 71.7) for CA19-9 alone; and among stage I PDAC cases, diagnostic sensitivity was 51.9% (95% CI, 31.9-71.3) vs 37.0% (95% CI, 19.4-57.6) for CA19-9 alone. In the validation control set, the variant-stratified diagnostic cutoff yielded a specificity of 98.2%.

Conclusion: Serum CPA activity has diagnostic utility before the emergence of pancreatic atrophy as a marker of localized PDAC, including stage I disease.

Keywords: CA19-9; CPA1; Carboxypeptidase A; Diagnosis; Genotyping; IPMN; Pancreatic Cancer; Serum.

Figure 1.. Serum CPA activity in PDAC cases and controls and the role of CPA1 genotypes

1A: Serum CPA activity levels in PDAC cases vs. controls. 1B: Serum CPA activity levels and tumor size in PDAC cases with vs. without pancreatic atrophy. 1C: Manhattan plot of 6,629 SNPs located within 1Mbp up/downstream from transcription starting site of CPA1 gene to identify candidate variants which located near upstream or downstream of candidate promoter/enhancer loci. 1D: (left) CPA activity levels in controls by SNP status (rs6955723, rs2284682); major alleles only vs. controls with one or more minor alleles vs. two or more minor alleles. (Intermediate) CPA activity major alleles only vs. one or more minor alleles. (Right) Distribution of alleles for SNPs rs6955723, rs2284682 in controls. 1E: Serum CPA activity levels in the validation set controls by SNP status. *, P<0.05; *** P<0.001.