A Combination of MUC5AC and CA19-9 Improves the Diagnosis of Pancreatic Cancer: A Multicenter Study

Abstract

OBJECTIVES Pancreatic cancer (PC) is a lethal malignancy that lacks specific diagnostic markers. The present study explores the diagnostic potential of the most differentially overexpressed secretory mucin MUC5AC alone and in combination with CA19-9 using multi-center training and validation sets. METHODS The expression of MUC5AC in benign pancreatic pathologies, PC precursor lesions, primary PC tissues and metastatic lesions was evaluated by immunohistochemistry. Circulating MUC5AC levels were measured using sandwich ELISA assay developed in-house, and CA19-9 was measured using radioimmunoassay. A combined training set (n =346) was used to evaluate the diagnostic (n =241) and predictive (n =105, total samples 201 from pre- and post-surgical and chemotherapy set) significance of MUC5AC. Results were further validated with a pre-defined cut-off value using independent sets from the Mayo Clinic (n =94) and the University of Pittsburgh Medical Center (n =321). RESULTS Tissue expression analyses indicated the de novo expression of MUC5AC in pancreatic intraepithelial precursor lesions 1A (PanIN1A); the expression was maintained through all stages of progression to invasive adenocarcinoma. The median circulating MUC5AC levels in patients with resectable early-stage PC (EPC) (stage 1/2; 67.2 ng/ml, IQR: 23.9–382.1) and unresectable late-stage PC (LPC) (stage 3/4; 389.7 ng/ml, IQR: 87.7–948.6) were significantly higher compared with (P-value ≤0.0001) benign controls (BC) (7.2 ng/ml, IQR: 0.4–26.5) and (P-value ≤0.0001) chronic pancreatitis (CP) controls (8.4 ng/ml, IQR: 1.5–19.2). In the diagnostic training set (n =241), MUC5AC efficiently differentiated EPC from healthy controls (HC) (83%/80% sensitive (SN)/specific (SP)), BC (67%/87% SN/SP), and CP (83%/77% SN/SP). Independent validation sets from the Mayo Clinic and UPMC confirmed the diagnostic potential of MUC5AC to differentiate EPC from BC (68%/73%; 65%/83%) and CP (68%/79%; 65%/72%). Furthermore, MUC5AC and CA19-9 combination significantly improved (p-value < 0.001) the diagnostic accuracy for differentiating resectable cases from controls. CONCLUSIONS MUC5AC is a valuable diagnostic biomarker, either alone or in combination with CA19-9, to differentiate PC from CP and benign controls.

Diagnosis and Management of Pancreatic Adenocarcinoma in the Background of Chronic Pancreatitis: Core Issues

“…Additional techniques used during EUS do not help in detection of a mass, but help to differentiate between pseudotumor and PDAC once detected, and include fine needle aspiration cytology/biopsy (FNAC/B), EUS elastography, contrast-enhanced EUS, and digital image analysis -a more objective computer-based method of image analysis [31][32][33]. EUS-FNAC has a very high sensitivity (> 85%) and specificity (> 95%) for diagnosis of malignancy in a solid pancreatic mass [33,34].…”

“…CA 19-9 is the gold standard PDAC biomarker and is the single most important predictive biomarker of malignancy in mass forming CP with a sensitivity and specificity of 77 and 86%, respectively [31]. However, it has a few limitations.…”

“…The biomarker combination found to be very promising is MUC5AC with CA 19-9 [31]. MUC5AC is a mucin family member produced from pancreatic intraepithelial neoplasm type IA, IB and well differentiated as well as poorly differentiated PDAC.…”

“…This combination outperforms both tests individually. A cutoff value of 20.4 ng/mL was found to DOI: 10.1159/000496507 differentiate all benign and normal controls from early PDAC [31]. PAM4 is a monoclonal antibody with high specificity for MUC1, which is found to be expressed in PDAC as compared to normal pancreatic tissue and pancreatitis [66].…”

A review of lifestyle, metabolic risk factors, and blood‐based biomarkers for early diagnosis of pancreatic ductal adenocarcinoma

“…However, when combined with CA 19‐9, the majority of these biomarkers have not been shown to improve the diagnostic accuracy compared with CA 19‐9 alone . Although additional studies are needed to validate the use of these biomarkers, a few studies have reported that macrophage colony‐stimulating factor 1, haptoglobin, tumor‐specific growth factor, heat shock protein 27, clivatuzumab, mucin 1, CEA‐related cell adhesion molecule 1, mucin 5AC, and miR‐1290 had higher sensitivity and specificity for diagnosis of PDAC than CA 19‐9 alone …”