First large-scale prospective evaluation of serum S100A6 as a complementary biomarker for early pancreatic cancer detection

Abstract

BACKGROUND

Pancreatic cancer (PC) remains one of the most lethal malignancies due to late diagnosis and lack of early detection strategies. Carbohydrate antigen 19-9 (CA19-9), the only Food and Drug Administration-approved biomarker, demonstrates limited sensitivity for early-stage disease and poor specificity in distinguishing PC from benign pancreatic conditions. S100A6, a calcium-binding protein implicated in cell proliferation and apoptosis, has been identified as a potential diagnostic biomarker in various malignancies. While overexpression of S100A6 has been reported in PC tissues, its diagnostic value as a serum biomarker for PC remains unexplored.

AIM

To assess the diagnostic value of serum S100A6, alone and combined with CA19-9 and carcinoembryonic antigen (CEA), for detecting PC, particularly early-stage disease.

METHODS

Serum samples from 414 subjects were analyzed: 301 PC patients (149 early-stage, 152 advanced-stage), 52 with chronic pancreatitis (CP) patients, and 61 healthy controls (HCs). Serum S100A6 was measured by enzyme-linked immunosorbent assay, while CA19-9 and CEA by electrochemiluminescence immunoassay. Logistic regression was used to adjust for covariates, and diagnostic performance was assessed using receiver operating characteristic curves. Internal validation was conducted using 2000 bootstrap resamples.

RESULTS

Serum S100A6 concentrations were significantly higher in both early- and late-stage PC compared with CP and HCs (P < 0.001). In multivariate logistic regression, only S100A6 [odds ratio (OR) = 1.82, 95% confidence interval (CI): 1.40-2.37, P < 0.001] and CA19-9 (OR = 2.21, 95%CI: 1.80-2.72, P < 0.001) remained independent predictors of PC. CA19-9 showed the highest area under the curve (AUC) among single markers (0.839, 95%CI: 0.802-0.877), but combined panel of S100A6, CA19-9, and CEA achieved a higher AUCs of 0.868 (95%CI: 0.834-0.902, P = 0.007). Critically, for distinguishing early-stage PC from CP, the triple panel of S100A6, CA19-9, and CEA achieved an AUC of 0.821 (95%CI: 0.763-0.879) and was the only panel to show a statistically significant improvement over CA19-9 alone (P = 0.017), underscoring its potential for more timely identification of surgically resectable PC.

CONCLUSION

This large cohort study is the first to demonstrate the diagnostic potential of serum S100A6 in PC. When combined with CA19-9, serum S100A6 improves diagnostic performance for both overall and early-stage PC, supporting its role as a complementary biomarker in clinical practice.

Keywords: S100A6; Early pancreatic cancer; Serum biomarker; Carbohydrate antigen 19-9; Carcinoembryonic antigen

Core Tip: This large-scale case-control study is the first to evaluate the clinical potential of serum S100A6 as a biomarker for pancreatic cancer (PC). When used together with carbohydrate antigen 19-9 (CA19-9), serum S100A6 significantly improved diagnostic accuracy over CA19-9 alone. Importantly, the triple panel including S100A6, CA19-9, and carcinoembryonic antigen significantly improved the differentiation of early-stage PC from chronic pancreatitis. These findings suggest that serum S100A6 may contribute to earlier and more accurate diagnosis of PC. Such improvement could enable timely identification of patients eligible for curative resection. Additional validation in independent and diverse patient populations is warranted.