Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with one of the poorest outcomes among all cancers, reflected in a 5-year survival rate of only 9% (1,2). Although early detection allows for curative surgical resection, approximately 85% of cases are diagnosed at advanced or metastatic stages due to the disease's subtle onset and rapid progression (3). Consequently, the development of novel, preferably noninvasive biomarkers with high sensitivity and specificity is essential for facilitating early diagnosis, increasing resectability, and improving survival outcomes.

Carbohydrate antigen 19-9 (CA19-9) remains the most widely used tumor marker for PDAC. However, its diagnostic performance is limited, with median sensitivity and specificity of 79 and 82%, respectively (4–9), and sensitivity dropping below 50% for tumors ≤2 cm (10). Moreover, individuals who lack Lewis antigens may exhibit false-negative CA19-9 results, further reducing its clinical utility (10–13). These limitations underscore the pressing need for complementary or alternative biomarkers.

The p53 protein is a key tumor suppressor frequently mutated across many cancer types. Mutant p53 accumulates in tumor cells, increasing immunogenicity and leading to serum autoantibody production in a subset of patients. Thus, serum p53 antibody (s-p53-Ab) positivity may function as an indirect marker of p53 mutation and tumor burden (14). Our research group have previously demonstrated the diagnostic relevance of s-p53-Ab in several solid tumors, including esophageal (15), gastric (16), colorectal (17), hepatocellular (18), and breast cancers (19), and has also explored the value of multi-autoantibody panels (17,18,20). Despite ongoing interest, reports on s-p53-Ab in PDAC are limited to five studies with small cohorts (22–82 cases), showing positivity rates of 5–28% (21–25). Importantly, no prior studies have focused solely on resectable PDAC cases or examined the prognostic implications of s-p53-Ab status.

Considering these gaps, this study aimed to clarify the clinicopathological features and prognostic significance of s-p53-Ab positivity in patients with PDCA.

This study examined the clinicopathological and prognostic significance of s-p53-Ab (+) in 124 patients with PDAC and demonstrated that 20% were s-p53-Ab (+), a status significantly associated with poorer RFS and OS.

No clear relationship was observed between s-p53-Ab positivity and clinicopathological variables, consistent with findings in other malignancies (14–18). Notably, the positivity rate in stage I (19%) and stage II (21%) patients were comparable to the overall cohort, aligning with previous reports in gastric (28), esophageal (29), colorectal (30), and hepatocellular cancers (18). Although s-p53-Ab alone was positive in 10% of stage I and 8% of stage II cases, CEA positivity was far lower (2 and 4%, respectively). These results suggest that s-p53-Ab is a supplementary diagnostic marker, particularly for early-stage PDAC, and we propose as a high-specificity ‘confirmatory’ adjunct to CA19-9, given the low sensitivity.

Regarding the prognostic significance of s-p53-Ab (+), it was identified as an independent poor prognostic factor for both RFS and OS in PDAC, suggesting that s-p53-Ab reflects the tumor's biological aggressiveness. The HRs for RFS and OS were comparable, with the HR for OS approximately 1.13 times that for RFS-similar to ratios observed with CA19-9 (×1.18) and CEA (×1.17). This suggests that patients positive for s-p53-Ab have a resistance to post-recurrence treatments comparable to those positive for CA19-9 or CEA.

Although preoperative s-p53-Ab (+) was not associated with lymph-node metastasis at surgery, it was significantly associated with postoperative lymph-node recurrence. Among patients with pathologically confirmed lymph-node metastasis, those with preoperative s-p53-Ab (+) had a markedly higher rate of lymph-node recurrence than s-p53-Ab (−) patients (8/14 vs. 8/52, P=0.028). This implies that elevated s-p53-Ab levels indicate early dissemination of cancer cells to extra-regional lymph nodes, possibly explaining the poorer RFS observed in s-p53-Ab (+) patients. s-p53-Ab might be a more sensitive indicator of occult micro-metastasis than current pathological staging.

Despite these promising results, several limitations must be acknowledged. First, the retrospective nature and single-institution design may introduce selection and information biases. Second, the unavailability of immunohistochemical analyses of tumor tissues by costs. Serum autoantibodies and expression in tumor tissue may be correlated (14). Since micro heterogeneity of p53 expression may affect induction of autoantibodies, further precise immunohistochemical analysis should be performed. Third, the biological mechanisms linking s-p53-Ab positivity to aggressive tumor behavior remain unclear; it is unknown whether s-p53-Ab simply reflects tumor immunogenicity or actively influences tumor progression or the host immune response. Further molecular and translational studies are needed to clarify this relationship. Forth, although a standardized cutoff value for s-p53-Ab (1.3 U/ml) was applied, the optimal threshold may vary depending on population characteristics, assay sensitivity, and clinical application (diagnosis vs. prognosis). Therefore, external validation in independent, multi-institutional cohorts is essential before routine clinical use. Future prospective research should confirm these findings and assess the value of incorporating s-p53-Ab into multi-marker panels or risk models to enhance pancreatic cancer management.

In conclusion, this study shows that serum s-p53-Ab is present in a subset of patients with resectable PDAC and that its positivity independently predicts poorer prognosis. s-p53-Ab may serve as a valuable adjunct biomarker for early detection and outcome prediction in PDAC.