The 2017 International Consensus Criteria (ICC) redefined borderline resectable pancreatic ductal adenocarcinoma according to its anatomical, biological, and conditional characteristics (1). Resectable (R) pancreatic cancer with markedly elevated carbohydrate antigen 19-9 (CA19-9) level is classified as biological borderline resectable (BR-B) and is associated with poor prognosis (2). However, consensus regarding the optimal preoperative treatment for BR-B remains lacking.

Although elevated CA19-9 levels clearly indicate the need for preoperative intervention (3), other biomarkers that may define BR-B have not yet been identified. C-reactive protein (CRP), a marker of systemic inflammation, and neutrophil-to-lymphocyte ratio (NLR), an index of inflammation and nutritional status, have been reported to be prognostic factors in pancreatic cancer (4–6). Nevertheless, no study has directly evaluated the combined prognostic significance of CA19-9, CRP, and NLR in resected pancreatic cancer. As such, we focused on CRP and NLR-simple, accessible preoperative biomarkers-and investigated their prognostic relevance alongside CA19-9 to develop an improved definition of BR-B.

Postoperative survival after resection of pancreatic cancer has improved with the introduction of multiagent adjuvant chemotherapy. Nevertheless, the outcomes for patients with BR-B pancreatic cancer remain poor, and several reports have emphasized the need for preoperative treatment strategies comparable with those used for anatomically borderline resectable disease (2,7). Therefore, a more refined biological definition of tumor resectability is clinically important.

Historically, BR-B pancreatic cancer was defined using criteria proposed in earlier studies, including CA19-9 level ≥200 U/ml (8–10), cancer-related symptoms lasting >40 days (8), and radiological or cytological suspicion of lymph node metastasis at diagnosis (1). However, the 2017 ICC first established CA19-9 levels >500 U/ml as the primary marker of BR-B pancreatic cancer; this threshold has since been widely adopted (1).

Although CA19-9 plays a central role in estimating tumor aggressiveness (3), it remains unclear whether additional biomarkers would further refine the definition of BR-B pancreatic cancer. As such, we focused on 2 easily measurable inflammatory markers-CRP level and NLR-which emerged as independent predictors of poor prognosis in our multivariate analysis and have been implicated in pancreatic cancer biology in the previous literature (4–6,11). Because these markers can be obtained through routine preoperative laboratory investigations, these markers are highly practical and broadly applicable.

Elevated CRP is not merely a bystander but reflects the complex interplay between the host and the tumor. Advanced tumor progression induces systemic inflammation via the upregulation of the interleukin (IL)-1-IL-6 cytokine network and the release of tumor-derived degradation products, leading to enhanced hepatic CRP production. High CRP levels characterize a proinflammatory tumor microenvironment (TME), which facilitates tumor proliferation, angiogenesis, and the metastatic cascade, while also potentially indicating tumor necrosis and a high tumor burden. Furthermore, CRP may be involved in complement activation and opsonization of tumor cells, thereby linking the innate and adaptive immune responses (12–15).

The prognostic significance of NLR in pancreatic cancer lies in its effect on the balance between tumor-promoting inflammation and anti-tumor immunity. Tumor-driven systemic inflammatory responses play a crucial role in malignant transformation by facilitating increased neutrophil infiltration within the TME, which is a hallmark of cancer progression. These neutrophils can suppress the cytotoxic activity of lymphocytes, whose infiltration is essential for a favorable prognosis but is frequently diminished in the advanced stages of disease. Therefore, an elevated NLR characterizes an immune environment that shifts toward tumor promotion and evasion (16–18).

Previous studies have examined pairwise combinations of CA19-9 levels and CRP or NLR. Nurmi et al (19) evaluated a prognostic score incorporating CA19-9 and CRP and demonstrated significantly worse DFS and disease-specific survival in patients with elevated levels of both markers, and significantly better outcomes when both were low. Similarly, Sakamoto et al (20) stratified patients according to NLR and CA19-9 and found that the group with elevated levels of both markers had the worst prognosis, whereas the double-low group had the best. Asaoka et al (21) also reported that elevated CA19-9 levels and NLR were associated with markedly reduced postoperative survival in pancreatic cancer. The relationship between CRP and NLR has also been described, with Schlick et al (22) reporting that prognosis worsens as the number of elevated markers increases (22,23). A unique feature of the present study was the simultaneous integration of CA19-9, CRP, and NLR, thereby capturing the complementary aspects of tumor burden, systemic inflammation, and host immune status. This three-factor approach enabled a more refined prognostic stratification than models based on a single inflammatory marker and identified a subgroup with particularly favorable outcomes in the absence of all elevated biomarkers.

Building on this evidence, our study explored the utility of combining and scoring 3 biological markers-CA19-9, CRP, and NLR-in the preoperative assessment of pancreatic cancer to refine the concept of BR-B disease. Using this three-factor model, we successfully identified the group with poor prognosis. This suggests that patients with multiple elevated biomarkers may benefit from intensified preoperative management, including more aggressive NAC or structured prehabilitation programs. Our findings suggest a practical framework for the preoperative risk stratification of anatomically resectable pancreatic cancers. Patients without elevated biomarker (CA19-9 <500 U/ml, CRP <0.3 mg/dl, and NLR <3.13) levels experienced favorable outcomes and may be suitable candidates for upfront surgery. In contrast, patients with multiple elevated biomarkers experienced substantially poorer survival and may benefit from more intensive preoperative strategies, including NAC and structured prehabilitation. Therefore, this three-factor model may refine the current definition of BR-B pancreatic cancer by incorporating markers of systemic inflammation and immune status in addition to tumor burden. However, this three-factor model should be regarded as exploratory and hypothesis-generating rather than a validated revised BR-B criterion or definitive treatment algorithm. External validation in larger multicenter cohorts is required before clinical implementation. Furthermore, because the model incorporates CRP and NLR, it may identify biologically aggressive diseases, even in Lewis antigen-negative patients who may not express CA19-9 (24). PD was more frequently performed in the CRP-high group, possibly reflecting differences in tumor location and surgical invasiveness. However, the surgical procedure was not identified as an independent prognostic factor in the multivariate analysis, suggesting that the prognostic significance of CRP and NLR was not solely attributable to differences in the surgical procedures. Interestingly, in the favorable prognosis subgroup (i.e., those with no elevated biomarkers), patients who underwent NAC exhibited poorer DFS outcomes than those who underwent upfront surgery (P=0.014). Although limited by the sample size and retrospective design of this study, this finding suggests that NAC may not be beneficial and may even be detrimental in biologically favorable cases. Therefore, biomarker-guided selection may help to avoid overtreatment. However, this observation should be interpreted with caution and a causal relationship should not be established.

The present study had several limitations, the first of which was its retrospective, single-center design and relatively small sample size, particularly the BR-B subgroup, which may have introduced a selection bias. All patients who underwent NAC were treated with GS and adjuvant chemotherapy consisting of S-1 administered for 6 months. However, treatment strategies have not been fully standardized with regard to the indications and timing of NAC, and whether adjuvant chemotherapy should be administered. In addition, the subgroup with three elevated biomarkers was very small (n=2); therefore, the corresponding findings should be considered exploratory and hypothesis-generating rather than definitive evidence and should be interpreted with caution. CRP and NLR are nonspecific biomarkers that may be influenced by factors unrelated to tumor biology, including the timing of measurement, transient inflammatory conditions, and interlaboratory variability. Although biomarker measurements were standardized to the pretreatment period and obtained only after the resolution of cholangitis or obstructive jaundice, residual confounding factors cannot be excluded. Postoperative complications were not included in the present analysis because this study focused on preoperative prognostic factors. External validation in larger multicenter cohorts is required to confirm the generalizability and clinical utility of the proposed three-factor model.

In conclusion, CRP level and NLR were identified as significant prognostic markers for pancreatic cancer. When combined with CA19-9, these markers enabled a more detailed preoperative stratification and may help identify patients requiring intensive treatment. Conversely, patients with favorable biomarker profiles may be candidates for upfront surgery without NAC. Thus, incorporating CA19-9, CRP, and NLR into the biological evaluation of pancreatic cancer may contribute to a more individualized and biologically informed treatment approach.