Biological Borderline Resectable Pancreatic Cancer Represents a Genetically and Immunologically Aggressive Subtype: A...

Biological borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC) refers to anatomically resectable tumors with markedly elevated serum CA19-9 levels (≥500 U/mL). This subtype is associated with poor prognosis, yet its molecular and immunopathological features remain incompletely understood.

We retrospectively analyzed 144 patients who underwent upfront surgical resection for PDAC without neoadjuvant therapy. Patients were stratified into three groups according to preoperative CA19-9: <37 U/mL (n=30), 37-499 U/mL (n=76), and ≥500 U/mL (biological BR; n=38). Clinicopathological characteristics, cancer-specific survival (CSS), driver gene alterations (KRAS, TP53, CDKN2A, SMAD4), and immune microenvironment parameters, including tumor-infiltrating lymphocytes and tertiary lymphoid structures (TLS), were evaluated.

CSS was significantly worse in patients with CA19-9 ≥500 U/mL compared with those <37 U/mL (P = 0.03). A significant stepwise increase in mutational burden was observed, with the frequency of tumors harboring ≥3 driver gene alterations rising across CA19-9 strata (Ptrend = 0.01). CDKN2A/p16 alterations also demonstrated a stepwise increase with higher CA19-9 levels (Ptrend = 0.006). TLS positivity declined progressively with increasing CA19-9 (Ptrend = 0.001), paralleled by a stepwise reduction in CD8⁺ T-cell density, although the difference did not reach statistical significance (Ptrend = 0.067). Moreover, peritoneal recurrence exhibited a stepwise increase across the groups (Ptrend = 0.047).

High preoperative CA19-9 identifies a biologically aggressive PDAC subset with increased genomic alterations and an immunosuppressive microenvironment. Recognizing CA19-9 ≥500 U/mL as a marker of high-risk disease may guide intensified perioperative strategies, even in cases deemed resectable by imaging.