MUC5AC profiling as a biomarker for predicting post-recurrence outcomes and guiding precision therapy in pancreatic ductal adenocarcinoma (PDA).

Abstract

e16374 Background: Our previous work on resected PDA patients did not fully explore the impact of MUC5AC profiling—including extracellular MUC5AC (EC-M) and intracellular mature (MM) and immature (IM) forms—beyond surgical outcomes in neoadjuvant therapy (NAT) and upfront surgery (UpS) groups. Surgery was identified as a significant confounder in assessing MUC5AC's role in chemotherapy outcomes and confirming preclinical evidence linking MM to gemcitabine (G) resistance. We hypothesized that MUC5AC profiles in recurrent lesions mirror their resected counterparts and can predict outcomes after recurrence for this study. Methods: Immunohistochemistry was performed on resected PDAs to evaluate the expression of the IM and MM of MUC5AC using their respective monoclonal antibodies, CLH2 (NBP2-44455) and 45M1 (ab3649) and the H-scores were calculated. Univariate (UVA) and multivariate (MVA) Cox regression models were used to estimate progression-free survival (R-PFS; recurrence to second progression or death) and survival (R-S; recurrence to death or last follow-up) after first recurrence. Results: The cohort included 100 patients (57 UpS, 43 NAT); 64 (33 UpS, 31 NAT) received second-line therapy (SLT) after progression. EC-M detection rates were higher in UpS (82%) vs. NAT (58%), as were MM (167 vs. 126) and IM (169 vs. 116) scores. In the NAT group, the common NAT regimen was FOLFIRINOX (FFX, 77%); post-operative therapy (PoT) was mainly G-only (26%) followed by FFX (13%) and none (35%); SLT was gemcitabine/nab-paclitaxel (G/NP, 67%). In UpS, G-only dominated PoT (58%); SLT included G/NP (33%), FFX (18%), or FOLFIRI (12%). EC-M, MM, and IM did not significantly impact PR outcomes in UVA. However, MVA incorporating other key clinical factors (see table) revealed EC-M significantly influenced R-PFS and R-S, with opposite effects in UpS and NAT groups. FFX and G/NP PoT outperformed G-only in improving outcomes, particularly in EC-M-positive tumors. For SLT, FFX provided superior outcomes in NAT, while G/NP or G/cisplatin were more effective in UpS. Conclusions: In UpS group, EC-M-positive tumors often received G-only PoT, resulting in residual or recurrent disease resistant to stronger regimens like FFX or G/NP. In NAT, EC-M-positive tumors likely received FFX, which may have enhanced responsiveness to G/NP in SLT. Integrating MUC5AC profiling into clinical workflows could guide biomarker-driven treatment selection, optimizing outcomes. UpS NAT p-value (hazard ratio) Factor R-PFS R-S R-PFS R-S EC-M detection 0.04 (5.02) 0.009 (13.7) 0.03 (0.01) 0.003 (0.001) IM 0.7 0.4 0.01 (0.92) 0.0005 (0.84) MM 0.5 0.6 0.01 (1.08) 0.0005 (1.2) PoT 0.1 0.03 0.03 0.02 SLT 0.02 0.04 0.07 0.02 Recurrence site(distant vs. local) 0.06 (12.4) 0.0006 (56) 0.02 (11.8) 0.003 (71) Margin positivity 0.01(4.64) 0.02 (3.9) 0.2 0.25 NAT regimen Not applicable 0.1 0.1422