Ultra-refractory PD–PD pancreatic cancer: Clinical and molecular insights across first- and second-line therapy.

Abstract

4206 Background: A subset of pancreatic cancer (PC) patients exhibits progressive disease (PD) as the best response to both first- and second-line chemotherapy (PD-PD), representing an ultra-refractory population with dismal outcomes. This group remains poorly characterized, highlighting a critical unmet need for novel therapeutic strategies. Methods: We retrospectively analyzed PC patients treated at Vall d’Hebron University Hospital (2012–2025) who received both first- and second-line chemotherapy with 5-FU- or gemcitabine-based regimens. Clinical, histopathological and molecular data were collected. Characteristics of PD-PD patients were compared with those achieving clinical benefit, defined as complete or partial response (CR/PR) in at least one treatment line. Progression-free survival (PFS2) was calculated from the start of first-line therapy to documented PD after second-line treatment. Overall survival (OS) was calculated from the start of first-line therapy to death or last follow-up. Survival curves were estimated using the Kaplan–Meier method. RNA-seq was performed on diagnostic tumor samples to explore transcriptomic features. Results: Median follow-up for the entire cohort was 58 months. Among 400 patients, 46 (12%) were classified as PD-PD. Median PFS2 was 5.4 months in PD-PD vs 14.5 months in CR/PR, and median OS was 8.1 vs 20.8 months, respectively (p < 0.001 for both). Treatment sequences in PD-PD patients included 5-FU followed by gemcitabine (18, 39%) and gemcitabine followed by 5-FU (28, 61%). Patients receiving 5-FU first were younger (median age 57 vs 72 years, p = 0.035). Histopathological features were similar in both groups. Inflammatory markers were largely comparable; however, median CRP/albumin ratio was higher in PD-PD, 0.86 vs 0.24 in CR/PR (p < 0.001). Molecular profiling was available for 34 (74%) of patients. Among these, KRAS mutations were present in 84% of patients, with G12V slightly more frequent in PD-PD than CR/PR (45% vs 31%, p = 0.5). TP53 mutations occurred in 81% vs 65% (p = 0.083), and SMAD4 alterations were more common in CR/PR (19% vs 6.3%, p = 0.082). DDR pathway alterations were rare in PD-PD patients. Exploratory RNA-seq of six PD-PD compared with CR/PR (n = 2) tumors revealed upregulation of coagulation and lipid metabolism genes ( FGB, APOA1 ) and downregulation of pancreatic function genes ( PNLIP, CPA1 ), suggesting potential alterations in inflammatory and metabolic pathways. Conclusions: PD-PD patients represent an ultra-refractory subset (~12%) of PC with very poor outcomes despite standard therapy. Differences in inflammatory markers and transcriptomic trends may reflect underlying biological features of this highly resistant phenotype. These findings underscore the need for further studies to clarify mechanisms of primary resistance and guide the development of novel therapeutic strategies in this high-risk population.