Integrative Metabolomic and Immune-Microbiome Profiling for Personalised Treatment Stratification in Unresectable Pancreatic Cancer

Detailed Description <Pancreatic cancer and current treatment landscape> Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterised by nearly equal incidence and mortality rates. Globally, in 2022, there were 511,000 new cases and 467,000 deaths, making PDAC the sixth leading cause of cancer mortality among both sexes combined. In Taiwan, pancreatic cancer ranks as the seventh leading cause of cancer death, accounting for 2,769 deaths in 2022. Over 80% of patients are diagnosed at an unresectable stage (locally advanced or metastatic), for which five-year survival is below 5%. Current systemic treatments such as FOLFIRINOX or gemcitabine-based chemotherapy provide only modest improvements in median survival, and most advanced PDAC ultimately develop therapeutic resistance. No effective stratification exists to guide individualised therapy in unresectable cases - all patients typically receive similar empiric regimens despite substantial biological heterogeneity.

<Preliminary Data on Dose Escalation in Radiotherapy> Between 2015 and 2022, 231 patients with pancreatic cancer underwent locoregional radiotherapy at Linkou Chang Gung Memorial Hospital (CGMH). After applying exclusion criteria (e.g., prior surgery, small cell or neuroendocrine histology, insufficient radiotherapy dose, and inadequate follow-up), 145 patients were included in a retrospective analysis. Kaplan-Meier estimates indicated that patients receiving proton beam therapy (PBT)-either alone or in combination with X-ray radiotherapy (XRT)-demonstrated significantly better local control (LC) than those treated with XRT alone. In multivariate analysis, PBT was associated with a hazard ratio of 0.52 (95% CI 0.28-0.97; p = 0.039) for improved LC, underscoring the potential efficacy of proton-based modalities in unresectable PDAC.

Additionally, dose escalation correlated strongly with improved local outcomes. Patients prescribed ≥5940 cGy showed significantly higher one- and two-year local control (LC) rates of 100% and 88.4%, respectively, as well as an extended median LC of 28.1 months, compared to those receiving 4500-5940 cGy, which had one- and two-year LC rates of 73.3% and 40.8%, respectively, and a median LC of 18.1 months. These data highlight a dose-response relationship in locally advanced PDAC. While higher-dose PBT seems beneficial, intensifying the dose may increase toxicity and may not be suitable for all patients. Importantly, no established biomarker exists to identify those most likely to benefit from dose escalation.

<Research Gap in Unresectable PDAC> The only widely used biomarker in PDAC is serum CA19-9, which has moderate prognostic and diagnostic value but has significant limitations. CA19-9 is false-negative in 5-10% of individuals who are Lewis-antigen negative and cannot produce the antigen. It also has poor specificity, being elevated in benign biliary obstruction and other conditions. Thus, patients (especially those without Lewis antigen expression or with jaundice) cannot rely on CA19-9 for stratification. In the absence of any robust alternative biomarker to predict which unresectable PDAC patients will benefit from intensive treatment versus those who might avoid futile toxicity, the critical research gap is to identify new biomarkers that can classify advanced PDAC patients into subgroups predictive of treatment response or prognosis. This gap is particularly pressing for unresectable PDAC, where inappropriate therapy can lead to significant toxicity without meaningful benefit.

<Metabolomic Alterations in PDAC> Metabolomics offers a high-throughput and quantitative perspective on tumor phenotype, bridging genotype and clinical outcome. In particular, it presents a novel approach to address this gap by capturing global biochemical changes related to tumor presence, host metabolic response, and cachexia. Once validated, metabolic biomarkers could be translated into rapid and cost-effective assays. Notably, recent studies indicate that metabolite panels can detect PDAC with high accuracy (e.g., plasma metabolic signatures that distinguish PDAC from healthy controls, achieving an AUC of approximately 0.92) and can stratify patients by survival duration. These findings suggest that metabolomic profiling can provide prognostic insights beyond conventional markers.