Indole 3-acetate and response to therapy in borderline resectable or locally advanced pancreatic cancer

Background Recently, Tintelnot et al reported that a higher concentration of the bacterially produced metabolite indole 3-acetate (3-IAA) in blood was linked to a better response to chemotherapy in people with metastatic pancreatic ductal adenocarcinoma (PDAC). Here, we aimed to extend these observations to people diagnosed with non-metastatic PDAC. Patients and methods We measured circulating 3-IAA in samples from a prospective population-based cohort of 124 individuals with borderline resectable or locally advanced PDAC who later underwent primary chemotherapy. The majority (61%) of the individuals were treated with FOLFIRINOX. We used univariable and multivariable Cox proportional hazards regression to estimate the association between pre-treatment 3-IAA and overall survival. Results The median serum 3-IAA concentration before chemotherapy was 290 (interquartile range 203–417) ng/mL. The unadjusted hazard ratio (HR) for pre-treatment log2(3-IAA) was 0.93, 95% confidence interval (CI) [0.74–1.16], p=0.52. When adjusting for age, ECOG, CA19-9 and tumor classification, the HR for log2(3-IAA) was 0.87, 95% CI [0.68–1.12], p=0.28. Conclusions Our findings suggest that the potentiating effect of 3-IAA observed in metastatic PDAC may not translate to borderline resectable or locally advanced PDAC. We recommend additional clinical validation of 3-IAA’s predictive value before implementation attempts in human studies are initiated. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The study and co-workers were funded by research grants from the Regional Health Authorities of South-Eastern Norway (no. 2018088, 2019029, 2023018) and the Norwegian Cancer Society (198039-2018), as well as by the strategic research area 'Personalized microbiota therapy in clinical medicine' at Oslo University Hospital. J.R.H. is in part funded by a grant from the European Research Council (no. 802544). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Regional Committee for Medical and Health Research Ethics gave ethical approval for this work (REK Nord 2017/1382, Norwegian Pancreatic Cancer Trial-2, NORPACT-2) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes