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

Front Oncol. 2024 Dec 20:14:1488749. doi: 10.3389/fonc.2024.1488749. eCollection 2024.

Abstract

Background/aims: It was recently 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 patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Here, we aimed to extend these observations to patients diagnosed with non-metastatic PDAC.

Method: We measured circulating 3-IAA in samples from a prospective population-based cohort of 124 patients with borderline resectable or locally advanced PDAC, collected before initiating neoadjuvant chemotherapy. The majority (61%) of the patients 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.

Conclusion: Our findings suggest that the potentiating effect of 3-IAA observed in metastatic PDAC undergoing chemotherapy may not translate to borderline resectable or locally advanced PDAC. We recommend additional clinical validation of 3-IAA's predictive value in different categories of PDAC before implementation attempts in human studies are initiated.

Keywords: 3-IAA; biomarkers; chemotherapy - oncology; indole 3-acetic acid; indoles; microbiome; pancreatic adenocarcinoma.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. 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. JH is in part funded by a grant from the European Research Council (no. 802544).