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

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.

Figure 1

(A–D) Distributions of 3-IAA by CT-response according to RECIST criteria (A), CA19-9 decrease > 50% (B), whether surgical resection after neoadjuvant chemotherapy was performed or not (C), and by one year survival status (D). Statistical significance was tested using Mann-Whitney U tests. (E) Kaplan-Meier survival curves for overall survival for participants categorized by their pre-treatment 3-IAA concentration (quartiles) with number at risk below the plot. The result from a univariable Cox model for log(3-IAA) is shown as inset in the plot. 3-IAA, indole 3-acetate; CI, confidence interval; HR, hazard ratio.