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. 2024 Sep 11:14:1437200.
doi: 10.3389/fonc.2024.1437200. eCollection 2024.

Development of transcriptomic tools for predicting the response to individual drug of the mFOLFIRINOX regimen in patients with metastatic pancreatic cancer

Nicolas Fraunhoffer  1   2 , Carlos Teyssedou  1   3 , Patrick Pessaux  4 , Martin Bigonnet  5 , Nelson Dusetti  1 , Juan Iovanna  1   6   7
Affiliations

Development of transcriptomic tools for predicting the response to individual drug of the mFOLFIRINOX regimen in patients with metastatic pancreatic cancer

Nicolas Fraunhoffer et al. Front Oncol. .

Abstract

Background: The utilization of modified FOLFIRINOX (mFFX) therapy has shown notable advancements in patient outcomes in both localized and metastatic PDAC. Nevertheless, the effectiveness of mFFX treatment comes at the cost of elevated toxicity, leading to its restriction to patients with adequate performance status. Consequently, the administration of mFFX is contingent upon patient performance rather than rational criteria. The ideal scenario would involve the ability to assess the sensitivity of each drug within the mFFX regimen, minimizing unnecessary toxicity without compromising clinical benefits.

Methods: We developed transcriptomic signatures for each drug of the mFFX regimen (5FU, oxaliplatin and irinotecan) by integrating transcriptomic data from PDC, PDO and PDX with their corresponding chemo-response profiles to capture the biological components responsible for the response to each drug. We further validated the signatures in a cohort of 167 patients with advanced and metastatic PDAC.

Results: All three signatures captured high responder patients for OS and PFS in the mFFX arm exclusively. We then studied the response of patients to 0, 1, 2 and 3 drugs and we identified a positive correlation between the number of drugs predicted as sensitive and the OS and PFS, and the with objective response rate.

Conclusions: We developed three novel transcriptome-based signatures which define sensitivity for each mFFX components that can be used to rationalize the administration of the mFFX regimen in patients with metastatic pancreatic cancer and could help to avoid unnecessary toxic effects.

Keywords: FOLFIRINOX; RNA signatures; chemosensitivity prediction; metastatic cancer; pancreatic cancer; precision medicine.

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Conflict of interest statement

ND and JI are founders of Predicting Med. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Development and analysis of mFFX component signatures. Diagram representing the workflow to extract and validate the transcriptomic signatures. CCL, commercial cell lines; PDC, patient-derived primary cell cultures; PDO, patient-derived organoids; PDX, patient-derived xenografts.
Figure 2
Figure 2
Kaplan-Meier curves for OS of patients according to the signatures and their interactions. (A) Kaplan-Meier curves for 5FUCore. (B) Kaplan-Meier curves for OxaCore. (C) Kaplan-Meier curves for IriCore. (D) Kaplan-Meier curves showing the interaction between signatures. The dashed lines represent the adjusted curves. OS, overall survival; Sens, Sensitive.
Figure 3
Figure 3
Kaplan-Meier curves for PFS of patients according to the signatures and their interactions. (A) Kaplan-Meier curves for 5FUCore. (B) Kaplan-Meier curves for OxaCore. (C) Kaplan-Meier curves for IriCore. (D) Kaplan-Meier curves showing the interaction between signatures. The dashed lines represent the adjusted curves. PFS, progression-free survival; Sens, Sensitive.
Figure 4
Figure 4
(A) Barplot displaying the association between each signature and the PurIST stratification. (B, C) multivariate Cox regression for OS and PFS, respectively. HR, hazard ratio; CI, confidence interval; OS, overall survival; PFS, progression-free survival.
Figure 5
Figure 5
Objective response rate for the signature interaction. ORR, objective response rate; CI, confidence interval.
See this image and copyright information in PMC

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