A multigene circulating biomarker to predict the lack of FOLFIRINOX response after a single cycle in patients with pancreatic ductal adenocarcinoma

Casper H J van Eijck; Willem de Koning; Fleur van der Sijde; Miranda Moskie; Bas Groot Koerkamp; Marjolein Y V Homs; Sjoerd H van der Burg; Casper H J van Eijck; Dana A M Mustafa

doi:10.1016/j.ejca.2022.12.024

A multigene circulating biomarker to predict the lack of FOLFIRINOX response after a single cycle in patients with pancreatic ductal adenocarcinoma

Casper H J van Eijck
, Willem de Koning
, Fleur van der Sijde
, Miranda Moskie
, Bas Groot Koerkamp
, Marjolein Y V Homs
, Sjoerd H van der Burg
, Casper H J van Eijck
, Dana A M Mustafa^*

^*Corresponding author for this work

Leiden University Medical Centre

Research output: Contribution to journal › Article › Academic › peer-review

13 Citations (Scopus)

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Abstract

INTRODUCTION: 5-fluorouracil, folinic acid, irinotecan and oxaliplatin (FOLFIRINOX) is promising in treating patients with pancreatic ductal adenocarcinoma. However, many patients and physicians are reluctant to start FOLFIRINOX due to its high toxicity and limited clinical response rates. In this study, we investigated the effect of a single FOLFIRINOX cycle, in combination with a granulocyte colony-stimulating factor, on the blood immune transcriptome of patients with pancreatic ductal adenocarcinoma. We aimed to identify an early circulating biomarker to predict the lack of FOLFIRINOX response.

METHODS: Blood samples of 68 patients from all disease stages, who received at least four FOLFIRINOX cycles, were collected at baseline and after the first cycle. The response to treatment was radiologically evaluated following the Response Evaluation Criteria in Solid Tumours criteria 1.1. Targeted immune-gene expression profiling (GEP) was performed using NanoString technologies. To predict the lack of FOLFIRINOX response, we developed a FOLFIRINOX delta GEP (FFX-ΔGEP) score.

RESULTS: A single FOLFIRINOX cycle significantly altered 395 genes, correlating to 30 significant alterations in relative immune cell abundances and pathway activities. The eight-gene (BID, FOXP3, KIR3DL1, MAF, PDGFRB, RRAD, SIGLEC1 and TGFB2) FFX-ΔGEP score predicted the lack of FOLFIRINOX response with a leave-one-out cross-validated area under the curve (95% confidence interval) of 0.87 (0.60-0.98), thereby outperforming the predictiveness of absolute and proportional Δcarbohydrate antigen19-9 values.

CONCLUSIONS: A single FOLFIRINOX cycle, combined with granulocyte colony-stimulating factor, alters the peripheral immune transcriptome indisputably. Our novel FFX-ΔGEP is, to our knowledge, the first multigene early circulating biomarker that predicts the lack of FOLFIRINOX response after one cycle. Validation in a larger independent patient cohort is crucial before clinical implementation.

Original language	English
Pages (from-to)	119-134
Number of pages	16
Journal	European Journal of Cancer
Volume	181
Early online date	Jan 2023
DOIs	https://doi.org/10.1016/j.ejca.2022.12.024
Publication status	Published - Mar 2023

Bibliographical note

Funding Information:
This work was financially supported by the Survival with Pancreatic Cancer Foundation ( www.supportcasper.nl ) [grant number OVIT17-06].

Publisher Copyright:
© 2022 The Authors

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van Eijck, C. H. J., de Koning, W., van der Sijde, F., Moskie, M., Groot Koerkamp, B., Homs, M. Y. V., van der Burg, S. H., van Eijck, C. H. J., & Mustafa, D. A. M. (2023). A multigene circulating biomarker to predict the lack of FOLFIRINOX response after a single cycle in patients with pancreatic ductal adenocarcinoma. European Journal of Cancer, 181, 119-134. https://doi.org/10.1016/j.ejca.2022.12.024

@article{17f8b7ce5e734adeb53dd805456d437b,

title = "A multigene circulating biomarker to predict the lack of FOLFIRINOX response after a single cycle in patients with pancreatic ductal adenocarcinoma",

abstract = "INTRODUCTION: 5-fluorouracil, folinic acid, irinotecan and oxaliplatin (FOLFIRINOX) is promising in treating patients with pancreatic ductal adenocarcinoma. However, many patients and physicians are reluctant to start FOLFIRINOX due to its high toxicity and limited clinical response rates. In this study, we investigated the effect of a single FOLFIRINOX cycle, in combination with a granulocyte colony-stimulating factor, on the blood immune transcriptome of patients with pancreatic ductal adenocarcinoma. We aimed to identify an early circulating biomarker to predict the lack of FOLFIRINOX response.METHODS: Blood samples of 68 patients from all disease stages, who received at least four FOLFIRINOX cycles, were collected at baseline and after the first cycle. The response to treatment was radiologically evaluated following the Response Evaluation Criteria in Solid Tumours criteria 1.1. Targeted immune-gene expression profiling (GEP) was performed using NanoString technologies. To predict the lack of FOLFIRINOX response, we developed a FOLFIRINOX delta GEP (FFX-ΔGEP) score.RESULTS: A single FOLFIRINOX cycle significantly altered 395 genes, correlating to 30 significant alterations in relative immune cell abundances and pathway activities. The eight-gene (BID, FOXP3, KIR3DL1, MAF, PDGFRB, RRAD, SIGLEC1 and TGFB2) FFX-ΔGEP score predicted the lack of FOLFIRINOX response with a leave-one-out cross-validated area under the curve (95\% confidence interval) of 0.87 (0.60-0.98), thereby outperforming the predictiveness of absolute and proportional Δcarbohydrate antigen19-9 values.CONCLUSIONS: A single FOLFIRINOX cycle, combined with granulocyte colony-stimulating factor, alters the peripheral immune transcriptome indisputably. Our novel FFX-ΔGEP is, to our knowledge, the first multigene early circulating biomarker that predicts the lack of FOLFIRINOX response after one cycle. Validation in a larger independent patient cohort is crucial before clinical implementation.",

author = "\{van Eijck\}, \{Casper H J\} and \{de Koning\}, Willem and \{van der Sijde\}, Fleur and Miranda Moskie and \{Groot Koerkamp\}, Bas and Homs, \{Marjolein Y V\} and \{van der Burg\}, \{Sjoerd H\} and \{van Eijck\}, \{Casper H J\} and Mustafa, \{Dana A M\}",

note = "Funding Information: This work was financially supported by the Survival with Pancreatic Cancer Foundation ( www.supportcasper.nl ) [grant number OVIT17-06]. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2023",

month = mar,

doi = "10.1016/j.ejca.2022.12.024",

language = "English",

volume = "181",

pages = "119--134",

journal = "European Journal of Cancer",

issn = "0959-8049",

publisher = "Elsevier Ltd.",

}

van Eijck, CHJ, de Koning, W, van der Sijde, F, Moskie, M, Groot Koerkamp, B, Homs, MYV, van der Burg, SH, van Eijck, CHJ & Mustafa, DAM 2023, 'A multigene circulating biomarker to predict the lack of FOLFIRINOX response after a single cycle in patients with pancreatic ductal adenocarcinoma', European Journal of Cancer, vol. 181, pp. 119-134. https://doi.org/10.1016/j.ejca.2022.12.024

TY - JOUR

T1 - A multigene circulating biomarker to predict the lack of FOLFIRINOX response after a single cycle in patients with pancreatic ductal adenocarcinoma

AU - van Eijck, Casper H J

AU - de Koning, Willem

AU - van der Sijde, Fleur

AU - Moskie, Miranda

AU - Groot Koerkamp, Bas

AU - Homs, Marjolein Y V

AU - van der Burg, Sjoerd H

AU - van Eijck, Casper H J

AU - Mustafa, Dana A M

N1 - Funding Information: This work was financially supported by the Survival with Pancreatic Cancer Foundation ( www.supportcasper.nl ) [grant number OVIT17-06]. Publisher Copyright: © 2022 The Authors

PY - 2023/3

Y1 - 2023/3

N2 - INTRODUCTION: 5-fluorouracil, folinic acid, irinotecan and oxaliplatin (FOLFIRINOX) is promising in treating patients with pancreatic ductal adenocarcinoma. However, many patients and physicians are reluctant to start FOLFIRINOX due to its high toxicity and limited clinical response rates. In this study, we investigated the effect of a single FOLFIRINOX cycle, in combination with a granulocyte colony-stimulating factor, on the blood immune transcriptome of patients with pancreatic ductal adenocarcinoma. We aimed to identify an early circulating biomarker to predict the lack of FOLFIRINOX response.METHODS: Blood samples of 68 patients from all disease stages, who received at least four FOLFIRINOX cycles, were collected at baseline and after the first cycle. The response to treatment was radiologically evaluated following the Response Evaluation Criteria in Solid Tumours criteria 1.1. Targeted immune-gene expression profiling (GEP) was performed using NanoString technologies. To predict the lack of FOLFIRINOX response, we developed a FOLFIRINOX delta GEP (FFX-ΔGEP) score.RESULTS: A single FOLFIRINOX cycle significantly altered 395 genes, correlating to 30 significant alterations in relative immune cell abundances and pathway activities. The eight-gene (BID, FOXP3, KIR3DL1, MAF, PDGFRB, RRAD, SIGLEC1 and TGFB2) FFX-ΔGEP score predicted the lack of FOLFIRINOX response with a leave-one-out cross-validated area under the curve (95% confidence interval) of 0.87 (0.60-0.98), thereby outperforming the predictiveness of absolute and proportional Δcarbohydrate antigen19-9 values.CONCLUSIONS: A single FOLFIRINOX cycle, combined with granulocyte colony-stimulating factor, alters the peripheral immune transcriptome indisputably. Our novel FFX-ΔGEP is, to our knowledge, the first multigene early circulating biomarker that predicts the lack of FOLFIRINOX response after one cycle. Validation in a larger independent patient cohort is crucial before clinical implementation.

AB - INTRODUCTION: 5-fluorouracil, folinic acid, irinotecan and oxaliplatin (FOLFIRINOX) is promising in treating patients with pancreatic ductal adenocarcinoma. However, many patients and physicians are reluctant to start FOLFIRINOX due to its high toxicity and limited clinical response rates. In this study, we investigated the effect of a single FOLFIRINOX cycle, in combination with a granulocyte colony-stimulating factor, on the blood immune transcriptome of patients with pancreatic ductal adenocarcinoma. We aimed to identify an early circulating biomarker to predict the lack of FOLFIRINOX response.METHODS: Blood samples of 68 patients from all disease stages, who received at least four FOLFIRINOX cycles, were collected at baseline and after the first cycle. The response to treatment was radiologically evaluated following the Response Evaluation Criteria in Solid Tumours criteria 1.1. Targeted immune-gene expression profiling (GEP) was performed using NanoString technologies. To predict the lack of FOLFIRINOX response, we developed a FOLFIRINOX delta GEP (FFX-ΔGEP) score.RESULTS: A single FOLFIRINOX cycle significantly altered 395 genes, correlating to 30 significant alterations in relative immune cell abundances and pathway activities. The eight-gene (BID, FOXP3, KIR3DL1, MAF, PDGFRB, RRAD, SIGLEC1 and TGFB2) FFX-ΔGEP score predicted the lack of FOLFIRINOX response with a leave-one-out cross-validated area under the curve (95% confidence interval) of 0.87 (0.60-0.98), thereby outperforming the predictiveness of absolute and proportional Δcarbohydrate antigen19-9 values.CONCLUSIONS: A single FOLFIRINOX cycle, combined with granulocyte colony-stimulating factor, alters the peripheral immune transcriptome indisputably. Our novel FFX-ΔGEP is, to our knowledge, the first multigene early circulating biomarker that predicts the lack of FOLFIRINOX response after one cycle. Validation in a larger independent patient cohort is crucial before clinical implementation.

UR - https://www.scopus.com/pages/publications/85146471278

U2 - 10.1016/j.ejca.2022.12.024

DO - 10.1016/j.ejca.2022.12.024

M3 - Article

C2 - 36652890

SN - 0959-8049

VL - 181

SP - 119

EP - 134

JO - European Journal of Cancer

JF - European Journal of Cancer

ER -

A multigene circulating biomarker to predict the lack of FOLFIRINOX response after a single cycle in patients with pancreatic ductal adenocarcinoma

Abstract

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