Promoter hypermethylation of SFRP1 as a prognostic and potentially predictive blood-based biomarker in patients with stage III or IV pancreatic ductal adenocarcinoma

Benjamin Stubbe; Poul H. Madsen; Anders Christian Larsen; Henrik B. Krarup; Inge S. Pedersen; Julia S. Johansen; Stine D. Henriksen; Ole Thorlacius-Ussing

doi:10.1016/j.pan.2023.05.003

Promoter hypermethylation of SFRP1 as a prognostic and potentially predictive blood-based biomarker in patients with stage III or IV pancreatic ductal adenocarcinoma

Benjamin Stubbe^*, Poul H. Madsen, Anders Christian Larsen, Henrik B. Krarup, Inge S. Pedersen, Julia S. Johansen, Stine D. Henriksen, Ole Thorlacius-Ussing

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

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Abstract

Background
Pancreatic ductal adenocarcinoma remains one of the major causes of cancer-related mortality globally. Unfortunately, current prognostic biomarkers are limited, and no predictive biomarkers exist. This study examined promoter hypermethylation of secreted frizzled-related protein 1 (phSFRP1) in cfDNA as a prognostic biomarker and predictor of treatment effect in patients with metastatic FOLFIRINOX-treated PDAC and locally advanced PDAC.

Methods
We performed methylation-specific PCR of the SFRP1 genes’ promoter region, based on bisulfite treatment. Survival was assessed as time-to-event data using the pseudo-observation method and analyzed with Kaplan-Meier curves and generalized linear regressions.

Results
The study included 52 patients with FOLFIRINOX-treated metastatic PDAC. Patients with unmethylated (um) SFRP1 (n = 29) had a longer median overall survival (15.7 months) than those with phSFRP1 (6.8 months). In crude regression, phSFRP1 was associated with an increased risk of death of 36.9% (95% CI 12.0%–61.7%) and 19.8% (95% CI 1.9–37.6) at 12 and 24-months, respectively. In supplementary regression analysis, interaction terms between SFRP1 methylation status and treatment were significant, indicating reduced benefit of chemotherapy. Forty-four patients with locally advanced PDAC were included. phSFRP1 was associated with an increased risk of death at 24-months

Conclusions
This indicates that phSFRP1 is a clinically useful prognostic biomarker in metastatic PDAC and possibly in locally advanced PDAC. Together with existing literature, results could indicate the value of cfDNA-measured phSFRP1 as a predictive biomarker of standard palliative chemotherapy in patients with metastatic PDAC. This could facilitate personalized treatment of patients with metastatic PDAC.

Original language	English
Journal	Pancreatology
Volume	23
Issue number	5
Pages (from-to)	512-521
Number of pages	10
ISSN	1424-3903
DOIs	https://doi.org/10.1016/j.pan.2023.05.003
Publication status	Published - Aug 2023

Keywords

Biomarker
Blood-based
DNA methylation
Pancreatic ductal adenocarcinoma
Prognosis
epigenetics
survival

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Stubbe, B., Madsen, P. H., Larsen, A. C., Krarup, H. B., Pedersen, I. S., Johansen, J. S., Henriksen, S. D., & Thorlacius-Ussing, O. (2023). Promoter hypermethylation of SFRP1 as a prognostic and potentially predictive blood-based biomarker in patients with stage III or IV pancreatic ductal adenocarcinoma. Pancreatology, 23(5), 512-521. https://doi.org/10.1016/j.pan.2023.05.003

@article{a5db5b62689744f8b46c67413b030d2c,

title = "Promoter hypermethylation of SFRP1 as a prognostic and potentially predictive blood-based biomarker in patients with stage III or IV pancreatic ductal adenocarcinoma",

abstract = "BackgroundPancreatic ductal adenocarcinoma remains one of the major causes of cancer-related mortality globally. Unfortunately, current prognostic biomarkers are limited, and no predictive biomarkers exist. This study examined promoter hypermethylation of secreted frizzled-related protein 1 (phSFRP1) in cfDNA as a prognostic biomarker and predictor of treatment effect in patients with metastatic FOLFIRINOX-treated PDAC and locally advanced PDAC.MethodsWe performed methylation-specific PCR of the SFRP1 genes{\textquoteright} promoter region, based on bisulfite treatment. Survival was assessed as time-to-event data using the pseudo-observation method and analyzed with Kaplan-Meier curves and generalized linear regressions.ResultsThe study included 52 patients with FOLFIRINOX-treated metastatic PDAC. Patients with unmethylated (um) SFRP1 (n = 29) had a longer median overall survival (15.7 months) than those with phSFRP1 (6.8 months). In crude regression, phSFRP1 was associated with an increased risk of death of 36.9% (95% CI 12.0%–61.7%) and 19.8% (95% CI 1.9–37.6) at 12 and 24-months, respectively. In supplementary regression analysis, interaction terms between SFRP1 methylation status and treatment were significant, indicating reduced benefit of chemotherapy. Forty-four patients with locally advanced PDAC were included. phSFRP1 was associated with an increased risk of death at 24-monthsConclusionsThis indicates that phSFRP1 is a clinically useful prognostic biomarker in metastatic PDAC and possibly in locally advanced PDAC. Together with existing literature, results could indicate the value of cfDNA-measured phSFRP1 as a predictive biomarker of standard palliative chemotherapy in patients with metastatic PDAC. This could facilitate personalized treatment of patients with metastatic PDAC.",

keywords = "Biomarker, Blood-based, DNA methylation, Pancreatic ductal adenocarcinoma, Prognosis, epigenetics, survival",

author = "Benjamin Stubbe and Madsen, {Poul H.} and Larsen, {Anders Christian} and Krarup, {Henrik B.} and Pedersen, {Inge S.} and Johansen, {Julia S.} and Henriksen, {Stine D.} and Ole Thorlacius-Ussing",

year = "2023",

month = aug,

doi = "10.1016/j.pan.2023.05.003",

language = "English",

volume = "23",

pages = "512--521",

journal = "Pancreatology",

issn = "1424-3903",

publisher = "Elsevier",

number = "5",

}

Stubbe, B, Madsen, PH , Larsen, AC , Krarup, HB , Pedersen, IS, Johansen, JS, Henriksen, SD & Thorlacius-Ussing, O 2023, 'Promoter hypermethylation of SFRP1 as a prognostic and potentially predictive blood-based biomarker in patients with stage III or IV pancreatic ductal adenocarcinoma', Pancreatology, vol. 23, no. 5, pp. 512-521. https://doi.org/10.1016/j.pan.2023.05.003

Promoter hypermethylation of SFRP1 as a prognostic and potentially predictive blood-based biomarker in patients with stage III or IV pancreatic ductal adenocarcinoma. / Stubbe, Benjamin; Madsen, Poul H.; Larsen, Anders Christian et al.
In: Pancreatology, Vol. 23, No. 5, 08.2023, p. 512-521.

Research output: Contribution to journal › Journal article › Research › peer-review

TY - JOUR

T1 - Promoter hypermethylation of SFRP1 as a prognostic and potentially predictive blood-based biomarker in patients with stage III or IV pancreatic ductal adenocarcinoma

AU - Stubbe, Benjamin

AU - Madsen, Poul H.

AU - Larsen, Anders Christian

AU - Krarup, Henrik B.

AU - Pedersen, Inge S.

AU - Johansen, Julia S.

AU - Henriksen, Stine D.

AU - Thorlacius-Ussing, Ole

PY - 2023/8

Y1 - 2023/8

N2 - BackgroundPancreatic ductal adenocarcinoma remains one of the major causes of cancer-related mortality globally. Unfortunately, current prognostic biomarkers are limited, and no predictive biomarkers exist. This study examined promoter hypermethylation of secreted frizzled-related protein 1 (phSFRP1) in cfDNA as a prognostic biomarker and predictor of treatment effect in patients with metastatic FOLFIRINOX-treated PDAC and locally advanced PDAC.MethodsWe performed methylation-specific PCR of the SFRP1 genes’ promoter region, based on bisulfite treatment. Survival was assessed as time-to-event data using the pseudo-observation method and analyzed with Kaplan-Meier curves and generalized linear regressions.ResultsThe study included 52 patients with FOLFIRINOX-treated metastatic PDAC. Patients with unmethylated (um) SFRP1 (n = 29) had a longer median overall survival (15.7 months) than those with phSFRP1 (6.8 months). In crude regression, phSFRP1 was associated with an increased risk of death of 36.9% (95% CI 12.0%–61.7%) and 19.8% (95% CI 1.9–37.6) at 12 and 24-months, respectively. In supplementary regression analysis, interaction terms between SFRP1 methylation status and treatment were significant, indicating reduced benefit of chemotherapy. Forty-four patients with locally advanced PDAC were included. phSFRP1 was associated with an increased risk of death at 24-monthsConclusionsThis indicates that phSFRP1 is a clinically useful prognostic biomarker in metastatic PDAC and possibly in locally advanced PDAC. Together with existing literature, results could indicate the value of cfDNA-measured phSFRP1 as a predictive biomarker of standard palliative chemotherapy in patients with metastatic PDAC. This could facilitate personalized treatment of patients with metastatic PDAC.

AB - BackgroundPancreatic ductal adenocarcinoma remains one of the major causes of cancer-related mortality globally. Unfortunately, current prognostic biomarkers are limited, and no predictive biomarkers exist. This study examined promoter hypermethylation of secreted frizzled-related protein 1 (phSFRP1) in cfDNA as a prognostic biomarker and predictor of treatment effect in patients with metastatic FOLFIRINOX-treated PDAC and locally advanced PDAC.MethodsWe performed methylation-specific PCR of the SFRP1 genes’ promoter region, based on bisulfite treatment. Survival was assessed as time-to-event data using the pseudo-observation method and analyzed with Kaplan-Meier curves and generalized linear regressions.ResultsThe study included 52 patients with FOLFIRINOX-treated metastatic PDAC. Patients with unmethylated (um) SFRP1 (n = 29) had a longer median overall survival (15.7 months) than those with phSFRP1 (6.8 months). In crude regression, phSFRP1 was associated with an increased risk of death of 36.9% (95% CI 12.0%–61.7%) and 19.8% (95% CI 1.9–37.6) at 12 and 24-months, respectively. In supplementary regression analysis, interaction terms between SFRP1 methylation status and treatment were significant, indicating reduced benefit of chemotherapy. Forty-four patients with locally advanced PDAC were included. phSFRP1 was associated with an increased risk of death at 24-monthsConclusionsThis indicates that phSFRP1 is a clinically useful prognostic biomarker in metastatic PDAC and possibly in locally advanced PDAC. Together with existing literature, results could indicate the value of cfDNA-measured phSFRP1 as a predictive biomarker of standard palliative chemotherapy in patients with metastatic PDAC. This could facilitate personalized treatment of patients with metastatic PDAC.

KW - Biomarker

KW - Blood-based

KW - DNA methylation

KW - Pancreatic ductal adenocarcinoma

KW - Prognosis

KW - epigenetics

KW - survival

UR - http://www.scopus.com/inward/record.url?scp=85159929104&partnerID=8YFLogxK

U2 - 10.1016/j.pan.2023.05.003

DO - 10.1016/j.pan.2023.05.003

M3 - Journal article

SN - 1424-3903

VL - 23

SP - 512

EP - 521

JO - Pancreatology

JF - Pancreatology

IS - 5

ER -

Promoter hypermethylation of SFRP1 as a prognostic and potentially predictive blood-based biomarker in patients with stage III or IV pancreatic ductal adenocarcinoma

Abstract

Keywords

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PROGNOSTIC IMPACT OF PROMOTER-HYPERMETHYLATED SFRP1 IN PANCREATIC DUCTAL ADENOCARCINOMA: A BLOOD-BASED BIOMARKER STUDY

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