Validation of SFRP1 Promoter Hypermethylation in Plasma as a Prognostic Marker for Survival and Gemcitabine Effectiveness in Patients with Stage IV Pancreatic Adenocarcinoma.

Benjamin Emil Stubbe,Henrik Bygum Krarup,Poul Henning Madsen,Martin Nygård Johansen,Ole Thorlacius-Ussing,Stine Dam Henriksen,Inge Søkilde Pedersen,Anders Christian Larsen

doi:10.3390/cancers13225717

Benjamin Emil Stubbe, Henrik Bygum Krarup + Show 6 more

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https://doi.org/10.3390/cancers13225717

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Journal: Cancers	Publication Date: Nov 15, 2021
Citations: 9	License type: CC BY 4.0

Affiliation: Aalborg University Hospital, Aalborg University

Abstract

Simple SummaryPancreatic adenocarcinoma (PDAC) is a disease with an incredibly grim prognosis. Most patients die within one year of receiving the diagnosis. There are currently very few tools to help the clinician decide between treatment options and evaluate prognosis at an individual level. The aim of the current study was to assess the effect of promoter hypermethylation of secreted frizzled-related protein 1 (phSFRP1) as an independent prognostic blood-based biomarker in gemcitabine-treated patients with advanced PDAC. The study was conducted as a combined discovery and validation study. Analysis in both cohorts confirmed that patients with phSFRP1 had overall poorer survival compared to those without hypermethylation. Thus, phSFRP1 shows promise as an independent prognostic biomarker in this patient group and can hopefully aid the clinician and patient find the correct balance between quantity and quality of life.No reliable predictive blood-based biomarkers are available for determining survival from pancreatic adenocarcinoma (PDAC). This combined discovery and validation study examines promoter hypermethylation (ph) of secreted frizzled-related protein 1 (SFRP1) in plasma-derived cell-free DNA as an independent prognostic marker for survival and Gemcitabine effectiveness in patients with stage IV PDAC. We conducted methylation-specific polymerase chain reaction analysis of the promoter region of the SFRP1 gene, based on bisulfite treatment. Survival was analyzed with Kaplan–Meier curves, log-rank test, and Cox regression. The discovery cohort included 40 patients, 25 receiving Gem. Gem-treated patients with phSFRP1 had a shorter median overall survival (mOS) (4.4 months) than unmethylated patients (11.6 months). Adjusted Cox-regression yielded a hazard rate (HR) of 3.48 (1.39–8.70). The validation cohort included 58 Gem-treated patients. Patients with phSFRP1 had a shorter mOS (3.2 months) than unmethylated patients (6.3 months). Adjusted Cox regression yielded an HR of 3.53 (1.85–6.74). In both cohorts, phSFRP1 was associated with poorer survival in Gem-treated patients. This may indicate that tumors with phSFRP1 are more aggressive and less sensitive to Gem treatment. This knowledge may facilitate tailored treatment of patients with stage IV PDAC. Further studies are planned to examine phSFRP1 in more intensive chemotherapy regimens.

Highlights

Pancreatic adenocarcinoma (PDAC) is one of the leading causes of cancer death worldwide with higher incidence rates in western countries than the rest of the world [1]
Patients were stratified into four groups according to secreted frizzled-related protein 1 (SFRP1) promoter hypermethylation status treatment with gemcitabine as monotherapy (Gem)/best supportive care (BSC)
A significant strength of the current study is the blood-based nature of the biomarker, as retrieving solid tumor biopsies can be challenging or even impossible. Our results from both the discovery and the validation cohort indicate that promoter-hypermethylated SFRP1 is a promising independent prognostic marker for survival in Gem-treated patients with stage IV PDAC

Summary

Introduction

Pancreatic adenocarcinoma (PDAC) is one of the leading causes of cancer death worldwide with higher incidence rates in western countries than the rest of the world [1]. In Denmark, the median overall survival (mOS) for patients eligible for resection was 21.9 months in the period 2011–2016 compared to 10.0 months in patients undergoing the FOLFIRINOX regime with moderate to severe side effects and 5.1 months in patients treated with the less aggressive gemcitabine as monotherapy (Gem) [2]. Useful biomarkers are desperately needed in this patient group. One example is patients with a mutation in one of the homologous recombination genes PALB2, BRCA1, or BRCA2. Loss of function of these genes leads to impaired ability to repair double-stranded DNA breaks—or homologous recombination deficiency (HRD). These patients are more sensitive to DNA-damaging agents, such as platinum-based chemotherapy. Only 6% of the overall PDAC population harbors these changes

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