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

Background: Pancreatic ductal adenocarcinoma remains one of the major causes of cancer-related mortality globally. Unfortunately, current prognostic biomarkers are limited, and no predictive bio-markers 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 met-astatic 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 1/4 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 supple-mentary 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-monthsConclusions: 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.& COPY; 2023 The Authors. Published by Elsevier B.V. on behalf of IAP and EPC. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Automated summary

This study examined the 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. The results showed that phSFRP1 is a clinically useful prognostic biomarker in metastatic PDAC and possibly in locally advanced PDAC.