# Promoter hypermethylation of SFRP1 is an allele fraction-dependent prognostic biomarker in metastatic pancreatic ductal adenocarcinoma

## TL;DR

This study shows that the level of SFRP1 promoter hypermethylation in cell-free DNA can predict survival in pancreatic cancer patients, with higher levels indicating worse outcomes.

## Contribution

The study demonstrates that the prognostic value of SFRP1 promoter hypermethylation depends on its allele fraction in metastatic pancreatic cancer.

## Key findings

- Patients with high SFRP1 promoter hypermethylation had significantly shorter survival compared to those with low or no hypermethylation.
- High SFRP1 hypermethylation was associated with increased mortality risk at 3, 6, and 12 months.
- SFRP1 hypermethylation improved mortality prediction compared to clinical variables alone.

## Abstract

Metastatic pancreatic ductal adenocarcinoma (PDAC) is highly lethal. Promoter hypermethylation of SFRP1 (phSFRP1) in cell-free DNA is an established prognostic biomarker in PDAC. We used digital droplet PCR (ddPCR) to examine whether the prognostic impact of phSFRP1 was allele fraction (AF) dependent.

Prospectively collected plasma samples were analyzed blinded. Dual-strand methylation ddPCR assays were designed for SFRP1, with single-strand assay for the reference gene EPHA3. Patients were stratified into unmethylated SFRP1 (umSFRP1), low phSFRP1 AF (phSFRP1low), and high phSFRP1 AF (phSFRP1high). Survival was assessed with Kaplan–Meier curves. The 3-, 6-, and 12-month absolute risk difference (ARD) was calculated, and performance assessed with ROC analyses.

Overall, 354 patients were included. Patients with umSFRP1 (n=137) had a mOS of 9.1 months compared to 7.2 months in phSFRP1low (n=78) and 3.4 months in phSFRP1high (n=143, P<0.01). phSFRP1high was associated with increased mortality at 3 (ARD 26%, 95%CI: 15, 37), 6 (ARD 37%, 95%CI: 26, 48), and 12 months (ARD 23%, 95%CI: 14, 33). phSFRP1low was associated with increased mortality at 12 months (ARD 13%, 95%CI: 2, 25) but not at 3 (ARD -3%, 95%CI: -13, 8) or 6 months (ARD 3%, 95%CI: -10, 17). phSFRP1 significantly improved performance in predicting mortality compared to only clinical variables (AUC: 0.70-0.71 vs. 0.54-0.57).

Patients with phSFRP1high had significantly shorter survival than phSFRP1low or umSFRP1, indicating AF-dependent prognostic effects. phSFRP1low had a worse prognosis than umSFRP1 at only 12 months, indicating dynamic changes. This could help personalize the treatment of PDAC.