Abstract B047: Promoter hypermethylation of SFRP1 as a prognostic and predictive blood-based biomarker in patients with stage IV pancreatic ductal adenocarcinoma

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is a disease with an abysmal prognosis. Unfortunately, no reliable prognostic or predictive blood-based biomarkers are currently available. An increasingly promising prognostic and predictive tool in cancer is the analysis of genetic and epigenetic alterations in cell-free DNA. One such alteration, promoter hypermethylation (ph) of SFRP1, has recently been linked to poor prognosis in gemcitabine-treated patients with stage IV PDAC. This study aimed to further examine phSFRP1 as a clinically relevant prognostic and predictive biomarker in FOLFIRINOX-treated patients with stage IV PDAC. Methods: Serum samples from patients with stage IV PDAC, treated with first-line FOLFIRINOX, were obtained from two danish biobanks. All blood samples were drawn before the initiation of palliative treatment. Based on a bisulfite treatment, we conducted a methylation-specific polymerase chain reaction analysis of the promoter region of the gene SFRP1. Methylation status was dichotomized based on the measured Cycle threshold. Survival according to SFRP1 promoter methylation status was assessed with Kaplan-Meier curves, log-rank tests, and Cox proportional hazard regression models. The adjusted Cox regression model included SFRP1 promoter methylation status, WHO performance status, age > 65 years, and sex. Results: Fifty-two FOLFIRINOX-treated patients with stage IV PDAC were included in the study. Patients with phSFRP1 (n = 23) had a median overall survival (mOS) of 6.8 months, significantly shorter than patients with unmethylated (um) SFRP1 (n = 29) who had a mOS of 15.7 months (log-rank test, p < 0.01). Likewise, in both crude and adjusted Cox-regression analysis, patients with phSFRP1 had an hazard ratio for death of 2.78 (95% CI 1.55-4.99) and 2.82 (95% CI 1.55-5.14) respectively, compared to patients with umSFRP1. Conclusions: Results indicate that FOLFIRINOX-treated stage IV PDAC patients with phSFRP1 have significantly shorter survival than patients with umSFRP1. Combined with previous literature, this indicates the value of phSFRP1 as a blood-based prognostic biomarker in patients with stage IV PDAC, regardless of the given first-line palliative chemotherapy. In addition, it indicates that phSFRP1 may also have predictive value for chemotherapy sensitivity in patients with stage IV PDAC. This knowledge may facilitate individualized treatment of patients with stage IV PDAC. Additionally, SFRP1 could be a valuable target for treatment with hypomethylating drugs to improve treatment response. Citation Format: Benjamin E. Stubbe, Stine D. Henriksen, Poul H. Madsen, Anders C. Larsen, Henrik B. Krarup, Inge S. Pedersen, Julia S. Johansen, Carsten P. Hansen, Ole Thorlacius-Ussing. Promoter hypermethylation of SFRP1 as a prognostic and predictive blood-based biomarker in patients with stage IV pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B047.