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 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.

Cell-free DNA promoter hypermethylation as a diagnostic marker for pancreatic ductal adenocarcinoma - An external validation study.

BACKGROUND: We recently identified a diagnostic prediction model based on promoter hypermethylation of eight selected genes in plasma cell-free (cf) DNA, which showed promising results as a diagnostic biomarker for pancreatic ductal adenocarcinoma (PDAC). The aim of the present study was to validate this biomarker profile in an external patient cohort and examine any additional effect of serum CA 19-9. METHODS: Patients with PDAC (n = 346, stage I-IV) and chronic pancreatitis (n = 25) were included. Methylation-specific PCR of a 28-gene panel was performed on serum cfDNA samples. The previously developed diagnostic prediction model (age>65 years, BMP3, RASSF1A, BNC1, MESTv2, TFPI2, APC, SFRP1 and SFRP2) was validated alone and in combination with serum CA 19-9 in this external patient cohort. RESULTS: Patients with PDAC had a higher number of hypermethylated genes (mean 8.11, 95% CI 7.70-8.52) than patients with chronic pancreatitis (mean 5.60, 95% CI 4.42-6.78, p = 0.011). Validation of the diagnostic prediction model yielded an AUC of 0.77 (95% CI 0.69-0.84). The combination of serum CA 19-9 and our test had an AUC of 0.93 (95% CI 0.89-0.96) in the primary study and 0.85 (95% CI 0.79-0.91) in the validation study. CONCLUSION: In this validation study, PDAC was associated with a higher number of hypermethylated genes in serum cfDNA than chronic pancreatitis. Our diagnostic test was superior to the predictive value of serum CA 19-9 alone in both the primary and the validation study. The combination of our test with CA 19-9 may serve as a clinically useful diagnostic biomarker for PDAC.