SFRP1 Promoter Hypermethylation as a Predictor of Survival and Gemcitabine Efficiency in Patients with Stage IV Pancreatic Adenocarcinoma

Introduction: No reliable predictive blood-based biomarkers are available for determining survival from pancreatic cancer. This combined explorative and validation study examines promoter hypermethylation of Secreted frizzled-related protein 1 (phSFRP1) in plasma-derived cell-free DNA as a predictive marker for survival and gemcitabine effectiveness in patients with stage IV pancreatic adenocarcinoma.
Materials and Methods: This work consists of an explorative study and a validation study. Patients were included prospectively. Blood samples were drawn before diagnostic workup and treatment. We conducted methylation-specific polymerase chain reaction analysis of the promoter region of the SFRP1 gene, based on bisulfite treatment. Survival was analyzed with log-rank test and Cox proportional hazard regression. The adjusted model included the variables age>65, WHO Performance Status, and gender.
Results: The explorative study included 40 patients. Patients not receiving chemotherapy (n=15) had a mOS of 2.0 months. In gemcitabine treated patients (n=25), phSFRP1 patients had a significantly shorter median overall survival of 4.4 months compared to 11.3 months in unmethylated patients. This difference was significant in adjusted cox-regression with a HR of 4.8 (95% CI; 1.5-15.3). The validation study included 58 patients who received gemcitabine. Patients with phSFRP1 had a shorter median overall survival (3·2 months) than the unmethylated group (6.3 months). This difference was significant in adjusted cox-regression with a HR of 3.5 (95% CI; 1.8-6.7).
Conlusions: In both the explorative and the validation study, phSFRP1 was associated with poorer survival in stage IV pancreatic cancer patients receiving gemcitabine treatment. This may indicate that SFRP1-positive tumors are more aggressive and less sensitive to gemcitabine treatment than tumors without SFRP1 hypermethylation. This knowledge may facilitate tailored treatment of patients with stage IV pancreatic adenocarcinoma.