Pronecrotic Mixed Lineage Kinase Domain-Like (MLKL) Protein Expression Is a Prognostic Biomarker in Patients With Resected Pancreatic Adenocarcinoma

Abstract

Mixed lineage kinase domain like protein (MLKL) is a necrosome component that mediates necrosis signaling and may play a role in cancer response to therapy. Our goal in this analysis was to evaluate MLKL as a novel prognostic factor in pancreatic adenocarcinoma (PAC) using immunohistochemistry (IHC) staining of resected PAC specimens. Eighty patients with tissue available for analysis were identified from a prospectively maintained database of patients undergoing resection for pancreas adenocarcinoma between January 2000 and October 2008. IHC analysis was performed for expression of MLKL in these resection specimens and scored using a previously established scoring system. Kaplan-Meier (KM) survival curves were generated for recurrence-free survival (RFS) and overall survival (OS) for all patients and for patients receiving adjuvant therapy. MLKL scores were correlated with RFS and OS using univariate (UV) and multivariate (MV) Cox regression analyses incorporating clinically relevant covariates. Median RFS and OS for all patients were 9.3 months (range, 0.6-110 months) and 15.4 months (range, 2.8-115 months), respectively. Twenty patients (24.5%) had positive margins and 48 (60%) had positive lymph nodes. Fifty-nine patients had adjuvant chemotherapy and only 2 patients had neoadjuvant chemotherapy. The most common chemotherapy agent utilized was gemcitabine (GEM) (n = 31 of 59; 52.5%) and most patients receiving adjuvant chemotherapy also received radiation therapy (39 of 59; 66.1%). On Kaplan-Meier analysis, low MLKL expression was associated with decreased OS (6 months vs 17 months; p = .006) in all patients. In the subset of patients receiving adjuvant chemotherapy, low MLKL expression was associated with decreased RFS (5 months vs 15 months; p = .006) in addition to decreased OS (6 months vs 19 months; p < .0001). On MV analysis after accounting for widely accepted adverse tumor characteristics, low MLKL expression remained a significant predictor of decreased OS in all patients (HR, 4.6; 95% CI, 1.6-13.8; p = .006) and of decreased RFS (HR, 6.4; 95% CI, 1.2-34.0; p = .03) and OS (HR, 3.9; 95% CI, 1.01-27.7; p = .048) in patients receiving adjuvant therapy (n = 59). In a subset of patients receiving GEM-based therapy (n = 31), low MLKL expression remained associated with decreased RFS (HR, 6.4; 95% CI, 1.2-34.0; p = .03) and OS (HR, 3.9; 95% CI, 1.01-27.7; p = .048). Low expression of MLKL is associated with significantly worse OS in all patients with early stage resected PAC. In patients receiving adjuvant therapy and in patients receiving gemcitabine-based adjuvant therapy, low MLKL expression is significantly associated with both decreased RFS and OS. MLKL may be a valuable prognostic biomarker in patients receiving adjuvant therapy may be helpful in personalizing pancreatic cancer therapy.