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Increased Cathepsin D expression has a negative prognostic effect on survival in gemcitabine treated patients with pancreatic ductal adenocarcinoma
13 August 2018 (online)
The lysosomal aspartic protease Cathepsin D (CatD) is overexpressed and hypersecreted in many cancers and hereby influences cell death. Previously, in the ESPAC-3 cohort we determined a significantly increased median overall survival in cathepsin D low expressing PDAC patients. Gemcitabine treatment was significantly less effective in patients with high CatD expression compared to 5FU treated patients. Here, we present a prospective validation study.
Sample size calculation based on the c2LR, 1DF [3.58] from our previous study warranted 76 gemcitabine treated patients asking for a power of 0.8 and p < 0.05. Tumor tissue microarrays of 79 patients from the „informative patients” with PDAC receiving adjuvant gemcitabine treatment recruited at a single center were stained with anti-CatD (C-20) antibody. Patients were dichotomously distributed in lower and higher H-scores (H-score cut-off: 22.35) for generating Kaplan-Meier curves and to perform log-rank testing and Cox proportional hazards models. All statistical tests were two-sided.
In our independent validation cohort with 228 cores from 79 patients (96.8%) median overall survival of patients was reported with 30.57 months (95%CI, 23.24 – 37.41). Median survival for patients for low CatD expression in the validation cohort was 48.92 (95%CI, 20.97 – 55.34) months vs. 25.08 (95%CI, 18.69 – 34.19) months for high CatD expression, c2 LR,1DF= 5.40; P = 0.02 confirming our null hypothesis. Multivariate analysis with sex, lymph node status, local invasion status and Cathepsin D expression revealed CatD expression as independent predictive marker in gemcitabine treated patients with a hazard ratio of 2.25 (95% CI, 1.03 – 4.94, p = 0.04).
Subject to prospective validation within a randomized trial, gemcitabine is less effective for patients with high CatD expression and could serve as a stratification marker for biomarker driven pancreatic cancer therapy.