JNCI Cancer Spectr 2020 Feb 16;4(1):pkz060. Epub 2019 Aug 16.
Department of Medicine II (UMM, EG, QL, FL, GB, JM), Department of Medicine III (SK, MvBB, VH, SB), Department of Radiation Oncology (CB), University Hospital, LMU-Munich, Munich, Germany; Department of Medicine A, University Medicine Greifswald, Greifswald, Germany (UMM, EL, GB, FUW, MS, MML, JM); National Institute for Health Research Liverpool Pancreas Biomedical Research Centre, University of Liverpool, UK (EC, WG, CH, PG, JPN); Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany (SO, TKi); Leibniz Institute for Prevention Research and Epidemiology - BIPS, Bremen, Germany (MM); Department of General, Visceral, and Tumor Surgery, University Hospital Cologne, Cologne, Germany (YZ, CJB); Department of Community Medicine, University Medicine Greifswald, Greifswald, Germany (TKo); Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany (JW, JGD); Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany (JPN, MWB); German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany (TKi, VH, SB).
Background: Cathepsin-D (CatD), owing to its dual role as a proteolytic enzyme and as a ligand, has been implicated in cancer progression. The role of CatD in pancreatic ductal adenocarcinoma is unknown.
Methods: CatD expression quantified by immunohistochemistry of tumor-tissue microarrays of 403 resected pancreatic cancer patients from the ESPAC-Tplus trial, a translational study within the ESPAC (European Study Group for Pancreatic Cancer) trials, was dichotomously distributed to low and high H scores (cut off 22.35) for survival and multivariable analysis. The validation cohort (n = 69) was recruited based on the hazard ratio of CatD from ESPAC-Tplus. 5-fluorouracil-, and gemcitabine-resistant pancreatic cancer cell lines were employed for mechanistic experiments. All statistical tests were two-sided.
Results: Median overall survival was 23.75 months and median overall survival for patients with high CatD expression was 21.09 (95% confidence interval [CI] = 17.31 to 24.80) months vs 27.20 (95% CI = 23.75 to 31.90) months for low CatD expression (χ = 4.00; = .04). Multivariable analysis revealed CatD expression as a predictive marker in gemcitabine-treated (z stat = 2.33; = .02) but not in 5-fluorouracil-treated (z stat = 0.21; = .82) patients. An independent validation cohort confirmed CatD as a negative predictive marker for survival (χ = 6.80; = .009) and as an independent predictive marker in gemcitabine-treated patients with a hazard ratio of 3.38 (95% CI = 1.36 to 8.38, = .008). Overexpression of CatD was associated with a concomitant suppression of the acid sphingomyelinase, and silencing of CatD resulted in upregulation of acid sphingomyelinase with rescue of gemcitabine resistance.
Conclusions: Adjuvant gemcitabine is less effective in pancreatic ductal adenocarcinoma with high CatD expression, and thus CatD could serve as a marker for biomarker-driven therapy.