Mahajan, U. M., Goni, E., Langhoff, E., Li, Q., Costello, E., Greenhalf, W., Kruger, S., Ormanns, S., Halloran, C., Ganeh, P., Marron, M., Lammerhirt, F., Zhao, Y., Beyer, G., Weiss, F. U., Sendler, M., Bruns, C. J., Kohlmann, T., Kirchner, T., Werner, J., D'Haese, J. G., von Bergwelt-Baildon, M., Heinemann, V., Neoptolemos, J. P., Buchler, M. W., Belka, C., Boeck, S., Lerch, M. M., and Mayerle, J. (2020). JNCI Cancer Spectr 4, pkz060. doi: 10.1093/jncics/pkz060
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 (χ2 LR, 1DF = 4.00; P = .04). Multivariable analysis revealed CatD expression as a predictive marker in gemcitabine-treated (z stat = 2.33; P = .02) but not in 5-fluorouracil-treated (z stat = 0.21; P = .82) patients. An independent validation cohort confirmed CatD as a negative predictive marker for survival (χ2 LR, 1DF = 6.80; P = .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, P = .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.