Abstract 387P
Background
Tricho-Rhino-Phalangeal Syndrome Type I Protein (TRPS1) is used as a diagnostic marker for breast cancer (BC) an its overexpression in BC is associated with increased malignancy. The effect of its expression on gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC) has not been studied yet.
Methods
The prognostic impact of TRPS1 expression was examined using immunhistochemistry in 400 resected PDAC (rPDAC) patients. The findings were validated using two independent RNAseq datasets with a total of 309 rPDAC patients and available information on adjuvant treatment.
Results
In the rPDAC cohort, 22 % of all samples showed distinct TRPS1 expression, conferring significantly shorter overall survival times (OS, HR 1.42; 95% CI 1.09-1.84, P = 0.009). TRPS1 was more frequently expressed in high grade tumors (p<0.001) but its expression did not correlate with other well established clinicopathological prognostic factors. In subgroup analyses, patients with TRPS1-positive tumors treated with gemcitabine-based adjuvant therapy (aGC) had significantly prolonged disease-free survival times (DFS, HR 0.48; 95% CI 0.28-0-84, p < 0.001) and OS times (HR 0.57; 95% CI 0.39-0.91, p = 0.02). Multivariate Cox regression analysis and RNAseq data from the validation cohorts confirmed the findings. In co-expression analyses in the examined RNAseq datasets, TRPS1 expression was associated with reduced activity of the Hippo-YAP-pathway.
Conclusions
High TRPS1 expression is a independent negative prognosticator in unselected rPDAC patients. Its expression defines a subgroup of highly aggressive and less differentiated tumors with reduced Hippo-YAP-pathway activity. However, TRPS1-positive tumors respond well to aGC as Hippo-YAP-pathway inactivation renders tumors sensitive to gemcitabine-based therapies in vitro and in vivo. Thus, examining TRPS1-expression could be used to inform clinical therapy decisions in routine practice.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.