Elevated Pre-Treatment Serum MMP-7 Levels Are Associated with the Presence of Metastasis and Poor Survival in Upper Tract Urothelial Carcinoma

Abstract

Upper tract urothelial carcinoma (UTUC) is a rare cancer with a barely predictable clinical behaviour. Serum MMP-7 is a validated prognostic marker in urothelial bladder cancer, a tumour entity with large clinical, histological, and molecular similarity to UTUC. The serum MMP-7 levels have not yet been investigated in UTUC. In the present study, we determined MMP-7 concentrations in an overall number of 103 serum samples from 57 UTUC patients who underwent surgical or systemic (platinum or immune checkpoint inhibitor) therapy by using the ELISA method. In addition to pre-treatment samples, the serum samples collected at predefined time points after or during therapy were also investigated. Serum MMP-7 concentrations were correlated with clinicopathological and follow-up data. Our results revealed significantly, two-fold elevated pre-treatment serum MMP-7 levels in metastatic cases of UTUC in both the radical surgery- and the chemotherapy-treated cohorts (p = 0.045 and p = 0.040, respectively). In addition, high serum MMP-7 levels significantly decreased after radical surgery, and high pre-treatment MMP-7 concentrations were associated with shorter survival both in the surgery- and chemotherapy-treated cohorts (p = 0.029 and p = 0.001, respectively). Our results revealed pre-treatment serum MMP-7 as a prognostic marker for UTUC, which may help to improve preoperative risk-stratification and thereby improve therapeutic decision-making.

High Pretreatment Serum PD-L1 Levels Are Associated with Muscle Invasion and Shorter Survival in Upper Tract Urothelial Carcinoma

“…MMP-7 has been formerly shown to proteolytically cleave membrane-bound PD-L1 releasing sPD-L1 into the circulation and we formerly determined serum MMP-7 concentrations in a largely overlapping UTUC patient cohorts [ 18 ]. Therefore, we performed an exploratory Spearmen’s rank correlation analysis between sPD-L1 and MMP-7 in the RNU, CTX and ICI cohorts, which revealed a significant positive correlation between the concentrations of these two serum proteins in the RNU cohort ( n = 34, rs = 0.445, p = 0.008) but not in the ICI cohort ( n = 5, rs = 0.900, p = 0.307) and CTX cohorts ( n = 25, rs = 0.217, p = 0.297) ( Supplementary Materials, Figures S1–S3 ).…”

“…Much fewer studies are available on circulating biomarkers in UTUC. Promising results have been published on the prognostic relevance of preoperative serum MMP-7, neutrophil-to-lymphocyte ratio and CRP levels; however, larger validation studies are missing and therefore these markers are to be considered as experimental [ 18 , 23 , 24 ]. Preoperative sPD-L1 levels have recently been shown to be independently associated with shorter survival in colorectal and gastric cancers [ 25 , 26 ].…”

“…Some members of the matrix metalloproteinase family, such as MMP-7, -9, -10, and -13 were shown to proteolytically cleave membrane-bound PD-L1, releasing the extracellular domain of the molecule into the blood circulation [ 36 , 37 ]. We recently assessed MMP-7 levels in serum samples of a largely overlapping UTUC cohort and found higher MMP-7 levels to be associated with higher tumor stages and the presence of metastasis [ 18 ]. Correlation analysis between serum MMP-7 and PD-L1 levels in the same samples revealed a significant direct correlation in the treatment-naive preoperative RNU samples.…”

“…In this study, MMP-7 concentrations were used for testing for a possible correlation between sPD-L1 and MMP-7. Detailed results of the MMP-7 analysis were provided in an earlier published study [ 18 ].…”

“…Receiver operating characteristics (ROC) curves were applied for the RNU and CTX treatment groups to determine sPD-L1 cut-off values with the highest sensitivity and specificity for the dichotomized endpoint of death during the follow-up period. Spearman’s rank correlation analysis was used to test for the correlation between formerly determined serum MMP-7 and sPD-L1 levels [ 18 ]. A p -value of < 0.05 was considered significant.…”