Abstract
Chemotherapy resistance is a main cause of therapeutic failure and death in bladder cancer. With the approval of immune checkpoint inhibitors, prediction of platinum treatment became of great clinical importance. Matrix metalloproteinase-7 (MMP-7) was shown to be involved in cisplatin resistance. Therefore, tissue and circulating MMP-7 levels were evaluated in 124 bladder cancer patients who received postoperative platinum-based chemotherapy. Tissue MMP-7 levels were analyzed by immunohistochemistry in 72 formalin-fixed, paraffin-embedded chemo-naïve tumor samples, while MMP-7 serum concentrations were determined in 132 serum samples of an independent cohort of 52 patients. MMP-7 tissue and serum levels were correlated with clinicopathological and follow-up data. MMP-7 gene expression was determined by RT-qPCR in 20 urothelial cancer cell lines and two non-malignant urothelial cell lines. MMP-7 was overexpressed in RT-112 and T-24 cells by stable transfection, to assess its functional involvement in platinum sensitivity. High MMP-7 tissue expression and pretreatment serum concentrations were independently associated with poor overall survival (tissue HR = 2.296, 95%CI = 1.235–4.268 and p = 0.009; serum HR = 2.743, 95%CI = 1.258–5.984 and p = 0.011). Therefore, MMP-7 tissue and serum analysis may help to optimize therapeutic decisions. Stable overexpression in RT-112 and T-24 cells did not affect platinum sensitivity.
Highlights
We demonstrated, for the first time, that high Matrix metalloproteinase-7 (MMP-7) tissue expressions and serum concentrations are independent risk factors for early disease proexpressions and serum concentrations are independent risk factors for early disease progression and poor survival in patients treated with cisplatin-based chemotherapy
Our present data revealed that high MMP-7 tissue expression and high pretreatment serum concentrations are independently associated with shorter overall survival (OS) in patients with platinum-treated MIBC
If these findings can be confirmed in independent studies, MMP-7 analysis might help to select patients who will benefit from a platinumcontaining chemotherapy, while other patients might be saved from unnecessary toxicity and may benefit from an early administration of other available therapies
Summary
About 70% of all BCs are diagnosed in a non-muscle invasive stage, 10–15%. Of patients will develop muscle-invasive (MIBC), locally advanced and/or metastatic disease. 10% of newly diagnosed patients have locally advanced and/or metastatic disease. For these patients, cisplatin-based combination chemotherapy with. Even though BC is considered a cisplatin-sensitive disease, only 40–60% of patients show a radiographic response [2]. Targeted FGFR2/3 and immune checkpoint inhibitors became available for patients with MIBC that had progressed during or following platinum-containing chemotherapy and later for patients who are ineligible for platinum therapy [3,4,5,6]
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