Expression of Markers Related to Mitochondrial Functionality in Carcinoma of the Urinary Bladder: Comparative Retrospective Analysis Between Recurrent Tumors ("Non-responders") and Non-recurrent Tumors ("Responders") After Intravesical Treatment With Chemotherapy or Immunotherapy (MITOMARKER-MIM)

Retrospective monocentric study evaluating different immunohistochemical phenotypes related to mitochondrial functions with treatment outcomes

Study Overview

• Status: Unknown
• Conditions: Bladder Cancer
• Intervention / Treatment: Other: No intervantion on patients. retrospective study is performed on paraffin embedded tumor tissue specimens routinely collected during TURBT.

Detailed Description

About 80% of newly diagnosed patients have non-muscle-invasive bladder cancer (NMIBC), including papillary lesions confined to the urothelium (stage Ta) or invading the lamina propria (stage T1), and carcinoma in situ (CIS). These tumors show low progression rates, but high recurrence. In particular, patients with multifocal high-grade urothelial carcinoma have a high risk of both recurrence (∼70% after 1 yr) and progression (5% after 1 yr). Initial NMIBC management is a transurethral resection of bladder tumor (TURBT), followed by adjuvant intravesical treatment with the chemotherapeutic agent Mitomycin C (MMC) or the immunotherapy Bacillus Calmette-Guérin (BCG). However, these therapies lead to variable clinical responses and patients recur shortly after surgery. Despite both therapies have been used for decades in the treatment of NMIBC, at the moment it is not possible to predict after initial staging which patients will benefit from them since neither resistance mechanisms nor genetic markers associated to relapse have been identified yet.

In a preliminary analysis, the invesitigators found that low expression of several proteins involved in mitochondrial functions correlate with a worst prognosis in bladder cancer patients. The aim of this study is to detect markers of mitochondrial dysfunction by immunohistochemistry in recurrent tumors ("non-responders") and non-recurrent tumors ("responders") after intravesical treatment with chemotherapy or immunotherapy, and determine the prognostic relevance of these different markers.

• Study Type: Observational
• Enrollment (Anticipated): 200

Contacts and Locations

Study Locations

• Italy
  • Milan
    • Rozzano, Milan, Italy, 20089
      • Recruiting
      • Humanitas reseach hospital (ICH)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: N/A
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with NMIBC at first diagnosis, pTa/pT1 (primary tumors) treated with MMC or BCG after TURBT will be selected from the institutional patient registry.

Description

Inclusion Criteria:

• >18 years of age at diagnosis
• Histologically confirmed NMIBC urothelial carcinoma of the urinary bladder (pTa, pT1, CIS)
• Primary NMIBC or not treated secondary NMIBC, after a primary non-invasive malignancy
• Patients underwent TURBT for NMIBC at Humanitas between 2000 and 2019
• Patients that received intravesical instillations with either MMC or BCG after TURBT at Humanitas between 2000 and 2019
• Written informed consent to research purpose

• For non-recurrent tumors ("responders"):

  • Patient treated with adjuvant MMC or BCG that did not experience recurrence for at least 42 months after TURBT
  • Patients are tumor-free at the moment of the analysis

• For recurrent tumors ("non-responders"):

  • Patient treated with adjuvant MMC or BCG that experienced recurrence in the first 24 months after TURBT.

Exclusion Criteria:

• Previous malignancies other that bladder cancer
• Patients with a history of treated bladder cancer recurrences

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Responder patients; Patients with NMIBC at first diagnosis, pTa/pT1 (primary tumors) treated with MMC or BCG after TURBT will be selected from the institutional patient registry.; Patient treated with adjuvant MMC or BCG that did not experience recurrence for at least 42 months after TURBT; Patients are tumor-free at the moment of the analysis	Other: No intervantion on patients. retrospective study is performed on paraffin embedded tumor tissue specimens routinely collected during TURBT.; evaluate an immunophenotypical profile related to mitochondrial functions in tumors responders vs non-responder to intravescical chemotherapy or immunotherapy. Verify the possible prognostic differences in clinical behavior between the two populations.
Non responder patients; Patients with NMIBC at first diagnosis, pTa/pT1 (primary tumors) treated with MMC or BCG after TURBT will be selected from the institutional patient registry. o Patient treated with adjuvant MMC or BCG that experienced recurrence in the first 24 months after TURBT.	Other: No intervantion on patients. retrospective study is performed on paraffin embedded tumor tissue specimens routinely collected during TURBT.; evaluate an immunophenotypical profile related to mitochondrial functions in tumors responders vs non-responder to intravescical chemotherapy or immunotherapy. Verify the possible prognostic differences in clinical behavior between the two populations.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immunohistochemestry analysis of biomarkers	perform an immunophenotypical analysis to assess the expression of key proteins involved in mitochondrial functionality in recurrent tumors ("non-responders") and non-recurrent tumors ("responders") after intravesical treatment with chemotherapy or immunotherapy.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation of biomarker expression with outcome	• To correlate the resulting phenotype with clinical/pathological response to adjuvant treatments (time to recurrence and presence of recurrence).	1 year

Collaborators and Investigators

• Sponsor: Istituto Clinico Humanitas

Publications and helpful links

General Publications

• Oresta B, Pozzi C, Braga D, Hurle R, Lazzeri M, Colombo P, Frego N, Erreni M, Faccani C, Elefante G, Barcella M, Guazzoni G, Rescigno M. Mitochondrial metabolic reprogramming controls the induction of immunogenic cell death and efficacy of chemotherapy in bladder cancer. Sci Transl Med. 2021 Jan 6;13(575):eaba6110. doi: 10.1126/scitranslmed.aba6110.

Study record dates

Study Major Dates

• Study Start (Actual): October 22, 2019
• Primary Completion (Anticipated): October 31, 2020
• Study Completion (Anticipated): December 31, 2020

Study Registration Dates

• First Submitted: February 3, 2020
• First Submitted That Met QC Criteria: February 3, 2020
• First Posted (Actual): February 5, 2020

Study Record Updates

• Last Update Posted (Actual): February 17, 2020
• Last Update Submitted That Met QC Criteria: February 12, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Urinary Bladder Diseases; Disease Attributes; Recurrence; Urinary Bladder Neoplasms
• Other Study ID Numbers: 1191

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Research outcome

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No