CAIX

Objectif(s) de la recherche et intérêt pour la santé publique

Finalité de l'étude

Objectifs poursuivis

Domaines médicaux investigués

Bénéfices attendus

Ce projet s'inscrit dans le cadre de l'exécution d'une mission d'intérêt public dans le domaine de la santé. Le traitement des données de santé est nécessaire à des fins de recherche scientifique tel que prévu à l'article 9.2.j du RGPD.

Contexte : Study of tissue expression of CAIX by Immunohistochemistry from frozen or paraffin-embedded tissue derived from biopsies or surgical resection of the kidney.

Primary Objective : Tissue expression of CAIX.

Primary Outcome : Qualitative expression of CAIX (yes/no).

Secondary Objectives :
- Recurrence-free and overall survival based on tissue expression of CAIX (quantitative and qualitative).
- Treatment response based on tissue expression of CAIX.

Secondary Outcomes :
- Quantitative expression of CAIX (< or > 85%).
- Recurrence-free survival in months
- Overall survival in months
- Response to systemic treatment according to RECIST criteria (Progression, Stable disease, Partial Response, Complete Response).

Rationale and hypothèse : CAIX, a transmembrane protein, is physiologically expressed in specific tissues, particularly the digestive tract, and its expression is regulated by hypoxia-inducible factor 1 alpha (HIF1-α). In clear cell renal cell carcinoma (ccRCC), up to 95% of tumors exhibit constitutive activation of HIF1 due to VHL gene mutations or deletions, leading to CAIX upregulation even in normoxic conditions. CAIX staining is predominantly observed in ccRCC (approximately 70% of RCC cases), clear-cell papillary renal cell carcinoma, and sometimes in non-type 1 papillary renal cell carcinoma. Girentuximab (cG250), an anti-CAIX chimeric antibody, serves as a molecular imaging tool for PET/CT imaging when labeled with isotopes like 131I, 124I, or 111In, paving the way for radioimmunotherapy (RIT) in ccRCC. Lindenberg et al. evaluated the PET/CT potential of girentuximab labeled with 124I in 195 patients undergoing renal mass resection, demonstrating 86% sensitivity and specificity for malignant kidney tumor detection. Hekman et al. conducted a clinical study using 89Zr-labeled girentuximab in PET/CT imaging, showing its capacity to predict ccRCC histology subtype and rule out recurrence in previously treated patients.
Minn et al. developed a novel dual motif ligand, 64Cu-XYIMSR-06, with high affinity for CAIX, facilitating PET/CT imaging schedules compared to
girentuximab.The tissue expression of CAIX serves as a prognostic and diagnostic marker [1]. Significant fixation occurs in small clear cell renal
carcinomas, enabling its diagnostic utility. Conversely, low tissue expression is associated with poor prognosis [5–8]. In a recent study, we investigated the potential prognostic and diagnostic role of CAIX-marked extracellular vesicles. We observed a linear increase in circulating extracellular vesicle levels in localized tumors but a sharp decrease in patients with more aggressive tumors (T3 ISUP4 and metastatic patients), confirming the hypothesis that tissue expression of CAIX diminishes in the most aggressive tumors [9]. We could hypothesize that an “aberrant” expression of CAIX in RCC tumors exists, which seems to be associated with poor prognosis, may reflect cancer dedifferentiation. This could potentially have a negative impact on the use of giretuximab in the staging and monitoring of metastatic kidney cancer and could hinder its development as a diagnostic tool. In this study, we aim to assess the tissue expression of CAIX at various stages of metastatic clear cell renal cancer.

Statistical Assumptions :
Immunohistochemistry analysis will be constructed from archival paraffin-embedded, formalin-fixed tissue blocks with representative tumour regions.
Immunohistochemestry for CAIX will be performed with rabbit polyclonal anti-CAIX antibody (clone M75, Absolute antibody). Staining intensity will be based on a scale from 0 to 3 and the percentage of positive cells (0<1%, 1 = 1 –10%, 2 = 10 – 50%, 3> 50%) (Ilie et al.British Journal of Cancer 2010).

The proposed study is an observational study for which a statistical hypothesis is not feasible. The proposed number of subjects corresponds to what is typically done in studies of this nature. It will suffice to verify or refute the hypothesis that aggressive ccRCC tumors lose CAIX expression. The proposed number of subjects is already available in the uroCCR database.