Article
First proof-of-concept of theranostic instillation therapy for muscle invasive bladder cancer patients within the Bladder BRIDGister study group
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Authors
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Dimitri Barski
- Rheinlandklinikum Neuss, Urologie, Neuss, Deutschland
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R. Wirtz
- STRATIFYER Molecular Pathology GmbH, Cologne, Germany
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L. Kastner
- Universitätsklinik Köln, Urologie, Köln, Deutschland
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P. C. Voß
- Charité-Universitätsmedizin Berlin, Berlin, Deutschland
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F. Friedersdorff
- Evangelisches Krankenhaus Königin Elisabeth Herzberge, Urologie, Berlin, Deutschland
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T. Otto
- Rheinlandklinikum Neuss, Urologie, Neuss, Deutschland
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Michael Waldner
- St. Elisabeth Krankenhaus, Urologie, Köln, Deutschland
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E. Veltrup
- STRATIFYER Molecular Pathology GmbH, Cologne, Germany
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F. Linden
- STRATIFYER Molecular Pathology GmbH, Cologne, Germany
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R. Hake
- St. Elisabeth Krankenhaus, Pathologie, Köln, Deutschland
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S. Eidt
- St. Elisabeth Krankenhaus, Pathologie, Köln, Deutschland
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J. Roggisch
- Helios Krankenhaus, Pathologie, Bad Saarow, Deutschland
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Constantin Rieger
- Universitätsklinik Köln, Urologie, Köln, Deutschland
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S. Koch
- Helios Krankenhaus, Pathologie, Bad Saarow, Deutschland
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T. Ecke
- Helios Krankenhaus, Urologie, Bad Saarow, Deutschland
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Axel Heidenreich
- Universitätsklinik Köln, Urologie, Köln, Deutschland
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L. Greifenstein
- CURANOSTICUM Wiesbaden-Frankfurt, Wiesbaden, Deutschland
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R. P. Baum
- CURANOSTICUM Wiesbaden-Frankfurt, Wiesbaden, Deutschland
| Published: | March 26, 2024 |
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Outline
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Background: Patients with muscle invasive urothelial carcinoma achieving pathological complete response (pCR) upon neoadjuvant chemotherapy (NACT) have improved prognosis. Interestingly the expression of the radioligand targets CXCR4 and FAP is found chemoresistant, stroma-associated tumors. The objective of this study was to prospectively validate the predictive value of molecular target typing from TUR biopsy tissue samples and to assess CXCR4 & FAP radioligand instillation imaging and therapy in selected patients.
Methods: FFPE tissues from TUR before chemotherapy and cystectomy samples after NACT of 36 patients were retrospectively collected and 650 TURB samples were prospectively collected. RNA from FFPE tissues were extracted by commercial kits, relative gene expression of subtyping markers (KRT5, KRT20, FGFR1) and radioligand target genes (CXCR4, FAP) were analyzed by standardized RT-qPCR systems. Hierarchical clustering, Kruskal-Wallis, chi square and contingency tests were done by JMP 9.0.0 (SAS software). PET/CT Imaging by CXCR4 instillation was performed after completion of cisplatinum based NACT. FAP treatment was performed subsequently by instillation +/- systemic application.
Results: The neoadjuvant cohort consisted of 36 patients (median age: 69, male 83% vs. female 17%). Hierarchical clustering revealed that CXCR4 and FAP are elevated in stromal rich, KRT5 & KRT20 negative tumors not responding to NACT. Elevated FAP above median mRNA expression was significantly associated with resistance to NACT (chi2 4.314 p=0.0378). Combining elevated FAP and CXCR4 mRNA expression did identify 28% of the patients to be at high risk of NACT resistance (90%). Exemplarily one pT2 G3 MIBC patient was selected for PET/CT imaging after two cycles that was predicted to be unresponsive to NACT. 68Ga CXCR4 showed tumor specific uptake into the tumor invading the adjacent soft tissue. Subsequent instillation and systemic therapy cycles with 177Lu-FAP also revealed strong uptake into the invading tumor. TURB after the second theranostic cycle revealed partial tumor response and increased immune cell infiltration.
Conclusions: Expression of the radioligand targets CXCR4 and FAP has been shown to be resistant to NACT. This could be validated by selecting patients for FAP & CXCR4 PET/CT imaging. Instillation of radioligands into the bladder revealed to be safe and effective for imaging and therapy in patients being unresponsive to standard chemo- or immune therapies.
