Molecular underpinnings of glandular tropism in metastatic clear cell renal cell carcinoma: therapeutic implications

Authors

  • Eduard Roussel Department of Urology, University Hospitals Leuven, Leuven, Belgium
  • Lisa Kinget Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium
  • Annelies Verbiest Department of Urology, University Hospitals Leuven, Leuven, Belgium
  • Bram Boeckx Laboratory of Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium; VIB Center for Cancer Biology, VIB, Leuven, Belgium
  • Jessica Zucman-Rossi Inserm, UMR-1162, Génomique fonctionnelle des tumeurs solides, Institut Universitaire Hématologie, Paris, France
  • Gabrielle Couchy Inserm, UMR-1162, Génomique fonctionnelle des tumeurs solides, Institut Universitaire Hématologie, Paris, France
  • Stefano Caruso Inserm, UMR-1162, Génomique fonctionnelle des tumeurs solides, Institut Universitaire Hématologie, Paris, France
  • Marcella Baldewijns Department of Pathology, University Hospitals Leuven, Leuven, Belgium
  • Steven Joniau Department of Urology, University Hospitals Leuven, Leuven, Belgium
  • Hendrik Van Poppel Department of Urology, University Hospitals Leuven, Leuven, Belgium
  • Diether Lambrechts Laboratory of Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium; VIB Center for Cancer Biology, VIB, Leuven, Belgium
  • Maarten Albersen Department of Urology, University Hospitals Leuven, Leuven, Belgium
  • Benoit Beuselinck Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium

DOI:

https://doi.org/10.1080/0284186X.2021.1962971

Keywords:

Glandular metastasis, gene expression, angiogenesis, immunotherapy, molecular subtypes

Abstract

Background

Glandular metastases (GM) have been associated with improved survival in metastatic clear cell renal cell carcinoma (m-ccRCC). We aimed to molecularly characterize m-ccRCC with GM.

Material and methods

We performed a retrospective cohort study on all m-ccRCC patients with available tissue at our institution, diagnosed with metastatic disease from 2000 to 2019. We determined previously described angiogenesis- and immune-related gene expression signatures (GES) and ccrcc molecular subtypes through whole transcriptome RNA sequencing of primary tumors and metastases. We tested differences in GES and molecular subtypes across groups and studied overall (OS) and progression-free survival (PFS) using Kaplan–Meier survival analysis and Cox regression models.

Results

Primary tumors of patients who developed GM (n = 55) had higher IMmotion Angio (p < 0.001) and JAVELIN Angio (p = 0.003) GES as well as a higher proportion of angiogenic ccrcc2 molecular subtypes (p = 0.008) than primary tumors of patients with non-GM (n = 128). Metastatic lesions in glandular organs (n = 32) also had higher IMmotion Angio (p = 0.008) and JAVELIN Angio (p = 0.02) GES and were more frequently of the ccrcc2 molecular subtype (p = 0.03), compared to metastatic lesions in non-glandular organs in patients who did not develop any GM (n = 231), but not compared to metastatic lesions in non-glandular organs in patients who also developed GM (n = 18). Patients with GM had better OS (HR 0.49, p < 0.001) and PFS on first-line vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) (HR 0.64, p = 0.045) than patients with non-GM. PFS on first- or any-line immuno-oncology (IO) was not different. IMmotion Angio, JAVELIN Angio GES, and ccrcc2 molecular subtype were associated with better OS and PFS on first-line VEGFR-TKIs, but not PFS on first or any-line IO.

Conclusions

Patients with m-ccRCC who develop GM are molecularly characterized by heightened angiogenesis, translating into better prognosis and better outcomes on VEGFR-TKIs, but not IO. Based on these findings, VEGFR-TKIs should be included in the first-line treatment of m-ccRCC patients with GM.

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Published

2021-11-02

How to Cite

Roussel, E., Kinget, L., Verbiest, A., Boeckx, B., Zucman-Rossi, J., Couchy, G., … Beuselinck, B. (2021). Molecular underpinnings of glandular tropism in metastatic clear cell renal cell carcinoma: therapeutic implications. Acta Oncologica, 60(11), 1499–1506. https://doi.org/10.1080/0284186X.2021.1962971