Angiogenic and immune predictors of neoadjuvant axitinib response in renal cell carcinoma with venous tumour thrombus
Venous tumour thrombus (VTT), where the primary tumour invades the renal vein and inferior vena cava, affects 10-15% of renal cell carcinoma (RCC) patients. Curative surgery for VTT is high-risk, but neoadjuvant therapy may improve outcomes. The NAXIVA trial demonstrated a 35% VTT response rate after 8 weeks of neoadjuvant axitinib, a VEGFR-directed therapy. However, understanding non-response is critical for better treatment. Here we show that response to axitinib in this setting is characterised by a distinct and predictable set of features. We conduct a multiparametric investigation of samples collected during NAXIVA using digital pathology, flow cytometry, plasma cytokine profiling and RNA sequencing. Responders have higher baseline microvessel density and increased induction of VEGF-A and PlGF during treatment. A multi-modal machine learning model integrating features predict response with an AUC of 0.868, improving to 0.945 when using features from week 3. Key predictive features include plasma CCL17 and IL-12. These findings may guide future treatment strategies for VTT, improving the clinical management of this challenging scenario.
Authors
- Stephan Ursprung (ORCID: https://orcid.org/0000-0003-2476-178X)
- Mireia Crispin‐Ortuzar (ORCID: https://orcid.org/0000-0002-4351-3709)
- Jacqueline D. Shields (ORCID: https://orcid.org/0000-0003-2153-9710)
- Sarah J. Welsh (ORCID: https://orcid.org/0000-0001-5690-2677)
- Iosif Mendichovszky (ORCID: https://orcid.org/0000-0002-3777-2827)
- Anne Y. Warren (ORCID: https://orcid.org/0000-0002-1170-7867)
- Ferdia A. Gallagher (ORCID: https://orcid.org/0000-0003-4784-5230)
- Johanna Barbieri
- James O. Jones (ORCID: https://orcid.org/0000-0002-2194-4903)
- A. Edwards (ORCID: https://orcid.org/0000-0003-0273-9549)
- Grant Duncan Stewart (ORCID: https://orcid.org/0000-0003-3188-9140)
- Thomas J. Mitchell (ORCID: https://orcid.org/0000-0003-0761-9503)
- Maike de la Roche (ORCID: https://orcid.org/0000-0002-0558-4119)
- Inês Machado (ORCID: https://orcid.org/0000-0003-4160-9624)
- Lauren Wallis
- Hania Paverd (ORCID: https://orcid.org/0009-0004-5317-9080)
- Farhana Easita
- Richard Wray
Institutions
- National Health Service Scotland (GB)
- NHS Lothian (GB)
- University of Nottingham (GB)
- Royal Free London NHS Foundation Trust (GB)
- Barts Health NHS Trust (GB)
- University of Cambridge (GB)
- Royal Devon & Exeter NHS Foundation Trust (GB)
- Western General Hospital (GB)
- Beatson West of Scotland Cancer Centre (GB)
- Cancer Research UK (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Edinburgh Cancer Research (GB)
- University of Warwick (GB)
- Cancer Research UK Cambridge Center (GB)
- Kidney Care UK (GB)
- Oncode Institute (NL)
- Public Health Scotland (GB)
- Royal Marsden Hospital (GB)
- Action Cancer (GB)
- Medizinische Hochschule Brandenburg Theodor Fontane (DE)
- Queen Elizabeth University Hospital (GB)
- University College London (GB)
- University of Glasgow (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-28
- DOI
- https://doi.org/10.1038/s41467-025-58436-8
- Citations
- 3
- Primary Topic
- Renal cell carcinoma treatment
- Type
- article
- Field-Weighted Citation Impact
- 4.56
Funders
- Pfizer
- AstraZeneca
- Wellcome Trust
- Mark Foundation For Cancer Research
- Cancer Research UK
- National Institute for Health and Care Research
- Department of Health and Social Care
- University of Cambridge
- Cambridge University Hospitals
- NIHR BioResource
- Medical Research Council
- NIHR Cambridge Biomedical Research Centre
- Cancer Research UK Cambridge Institute, University of Cambridge