Angiogenic and immune predictors of neoadjuvant axitinib response in renal cell carcinoma with venous tumour thrombus
Abstract
Abstract 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.
Article Details
Authors (79)
Rebecca Wray
Hania Paverd
Ines Machado
Johanna Barbieri
Farhana Easita
Abigail R. Edwards
Ferdia A. Gallagher
Department of Radiology, Addenbrooke’s Hospital and University of Cambridge
Iosif A. Mendichovszky
Thomas J. Mitchell
Maike de la Roche
Jacqueline D. Shields
Stephan Ursprung
Lauren Wallis
Anne Y. Warren
Department of Pathology, Cambridge University Hospitals National Health Service Foundation Trust
Sarah J. Welsh
Mireia Crispin-Ortuzar
Grant D. Stewart
James O. Jones
Niki Couper
Lisa E. M. Hopcroft
Robert Hill
Athena Matakidou
Cara Caasi
James Watson
Ruby Cross
Sarah W. Burge
Anne George
Tobias Klatte
Tevita F. Aho
James N. Armitage
Sabrina Helena Rossi
Charlie Massie
Shubha Anand
Tiffany Haddow
Marc Dodd
Wenhan Deng
Ezequiel Martin
Department of Genomic Medicine, University of Cambridge and National Institute for Health and Care Research Cambridge Biomedical Research Centre
Philip Howden
Stephanie Wenlock
Evis Sala
Stefan Symeonides
Lynn Ho
Jennifer Baxter
Stuart Leslie
Duncan McLaren
John Brush
Marie O’Donnell
Alisa Griffin
Ruth Orr
Catriona Cowan
Thomas Powles
Department of Medical Oncology Barts Cancer Institute Queen Mary University of London London UK
Anna Pejnovic
Sophia Tincey
Lee Grant
Martin Nuttall
Lucy Willsher
Christian Barnett
David Nicol
James Larkin
Alison Fielding
Christopher G. Smith
Axel Bex
Ekaterini Boleti
Jade Carruthers
Tim Eisen
Kate Fife
Angela Godoy
Abdel Hamid
Alexander Laird
Steve Leung
Jahangeer Malik
Faiz Mumtaz
Grenville Oades
Andrew N. Priest
Antony C. P. Riddick
Balaji Venugopal
Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom
Michelle Welsh
Kathleen Riddle
Public Health Scotland, Edinburgh
Robert J. Jones