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  • Tim Smith
    Manchester University
  • Catharine West
    Manchester University
  • Nuradh Joseph
    Sri Lanka Cancer Research
  • Brian Lane
    University of Manchester
  • Joely Irlam-Jones
    University of Manchester
  • Elisabet More
    University of Manchester
  • Hitesh Mistry
    University of Manchester
  • Kimberley Reeves
    University of Manchester
  • Yee Pei Song
    The Christie NHS Foundation Trust
  • Mark Reardon
    University of Manchester
  • Peter Hoskin
    University of Manchester
  • Syed Hussain
    Department of Oncology and MetabolismUniversity of Sheffield
  • Helen Denley
    Shrewsbury and Telford Hospital NHS Trust
  • Emma Hall
    Institute of Cancer Research
  • Nuria Porta
    Institute of Cancer Research
  • Robert Huddart
    Royal Marsden NHS Foundation Trust
  • Nicholas James
    Royal Marsden NHS Foundation Trust
  • Ananya Choudhury
    Christie Hospital NHS Foundation Trust
BC2001 showed combining chemotherapy (5-FU + mitomycin-C) with radiotherapy improves loco-regional disease-free survival in patients with muscle-invasive bladder cancer (MIBC). We previously showed a 24-gene hypoxia-associated signature predicted benefit from hypoxia-modifying radiosensitisation in BCON and hypothesised that only patients with low hypoxia scores (HSs) would benefit from chemotherapy in BC2001. BC2001 allowed conventional (64Gy/32 fractions) or hypofractionated (55Gy/20 fractions) radiotherapy. An exploratory analysis tested an additional hypothesis that hypofractionation reduces reoxygenation and would be detrimental for patients with hypoxic tumours. RNA was extracted from pre-treatment biopsies (298 BC2001 patients), transcriptomic data generated (Affymetrix Clariom-S arrays), HSs calculated (median expression of 24-signature genes) and patients stratified as hypoxia-high or -low (cut-off: cohort median). invasive loco-regional control (ILRC); secondary overall survival. Hypoxia affected overall survival (HR = 1.30; 95% CI 0.99-1.70; p = 0.062): more uncertainty for ILRC (HR = 1.29; 95% CI 0.82-2.03; p = 0.264). Benefit from chemotherapy was similar for patients with high or low HSs, with no interaction between HS and treatment arm. High HS associated with poor ILRC following hypofractionated (n = 90, HR 1.69; 95% CI 0.99-2.89 p = 0.057) but not conventional (n = 207, HR 0.70; 95% CI 0.28-1.80, p = 0.461) radiotherapy. The finding was confirmed in an independent cohort (BCON) where hypoxia associated with a poor prognosis for patients receiving hypofractionated (n = 51; HR 14.2; 95% CI 1.7-119; p = 0.015) but not conventional (n = 24, HR 1.04; 95% CI 0.07-15.5, p = 0.978) radiotherapy. Tumour hypoxia status does not affect benefit from BC2001 chemotherapy. Hypoxia appears to affect fractionation sensitivity. Use of HSs to personalise treatment needs testing in a biomarker-stratified trial. Cancer Research UK, NIHR, MRC. [Abstract copyright: Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.]

Keywords

  • Biomarkers, Disease-Free Survival, Dose Fractionation, Radiation, Humans, Hypoxia, Mitomycin, Treatment Outcome
Original languageEnglish
Article number105032
Pages (from-to)105032
Number of pages14
JournaleBioMedicine
Volume101
Early online date21 Feb 2024
DOIs
Publication statusPublished - 1 Mar 2024
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