A hypoxia biomarker does not predict benefit from giving chemotherapy with radiotherapy in the BC2001 randomised controlled trialResearch in context
Tim A.D. Smith,
Catharine M.L. West,
Nuradh Joseph,
Brian Lane,
Joely Irlam-Jones,
Elisabet More,
Hitesh Mistry,
Kimberley J. Reeves,
Yee Pei Song,
Mark Reardon,
Peter J. Hoskin,
Syed A. Hussain,
Helen Denley,
Emma Hall,
Nuria Porta,
Robert A. Huddart,
Nick D. James,
Ananya Choudhury
Affiliations
Tim A.D. Smith
Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Cancer Research Centre, Christie NHS Foundation Trust, Manchester, UK; Nuclear Futures Institute, School of Computer Science and Electronic Engineering, Bangor University, Bangor, UK
Catharine M.L. West
Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Cancer Research Centre, Christie NHS Foundation Trust, Manchester, UK; Corresponding author. Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, 555 Wilmslow Road, Manchester, M20. 4GJ, UK.
Nuradh Joseph
Sri Lanka Cancer Research Group, Maharagama, Sri Lanka
Brian Lane
Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Cancer Research Centre, Christie NHS Foundation Trust, Manchester, UK
Joely Irlam-Jones
Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Cancer Research Centre, Christie NHS Foundation Trust, Manchester, UK
Elisabet More
Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Cancer Research Centre, Christie NHS Foundation Trust, Manchester, UK
Hitesh Mistry
Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Cancer Research Centre, Christie NHS Foundation Trust, Manchester, UK
Kimberley J. Reeves
Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Cancer Research Centre, Christie NHS Foundation Trust, Manchester, UK
Yee Pei Song
Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Cancer Research Centre, Christie NHS Foundation Trust, Manchester, UK
Mark Reardon
Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Cancer Research Centre, Christie NHS Foundation Trust, Manchester, UK
Peter J. Hoskin
Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Cancer Research Centre, Christie NHS Foundation Trust, Manchester, UK; Mount Vernon Cancer Centre, Northwood, London, UK
Syed A. Hussain
Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
Helen Denley
Pathology Centre, Shrewsbury and Telford NHS Trust, Royal Shrewsbury Hospital, Shrewsbury, UK
Emma Hall
Institute of Cancer Research, Clinical Trials & Statistics Unit, London, UK
Nuria Porta
Institute of Cancer Research, Clinical Trials & Statistics Unit, London, UK
Robert A. Huddart
Royal Marsden NHS Trust, Department of Oncology, Downs Road, Sutton, Surrey, England, UK
Nick D. James
Royal Marsden NHS Trust, Department of Oncology, Downs Road, Sutton, Surrey, England, UK
Ananya Choudhury
Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Cancer Research Centre, Christie NHS Foundation Trust, Manchester, UK
Summary: Background: 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. Methods: 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). Primary endpoint: invasive loco-regional control (ILRC); secondary overall survival. Findings: 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. Interpretation: 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. Funding: Cancer Research UK, NIHR, MRC.
