A hypoxia biomarker does not predict benefit from giving chemotherapy with radiotherapy in the BC2001 randomised controlled trial
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Authors
Smith, Tim A DWest, Catherine M L
Joseph, N.
Lane, Brian
Irlam-Jones, Joely
More, Elisabet
Mistry, Hitesh
Reeves, Kimberley J
Song, Yee P
Reardon, Mark
Hoskin, Peter J
Hussain, S. A.
Denley, H.
Hall, E.
Porta, N.
Huddart, R. A.
James, N. D.
Choudhury, A.
Affiliation
Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Cancer Research Centre, Christie NHS Foundation Trust, Manchester, UKIssue Date
2024
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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.Citation
Smith TAD, West CML, Joseph N, Lane B, Irlam-Jones J, More E, et al. A hypoxia biomarker does not predict benefit from giving chemotherapy with radiotherapy in the BC2001 randomised controlled trial. EBioMedicine. 2024 Mar;101:105032. PubMed PMID: 38387404. Pubmed Central PMCID: PMC10897900. Epub 2024/02/23. eng.Journal
EBioMedicineDOI
10.1016/j.ebiom.2024.105032PubMed ID
38387404Additional Links
https://dx.doi.org/10.1016/j.ebiom.2024.105032Type
ArticleLanguage
enae974a485f413a2113503eed53cd6c53
10.1016/j.ebiom.2024.105032
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