TY - JOUR

T1 - Hypoxia-associated gene signatures are not prognostic in high-risk localised prostate cancers undergoing androgen deprivation therapy with radiotherapy

AU - Reardon, Mark

AU - Bibby, Becky

AU - Thiruthaneeswaran, Niluja

AU - Pereira, Ronnie

AU - Mistry, Hitesh

AU - More, Elisabet

AU - Tsang, Yatman

AU - Vickers, Alexander

AU - Reeves, Kimberley

AU - Hendry, Ann

AU - Denley, Helen

AU - Wyley, James

AU - Sprat, Daniel

AU - Hakansson, Alex

AU - Ryu, Monica

AU - Smith, Tim

AU - Hoskin, Peter

AU - Bristow, Rob

AU - Choudhury, Ananya

AU - West, Catharine

PY - 2024

Y1 - 2024

N2 - Men with high-risk prostate cancer (PCa) are treated with androgen deprivation therapy (ADT) and radiotherapy, but the disease reoccurs in 30% of patients. Biochemical recurrence of PCa after treatment is influenced by tumour hypoxia. Tumours with high levels of hypoxia are aggressive, resistant to treatment, and have increased metastatic capacity. Gene expression signatures derived from diagnostic biopsies can predict tumour hypoxia and radiosensitivity, but none are in routine clinical use, due to concerns about the applicability of these biomarkers to new patient cohorts. There has been no or limited testing in cohorts of high-risk PCa. We generated transcriptomic data for cohorts of high-risk PCa patients. Patients were treated with ADT followed by external beam radiotherapy with or without a brachytherapy boost. Biomarkers curated from the literature were calculated from pre-treatment biopsy gene expression data. The primary endpoint for survival analyses was biochemical recurrence-free survival (bRFS) and the secondary endpoints were distant metastasis-free survival (DMFS) and overall survival. The performance of the selected biomarkers was poor, with none achieving prognostic significance for bRFS or DMFS in any cohort. The brachytherapy boost cohort received shorter durations of ADT than the conventionally fractionated or hypofractionated cohorts (Wilcoxon rank sum test, p=2.1 × 10 and 2.3 × 10 respectively) and had increased risk of distant metastasis (log-rank test, p=8 × 10 ). There were no consistent relationships between biomarker score and outcome for any of the endpoints. Hypoxia and radiosensitivity biomarkers were not prognostic in high-risk PCa patients treated with ADT plus radiotherapy. We speculate that the lack of prognostic capability could be caused by the variable hypoxia-modifying effects of the ADT that these high-risk patients received before and during definitive treatment with radiotherapy. A deeper understanding of biomarker construction, performance and inter-cohort transferability in relation to patient characteristics, sample handling and treatment modalities is required before hypoxia biomarkers can be recommended for routine clinical use in the pre-treatment setting. [Abstract copyright: Copyright © 2024. Published by Elsevier Inc.]

AB - Men with high-risk prostate cancer (PCa) are treated with androgen deprivation therapy (ADT) and radiotherapy, but the disease reoccurs in 30% of patients. Biochemical recurrence of PCa after treatment is influenced by tumour hypoxia. Tumours with high levels of hypoxia are aggressive, resistant to treatment, and have increased metastatic capacity. Gene expression signatures derived from diagnostic biopsies can predict tumour hypoxia and radiosensitivity, but none are in routine clinical use, due to concerns about the applicability of these biomarkers to new patient cohorts. There has been no or limited testing in cohorts of high-risk PCa. We generated transcriptomic data for cohorts of high-risk PCa patients. Patients were treated with ADT followed by external beam radiotherapy with or without a brachytherapy boost. Biomarkers curated from the literature were calculated from pre-treatment biopsy gene expression data. The primary endpoint for survival analyses was biochemical recurrence-free survival (bRFS) and the secondary endpoints were distant metastasis-free survival (DMFS) and overall survival. The performance of the selected biomarkers was poor, with none achieving prognostic significance for bRFS or DMFS in any cohort. The brachytherapy boost cohort received shorter durations of ADT than the conventionally fractionated or hypofractionated cohorts (Wilcoxon rank sum test, p=2.1 × 10 and 2.3 × 10 respectively) and had increased risk of distant metastasis (log-rank test, p=8 × 10 ). There were no consistent relationships between biomarker score and outcome for any of the endpoints. Hypoxia and radiosensitivity biomarkers were not prognostic in high-risk PCa patients treated with ADT plus radiotherapy. We speculate that the lack of prognostic capability could be caused by the variable hypoxia-modifying effects of the ADT that these high-risk patients received before and during definitive treatment with radiotherapy. A deeper understanding of biomarker construction, performance and inter-cohort transferability in relation to patient characteristics, sample handling and treatment modalities is required before hypoxia biomarkers can be recommended for routine clinical use in the pre-treatment setting. [Abstract copyright: Copyright © 2024. Published by Elsevier Inc.]

KW - androgen deprivation therapy

KW - biochemical recurrence

KW - hypoxia

KW - prostate cancer

U2 - 10.1016/j.ijrobp.2024.10.002

DO - 10.1016/j.ijrobp.2024.10.002

M3 - Article

JO - international journal of Radiation Oncology Biology Physics

JF - international journal of Radiation Oncology Biology Physics

ER -