Reardon Mark D, Bibby Becky A S, Thiruthaneeswaran Niluja, Pereira Ronnie R, Mistry Hitesh, More Elisabet, Tsang Yatman, Vickers Alexander J, Reeves Kimberley J, Henry Ann, Denley Helen, Wylie James, Spratt Daniel E, Hakansson Alex, Ryu Monica, Smith Tim A D, Hoskin Peter J, Bristow Robert, Choudhury Ananya, West Catharine M L
Translational Radiobiology Group, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine & Health, The University of Manchester, Manchester, United Kingdom.
Translational Radiobiology Group, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine & Health, The University of Manchester, Manchester, United Kingdom.
Int J Radiat Oncol Biol Phys. 2025 Mar 1;121(3):752-760. doi: 10.1016/j.ijrobp.2024.10.002. Epub 2024 Oct 16.
Men with high-risk prostate cancer (PCa) are treated with androgen deprivation therapy (ADT) and radiation therapy, but the disease reoccurs in 30% of patients. Biochemical recurrence of PCa after treatment is influenced by tumor hypoxia. Tumors with high levels of hypoxia are aggressive, resistant to treatment, and have increased metastatic capacity. Gene expression signatures derived from diagnostic biopsies can predict tumor 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 patients with high-risk PCa. Patients were treated with ADT followed by external beam radiation therapy with or without a brachytherapy boost. Biomarkers curated from the literature were calculated from pretreatment biopsy gene expression data. The primary endpoint for survival analyses was biochemical recurrence-free survival and the secondary endpoints were distant metastasis-free survival and overall survival.
The performance of the selected biomarkers was poor, with none achieving prognostic significance for biochemical recurrence-free survival or distant metastasis-free survival 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 patients with high-risk PCa treated with ADT plus radiation therapy. 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 radiation therapy. 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 pretreatment setting.
高危前列腺癌（PCa）男性患者接受雄激素剥夺疗法（ADT）和放射治疗，但仍有30%的患者疾病复发。治疗后PCa的生化复发受肿瘤缺氧影响。缺氧水平高的肿瘤具有侵袭性、对治疗耐药且转移能力增强。源自诊断性活检的基因表达特征可预测肿瘤缺氧和放射敏感性，但由于担心这些生物标志物对新患者队列的适用性，目前尚无一种在常规临床中使用。在高危PCa队列中尚未进行或仅有有限的测试。
我们生成了高危PCa患者队列的转录组数据。患者接受ADT治疗，随后接受外照射放疗，部分患者接受或不接受近距离放疗强化。从文献中筛选的生物标志物根据治疗前活检基因表达数据计算得出。生存分析的主要终点是无生化复发生存期，次要终点是无远处转移生存期和总生存期。
所选生物标志物的表现不佳，在任何队列中均未对无生化复发生存期或无远处转移生存期达到预后意义。接受近距离放疗强化的队列接受ADT的时间比常规分割或大分割队列短（分别为Wilcoxon秩和检验，P = 2.1×10和2.3×10），且远处转移风险增加（对数秩检验，P = 8×10）。对于任何终点，生物标志物评分与结局之间均无一致关系。
缺氧和放射敏感性生物标志物对接受ADT加放射治疗的高危PCa患者无预后价值。我们推测，缺乏预后能力可能是由于这些高危患者在确定性放疗之前和期间接受的ADT对缺氧的调节作用存在差异。在缺氧生物标志物可被推荐用于预处理环境的常规临床使用之前，需要更深入地了解生物标志物的构建、性能以及与患者特征、样本处理和治疗方式相关的队列间可转移性。
