Development of a Hypoxia Gene Expression Classifier with Predictive Impact for Hypoxic Modification of Radiotherapy in Head and Neck Cancer
Development of a Hypoxia Gene Expression Classifier with Predictive Impact for Hypoxic Modification of Radiotherapy in Head and Neck Cancer
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DOI：
10.1158/0008-5472.can-11-1182
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发表时间：
2011-09-01
期刊：
影响因子：
11.2
通讯作者：
Overgaard, Jens
中科院分区：
文献类型：
--
作者：
Toustrup, Kasper;Sorensen, Brita Singers;Overgaard, Jens
缺氧是实体瘤微环境的一个常见特征，与放疗抵抗、治疗反应降低和临床结局较差相关。在头颈部鳞状细胞癌（HNSCC）中，低氧对放射治疗的负面影响可以通过在放射治疗中加入低氧修饰来抵消。为了预测哪些患者患有缺氧性肿瘤并因此受益于缺氧性修饰，需要临床上适用的治疗前缺氧评估和分类方法。在这项研究中，我们开发了一个基于基因表达的缺氧分类器。通过对人鳞状细胞癌细胞系异种移植瘤的研究，我们验证了先前在体外鉴定的低氧诱导基因的体内相关性。然后，我们评估了58个缺氧评估的HNSCC的训练集，以生成包含15个基因的基因表达分类器。这个15基因缺氧分类器在323例HNSCC患者中进行了验证，这些患者随机接受缺氧修饰或安慰剂联合放疗。根据分类器分类为缺氧的肿瘤与非缺氧肿瘤相比，临床结局明显较差。通过添加低氧修饰，该结果得到改善并与非低氧肿瘤相等。因此，研究结果表明，分类器实现了预后和预测的影响，其治疗前的使用可能提供一种方法，以确定这些患者谁将受益于低氧修改放疗。Cancer Res; 71（17）; 5923-31. (C)2011年AACR。
Hypoxia, a common feature of the microenvironment in solid tumors, is associated with resistance to radiotherapy, reduced therapeutic response, and a poorer clinical outcome. In head and neck squamous cell carcinomas (HNSCC), the negative effect of hypoxia on radiotherapy can be counteracted via addition of hypoxic modification to the radiotherapy. To predict which patients harbor hypoxic tumors and would therefore benefit from hypoxic modification, clinically applicable methods for pretherapeutic hypoxic evaluation and categorization are needed. In this study, we developed a hypoxia classifier based on gene expression. Through study of xenograft tumors from human squamous cell carcinoma cell lines, we verified the in vivo relevance of previously identified in vitro derived hypoxia-induced genes. We then evaluated a training set of 58 hypoxia-evaluated HNSCCs to generate a gene expression classifier containing 15 genes. This 15-gene hypoxia classifier was validated in 323 patients with HNSCC randomized for hypoxic modification or placebo in combination with radiotherapy. Tumors categorized as hypoxic on the basis of the classifier were associated with a significantly poorer clinical outcome than nonhypoxic tumors. This outcome was improved and equalized to the nonhypoxic tumors by addition of hypoxic modification. Thus, findings show that the classifier attained both prognostic and predictive impact, and its pretherapeutic use may provide a method to identify those patients who will benefit from hypoxic modification of radiotherapy. Cancer Res; 71(17); 5923-31. (C) 2011 AACR.