Nuclear excision repair-based personalized therapy for non-small cell lung cancer: From hypothesis to reality
Nuclear excision repair-based personalized therapy for non-small cell lung cancer: From hypothesis to reality
复制标题
DOI：
10.1016/j.biocel.2007.05.006
复制
发表时间：
2007-01-01
影响因子：
4
通讯作者：
Bepler, Gerold
中科院分区：
文献类型：
--
作者：
Simon, George R.;Ismail-Khan, Roohi;Bepler, Gerold
非小细胞肺癌（NSCLC）现有治疗模式的关键“缺陷”是“一刀切”。因此，所有患者都接受辅助化疗，以使少数患者受益，而在转移性疾病中，双重化疗仅能适度改善缓解率和生存率。因此，迫切需要个性化的治疗选择方法。遗传信息存储在DNA的化学结构中。为了维持DNA的结构完整性，进化出了一个复杂的DNA修复系统网络。其中之一是核苷酸切除修复（NER），这是一种高度通用和复杂的DNA损伤去除途径。我们在这里表明，这种DNA修复机制有助于确定预后和对治疗的反应。ERCC1是该途径中的蛋白质之一，测量以评估其NER途径的功能状态。在早期NSCLC患者中，低ERCC1预测复发，并选择将从基于顺铂的辅助化疗中获益的患者。相反，ERCC1阳性的切除患者具有更好的内在预后，并且不太可能从基于铂的化疗中获益。在转移性疾病的11期试验中，我们表明，通过使用ERCC1和RRM1定制化疗，我们可以获得60%的1年生存率（与历史对照中的约36%相比）和42%的反应率（与历史对照中的25%相比）。这种方法目前正在一项前瞻性III期试验中得到验证。在未来，NER功能的评估可能在NSCLC治疗决策中发挥核心作用。(c)2007爱思唯尔有限公司保留所有权利。
The crucial 'flaw' in the existing treatment paradigm for non-small cell lung cancer (NSCLC) is the 'one size fits all approach'. Consequently, adjuvant chemotherapy is given to all patients to benefit a minority and, in the metastatic setting doublet chemotherapy only provides modest improvements in response rates and survival. A personalized approach of treatment selection is therefore desperately needed. Genetic information is stored in the chemical structure of DNA. To maintain the structural integrity of DNA, an intricate network of DNA repair systems have evolved. One of these is the nucleotide excision repair (NER), a highly versatile and sophisticated DNA damage removal pathway. We show here that this DNA repair mechanism is instrumental in defining prognosis and response to treatment. ERCC1, one of the proteins in this pathway, is measured to assess its functional status of the NER pathway. In patients with early stage NSCLC, low ERCC1 predicts for relapse and selects for patients who will benefit from adjuvant cisplatin-based chemotherapy. Conversely, ERCC1-positive resected patients have a better intrinsic prognosis and are not likely to benefit from platinum based chemotherapy. In a phase 11 trial in metastatic disease, we show that by tailoring chemotherapy using ERCC1 and RRM1 we can obtain 1-year survival of 60% (versus approximately 36% in historical controls) and response rates of 42% (versus 25% in historical controls). This approach is currently being validated in a prospective phase III trial. In the future, assessment of NER function may play a central role in NSCLC treatment decision making. (c) 2007 Elsevier Ltd. All rights reserved.