Department of Medical Oncology, Institut Bergonié, Bordeaux, France.
Cancer. 2011 Aug 1;117(15):3445-56. doi: 10.1002/cncr.25925. Epub 2011 Feb 1.
The objective of this study was to determine whether specific single nucleotide polymorphisms (SNPs) from nucleotide excision repair (NER) and homologous recombination (HR) DNA repair pathways are associated with sensitivity to trabectedin in patients with soft tissue sarcoma (STS).
The authors analyzed excision repair cross-complementation group 5/xeroderma pigmentosum group G (ERCC5/XPG) (NER), excision repair cross-complementation group 1 (ERCC1) (NER), and breast cancer 1 (BRCA1) (HR) SNPs and messenger RNA expression levels in tumor specimens from 113 patients with advanced STS who were enrolled in previously published phase 2 trials or in a compassionate-use program. The 6-month progression-free rate (PFR), progression-free survival (PFS), and overall survival (OS) were analyzed according to ERCC5, ERCC1, and BRCA1 status using log-rank tests.
High expression of the common allele (aspartic acid at codon 1104) of ERCC5, high expression of ERCC1, and BRCA1 haplotype were associated significantly with improved PFR, PFS, and OS. The ERCC1 thymine-to-cytosine (T→C) SNP at codon 19007 and BRCA1 expression were not associated with outcome. On univariate analysis, tumor histology, favorable NER status (high expression of common ERCC5 and/or high ERCC1 expression status), and favorable BRCA1 haplotype (at least 1 triple-adenine plus guanine [AAAG] allele) were the sole variables associated significantly with PFS and OS.
In the current study, ERCC5, ERCC1, and BRCA1 status represented a potential DNA repair signature that could be used for the prediction of clinical response to trabectedin in patients with STS.
本研究旨在确定核苷酸切除修复(NER)和同源重组(HR)DNA 修复途径中的特定单核苷酸多态性(SNP)是否与软组织肉瘤(STS)患者对 trabectedin 的敏感性相关。
作者分析了 113 名晚期 STS 患者肿瘤标本中切除修复交叉互补组 5/xeroderma pigmentosum 组 G(ERCC5/XPG)(NER)、切除修复交叉互补组 1(ERCC1)(NER)和乳腺癌 1(BRCA1)(HR)SNP 和信使 RNA 表达水平,这些患者先前已被纳入发表的 2 期试验或同情使用计划中。使用对数秩检验根据 ERCC5、ERCC1 和 BRCA1 状态分析 6 个月无进展率(PFR)、无进展生存期(PFS)和总生存期(OS)。
ERCC5 常见等位基因(天冬氨酸密码子 1104)的高表达、ERCC1 高表达和 BRCA1 单倍型与改善的 PFR、PFS 和 OS 显著相关。BRCA1 表达与 ERCC1 胸腺嘧啶到胞嘧啶(T→C)SNP (密码子 19007)无关。单因素分析显示,肿瘤组织学、有利的 NER 状态(常见 ERCC5 高表达和/或 ERCC1 高表达状态)和有利的 BRCA1 单倍型(至少有 1 个三腺嘌呤加鸟嘌呤[AAAG]等位基因)是唯一与 PFS 和 OS 显著相关的变量。
在本研究中,ERCC5、ERCC1 和 BRCA1 状态代表了一种潜在的 DNA 修复特征,可用于预测 trabectedin 治疗 STS 患者的临床反应。