Manié Elodie, Popova Tatiana, Battistella Aude, Tarabeux Julien, Caux-Moncoutier Virginie, Golmard Lisa, Smith Nicholas K, Mueller Christopher R, Mariani Odette, Sigal-Zafrani Brigitte, Dubois Thierry, Vincent-Salomon Anne, Houdayer Claude, Stoppa-Lyonnet Dominique, Stern Marc-Henri
Centre De Recherche, Institut Curie, Paris, F-75248, France.
INSERM U830, Paris, F-75248, France.
Int J Cancer. 2016 Feb 15;138(4):891-900. doi: 10.1002/ijc.29829. Epub 2015 Sep 24.
Therapeutic strategies targeting Homologous Recombination Deficiency (HRD) in breast cancer requires patient stratification. The LST (Large-scale State Transitions) genomic signature previously validated for triple-negative breast carcinomas (TNBC) was evaluated as biomarker of HRD in luminal (hormone receptor positive) and HER2-overexpressing (HER2+) tumors. The LST genomic signature related to the number of large-scale chromosomal breakpoints in SNP-array tumor profile was applied to identify HRD in in-house and TCGA sets of breast tumors, in which the status of BRCA1/2 and other genes was also investigated. In the in-house dataset, HRD was predicted in 5% (20/385) of sporadic tumors luminal or HER2+ by the LST genomic signature and the inactivation of BRCA1, BRCA2 or RAD51C confirmed this prediction in 75% (12/16) of the tested cases. In 14% (6/43) of tumors occurring in BRCA1/2 mutant carriers, the corresponding wild-type allele was retained emphasizing the importance of determining the tumor status. In the TCGA luminal and HER2+ subtypes HRD incidence was estimated at 5% (18/329, 95%CI: 5-8%) and 2% (1/59, 95%CI: 2-9%), respectively. In TNBC cisplatin-based neo-adjuvant clinical trials, HRD is shown to be a necessary condition for cisplatin sensitivity. This analysis demonstrates the high performance of the LST genomic signature for HRD detection in breast cancers, which suggests its potential as a biomarker for genetic testing and patient stratification for clinical trials evaluating platinum salts and PARP inhibitors.
针对乳腺癌同源重组缺陷（HRD）的治疗策略需要对患者进行分层。先前已在三阴性乳腺癌（TNBC）中得到验证的LST（大规模状态转换）基因组特征，被评估为管腔型（激素受体阳性）和HER2过表达（HER2+）肿瘤中HRD的生物标志物。将与SNP阵列肿瘤图谱中大规模染色体断点数量相关的LST基因组特征应用于识别内部和TCGA乳腺癌数据集的HRD，同时还研究了BRCA1/2和其他基因的状态。在内部数据集中，LST基因组特征预测5%（20/385）的散发性管腔型或HER2+肿瘤存在HRD，对BRCA1、BRCA2或RAD51C的失活在75%（12/16）的测试病例中证实了这一预测。在BRCA1/2突变携带者发生的14%（6/43）肿瘤中，相应的野生型等位基因得以保留，这凸显了确定肿瘤状态的重要性。在TCGA管腔型和HER2+亚型中，HRD发生率估计分别为5%（18/329，95%CI：5-8%）和2%（1/59，95%CI：2-9%）。在TNBC基于顺铂的新辅助临床试验中，HRD被证明是顺铂敏感性的必要条件。该分析证明了LST基因组特征在乳腺癌HRD检测方面的高性能，这表明其作为基因检测生物标志物以及在评估铂盐和PARP抑制剂的临床试验中对患者进行分层的潜力。
