Gene Expression Profile of BRCAness That Correlates With Responsiveness to Chemotherapy and With Outcome in Patients With Epithelial Ovarian Cancer
Gene Expression Profile of BRCAness That Correlates With Responsiveness to Chemotherapy and With Outcome in Patients With Epithelial Ovarian Cancer
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DOI：
10.1200/jco.2009.27.5719
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发表时间：
2010-08-01
影响因子：
45.3
通讯作者：
Cannistra, Stephen A.
中科院分区：
文献类型：
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作者：
Konstantinopoulos, Panagiotis A.;Spentzos, Dimitrios;Cannistra, Stephen A.
目的：探讨与上皮性卵巢癌（EOC）化疗反应和预后相关的BRCAness基因表达谱。方法使用公开的微阵列数据集，包括61例散发疾病或BRCA1/2种系突变的EOC患者，用于BRCAness谱的开发。在6例BRCA种系突变患者的铂敏感和铂耐药肿瘤活检标本中评估与铂反应性的相关性。在Capan-1细胞系克隆中评估了与多adp核糖聚合酶（PARP）抑制剂反应性和辐射诱导的RAD51灶形成（同源重组的替代物）的关联。BRCAness在70例散发性疾病患者中得到验证，以评估其与预后的关系。结果BRCAness谱准确预测了10例患者源性肿瘤标本中8例的铂反应性和突变状态，以及4例Capan-1克隆中4例parp抑制剂的敏感性和耐药性。当应用于70例散发性疾病患者时，与非brca样（NBL）患者相比，brca样（BL）患者的无病生存期（34个月vs 15个月；log-rank P = 0.013）和总生存期（72个月vs 41个月；log-rank P = 0.006）分别有所改善。BRCAness在控制其他已知临床预后因素的多变量分析中保持独立的预后价值。BRCAness特征与对铂和PARP抑制剂的反应性相关，并确定了零星患者预后改善的子集。有必要对该特征进行进一步评估，以作为散发性EOC患者的预测工具。
PurposeTo define a gene expression profile of BRCAness that correlates with chemotherapy response and outcome in epithelial ovarian cancer (EOC).MethodsA publicly available microarray data set including 61 patients with EOC with either sporadic disease or BRCA1/2 germline mutations was used for development of the BRCAness profile. Correlation with platinum responsiveness was assessed in platinum-sensitive and platinum-resistant tumor biopsy specimens from six patients with BRCA germline mutations. Association with poly-ADP ribose polymerase (PARP) inhibitor responsiveness and with radiation-induced RAD51 foci formation (a surrogate of homologous recombination) was assessed in Capan-1 cell line clones. The BRCAness profile was validated in 70 patients enriched for sporadic disease to assess its association with outcome.ResultsThe BRCAness profile accurately predicted platinum responsiveness and mutation status in eight of 10 patient-derived tumor specimens and between PARP-inhibitor sensitivity and resistance in four of four Capan-1 clones. When applied to the 70 patients with sporadic disease, patients with the BRCA-like (BL) profile had improved disease-free survival (34 months v 15 months; log-rank P = .013) and overall survival (72 months v 41 months; log-rank P = .006) compared with patients with a non-BRCA-like (NBL) profile, respectively. The BRCAness profile maintained independent prognostic value in multivariate analysis, which controlled for other known clinical prognostic factors.ConclusionThe BRCAness profile correlates with responsiveness to platinum and PARP inhibitors and identifies a subset of sporadic patients with improved outcome. Additional evaluation of this profile as a predictive tool in patients with sporadic EOC is warranted.