An aCGH classifier derived from BRCA1-mutated breast cancer and benefit of high-dose platinum-based chemotherapy in HER2-negative breast cancer patients.
An aCGH classifier derived from BRCA1-mutated breast cancer and benefit of high-dose platinum-based chemotherapy in HER2-negative breast cancer patients.
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DOI：
10.1093/annonc/mdq624
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发表时间：
2011-07
期刊：
影响因子：
--
通讯作者：
Linn SC
中科院分区：
文献类型：
--
作者：
Vollebergh MA;Lips EH;Nederlof PM;Wessels LFA;Schmidt MK;van Beers EH;Cornelissen S;Holtkamp M;Froklage FE;de Vries EGE;Schrama JG;Wesseling J;van de Vijver MJ;van Tinteren H;de Bruin M;Hauptmann M;Rodenhuis S;Linn SC
背景：BRCA1基因缺失的乳腺癌细胞对引起DNA双链断裂(DSB)的药物如双功能烷化剂和铂类药物高度敏感。早些时候，我们开发了一种基于BRCA1突变乳腺癌的比较基因组杂交(CGH)分类器。我们推测，这种类似BRCA1的CGH分类器也可以检测到除突变以外的其他原因导致的BRCA1功能丧失，从而可能预测对DSB诱导剂的敏感性。患者和方法：我们在III期乳腺癌患者中评估了该分类器，这些患者被随机分配到辅助大剂量铂类(HD-PB)化疗、DSB诱导方案和传统的基于蒽环类药物的化疗之间。此外，我们通过突变或启动子甲基化以及免疫组织化学基底样状态在三阴性亚组(TN亚组)中评估了BRCA1缺失。结果：与非BRCA1样CGH患者(189/230=82%，HR=0.78，95%CI0.50~1.20)相比，HD-PB化疗的益处明显高于常规化疗[41/230=18%，多因素风险比(HR)=0.12，95%可信区间(CI)0.04~0.43]，有显著差异(交互作用检验P=0.006)。当分析局限于TN亚组时，在总体生存方面也得到了类似的结果(P交互作用=0.04)。在可评估的BRCA1样CGH肿瘤中，63%(20/32)存在BRCA1突变(n=8)或BRCA1甲基化(n=12)。结论：通过CGH分析评估BRCA1丢失可以确定与我们系列中标准的基于蒽环类药物的化疗相比，辅助性DSB诱导化疗后患者的预后有显著改善。
Background: Breast cancer cells deficient for BRCA1 are hypersensitive to agents inducing DNA double-strand breaks (DSB), such as bifunctional alkylators and platinum agents. Earlier, we had developed a comparative genomic hybridisation (CGH) classifier based on BRCA1-mutated breast cancers. We hypothesised that this BRCA1-likeCGH classifier could also detect loss of function of BRCA1 due to other causes besides mutations and, consequently, might predict sensitivity to DSB-inducing agents. Patients and methods: We evaluated this classifier in stage III breast cancer patients, who had been randomly assigned between adjuvant high-dose platinum-based (HD-PB) chemotherapy, a DSB-inducing regimen, and conventional anthracycline-based chemotherapy. Additionally, we assessed BRCA1 loss through mutation or promoter methylation and immunohistochemical basal-like status in the triple-negative subgroup (TN subgroup). Results: We observed greater benefit from HD-PB chemotherapy versus conventional chemotherapy among patients with BRCA1-likeCGH tumours [41/230 = 18%, multivariate hazard ratio (HR) = 0.12, 95% confidence interval (CI) 0.04–0.43] compared with patients with non-BRCA1-likeCGH tumours (189/230 = 82%, HR = 0.78, 95% CI 0.50–1.20), with a significant difference (test for interaction P = 0.006). Similar results were obtained for overall survival (P interaction = 0.04) and when analyses were restricted to the TN subgroup. Sixty-three percent (20/32) of assessable BRCA1-likeCGH tumours harboured either a BRCA1 mutation (n = 8) or BRCA1 methylation (n = 12). Conclusion: BRCA1 loss as assessed by CGH analysis can identify patients with substantially improved outcome after adjuvant DSB-inducing chemotherapy when compared with standard anthracycline-based chemotherapy in our series.
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影响因子：
45.3
作者：
Hugh, Judith;Hanson, John;Vogel, Charles
通讯作者：
Vogel, Charles
影响因子：
45.3
作者：
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通讯作者：
Cannistra, Stephen A.
影响因子：
11.5
作者：
Diallo-Danebrock, Raihanatou;Ting, Evelyn;Poremba, Christopher
通讯作者：
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影响因子：
10.3
作者：
Esteller, M;Silva, JM;Herman, JG
通讯作者：
Herman, JG
自动化阵列CGH用于用于档案中的福尔马林固定，石蜡包裹的肿瘤材料。
影响因子：
3.8
作者：
Joosse, Simon A.;van Beers, Erik H.;Nederlof, Petra M.
通讯作者：
Nederlof, Petra M.