UCD Conway Institute, University College Dublin, Belfield, Ireland.
BMC Cancer. 2010 Nov 23;10:639. doi: 10.1186/1471-2407-10-639.
Conflicting data exist regarding the prognostic and predictive impact of survivin (BIRC5) in breast cancer. We previously reported survivin cytoplasmic-to-nuclear ratio (CNR) as an independent prognostic indicator in breast cancer. Here, we validate survivin CNR in a separate and extended cohort. Furthermore, we present new data suggesting that a low CNR may predict outcome in tamoxifen-treated patients.
Survin expression was assessed using immunhistochemistry on a breast cancer tissue microarray (TMA) containing 512 tumours. Whole slide digital images were captured using an Aperio XT scanner. Automated image analysis was used to identify tumour from stroma and then to quantify tumour-specific nuclear and cytoplasmic survivin. A decision tree model selected using a 10-fold cross-validation approach was used to identify prognostic subgroups based on nuclear and cytoplasmic survivin expression.
Following optimisation of the staining procedure, it was possible to evaluate survivin protein expression in 70.1% (n = 359) of the 512 tumours represented on the TMA. Decision tree analysis predicted that nuclear, as opposed to cytoplasmic, survivin was the most important determinant of overall survival (OS) and breast cancer-specific survival (BCSS). The decision tree model confirmed CNR of 5 as the optimum threshold for survival analysis. Univariate analysis demonstrated an association between a high CNR (>5) and a prolonged BCSS (HR 0.49, 95% CI 0.29-0.81, p = 0.006). Multivariate analysis revealed a high CNR (>5) was an independent predictor of BCSS (HR 0.47, 95% CI 0.27-0.82, p = 0.008). An increased CNR was associated with ER positive (p = 0.045), low grade (p = 0.007), Ki-67 (p = 0.001) and Her2 (p = 0.026) negative tumours. Finally, a high CNR was an independent predictor of OS in tamoxifen-treated ER-positive patients (HR 0.44, 95% CI 0.23-0.87, p = 0.018).
Using the same threshold as our previous study, we have validated survivin CNR as a marker of good prognosis in breast cancer in a large independent cohort. These findings provide robust evidence of the importance of survivin CNR as a breast cancer biomarker, and its potential to predict outcome in tamoxifen-treated patients.
关于生存素（BIRC5）在乳腺癌中的预后和预测影响存在相互矛盾的数据。我们之前报道了生存素细胞质-核比值（CNR）作为乳腺癌的独立预后指标。在这里，我们在一个单独的扩展队列中验证了生存素 CNR。此外，我们提出了新的数据表明，低 CNR 可能预测他莫昔芬治疗患者的结局。
使用包含 512 个肿瘤的乳腺癌组织微阵列（TMA）上的免疫组织化学评估生存素表达。使用 Aperio XT 扫描仪捕获全幻灯片数字图像。使用 10 倍交叉验证方法选择的决策树模型用于根据核和细胞质生存素表达识别预后亚组。
在优化染色程序后，有可能评估 TMA 上代表的 512 个肿瘤中的 70.1%（n = 359）的生存素蛋白表达。决策树分析预测，核生存素而不是细胞质生存素是总生存（OS）和乳腺癌特异性生存（BCSS）的最重要决定因素。决策树模型证实 CNR 为 5 是生存分析的最佳阈值。单因素分析表明，高 CNR（>5）与延长 BCSS 之间存在关联（HR 0.49，95%CI 0.29-0.81，p = 0.006）。多因素分析显示高 CNR（>5）是 BCSS 的独立预测因子（HR 0.47，95%CI 0.27-0.82，p = 0.008）。高 CNR 与 ER 阳性（p = 0.045）、低分级（p = 0.007）、Ki-67（p = 0.001）和 Her2（p = 0.026）阴性肿瘤有关。最后，高 CNR 是他莫昔芬治疗的 ER 阳性患者 OS 的独立预测因子（HR 0.44，95%CI 0.23-0.87，p = 0.018）。
使用与我们之前研究相同的阈值，我们在一个大型独立队列中验证了生存素 CNR 作为乳腺癌预后良好的标志物。这些发现为生存素 CNR 作为乳腺癌生物标志物的重要性及其预测他莫昔芬治疗患者结局的潜力提供了有力证据。
