Sgroi Dennis C, Chapman Judy-Anne W, Badovinac-Crnjevic T, Zarella Elizabeth, Binns Shemeica, Zhang Yi, Schnabel Catherine A, Erlander Mark G, Pritchard Kathleen I, Han Lei, Shepherd Lois E, Goss Paul E, Pollak Michael
Molecular Pathology Unit, Pathology Research Center, Massachusetts General Hospital, MGH East, Molecular Pathology, Research, 149 13th Street, Charlestown, MA, 02129, USA.
Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA, USA.
Breast Cancer Res. 2016 Jan 4;18(1):1. doi: 10.1186/s13058-015-0660-6.
Biomarkers that can be used to accurately assess the residual risk of disease recurrence in women with hormone receptor-positive breast cancer are clinically valuable. We evaluated the prognostic value of the Breast Cancer Index (BCI), a continuous risk index based on a combination of HOXB13:IL17BR and molecular grade index, in women with early breast cancer treated with either tamoxifen alone or tamoxifen plus octreotide in the NCIC MA.14 phase III clinical trial (ClinicalTrials.gov Identifier NCT00002864; registered 1 November 1999).
Gene expression analysis of BCI by real-time polymerase chain reaction was performed blinded to outcome on RNA extracted from archived formalin-fixed, paraffin-embedded tumor samples of 299 patients with both lymph node-negative (LN-) and lymph node-positive (LN+) disease enrolled in the MA.14 trial. Our primary objective was to determine the prognostic performance of BCI based on relapse-free survival (RFS). MA.14 patients experienced similar RFS on both treatment arms. Association of gene expression data with RFS was evaluated in univariate analysis with a stratified log-rank test statistic, depicted with a Kaplan-Meier plot and an adjusted Cox survivor plot. In the multivariate assessment, we used stratified Cox regression. The prognostic performance of an emerging, optimized linear BCI model was also assessed in a post hoc analysis.
Of 299 samples, 292 were assessed successfully for BCI for 146 patients accrued in each MA.14 treatment arm. BCI risk groups had a significant univariate association with RFS (stratified log-rank p = 0.005, unstratified log-rank p = 0.007). Adjusted 10-year RFS in BCI low-, intermediate-, and high-risk groups was 87.5 %, 83.9 %, and 74.7 %, respectively. BCI had a significant prognostic effect [hazard ratio (HR) 2.34, 95 % confidence interval (CI) 1.33-4.11; p = 0.004], although not a predictive effect, on RFS in stratified multivariate analysis, adjusted for pathological tumor stage (HR 2.22, 95 % CI 1.22-4.07; p = 0.01). In the post hoc multivariate analysis, higher linear BCI was associated with shorter RFS (p = 0.002).
BCI had a strong prognostic effect on RFS in patients with early-stage breast cancer treated with tamoxifen alone or with tamoxifen and octreotide. BCI was prognostic in both LN- and LN+ patients. This retrospective study is an independent validation of the prognostic performance of BCI in a prospective trial.
可用于准确评估激素受体阳性乳腺癌女性疾病复发残余风险的生物标志物具有临床价值。我们在NCIC MA.14 III期临床试验（ClinicalTrials.gov标识符NCT00002864；1999年11月1日注册）中，评估了基于HOXB13:IL17BR与分子分级指数组合的连续风险指数——乳腺癌指数（BCI）在单独使用他莫昔芬或他莫昔芬加奥曲肽治疗的早期乳腺癌女性中的预后价值。
对MA.14试验中入组的299例淋巴结阴性（LN-）和淋巴结阳性（LN+）疾病患者的存档福尔马林固定、石蜡包埋肿瘤样本提取的RNA进行实时聚合酶链反应，对BCI进行基因表达分析，分析过程对结果设盲。我们的主要目的是基于无复发生存期（RFS）确定BCI的预后性能。MA.14试验两个治疗组的患者RFS相似。采用分层对数秩检验统计量进行单变量分析评估基因表达数据与RFS的相关性，用Kaplan-Meier图和调整后的Cox生存图表示。在多变量评估中，我们使用分层Cox回归。还在事后分析中评估了一种新出现的、优化的线性BCI模型的预后性能。
在299个样本中，成功评估了292个样本的BCI，每个MA.14治疗组有146例患者。BCI风险组与RFS有显著的单变量相关性（分层对数秩p = 0.005，未分层对数秩p = 0.007）。BCI低、中、高风险组调整后的10年RFS分别为87.5%、83.9%和74.7%。在分层多变量分析中，调整病理肿瘤分期后，BCI对RFS有显著的预后作用[风险比（HR）2.34，95%置信区间（CI）1.33 - 4.11；p = 0.004]，但无预测作用（HR 2.22，95% CI 1.22 - 4.07；p = 0.01）。在事后多变量分析中，较高的线性BCI与较短的RFS相关（p = 0.002）。
BCI对单独使用他莫昔芬或他莫昔芬与奥曲肽治疗的早期乳腺癌患者的RFS有很强的预后作用。BCI在LN-和LN+患者中均具有预后价值。这项回顾性研究是对BCI在一项前瞻性试验中预后性能的独立验证。
