原位定量测量HER2mRNA可预测一组转移性乳腺癌患者接受含曲妥珠单抗化疗的获益情况。
In situ quantitative measurement of HER2mRNA predicts benefit from trastuzumab-containing chemotherapy in a cohort of metastatic breast cancer patients.
作者信息
Vassilakopoulou Maria, Togun Taiwo, Dafni Urania, Cheng Huan, Bordeaux Jennifer, Neumeister Veronique M, Bobos Mattheos, Pentheroudakis George, Skarlos Dimosthenis V, Pectasides Dimitrios, Kotoula Vassiliki, Fountzilas George, Rimm David L, Psyrri Amanda
机构信息
Yale University, School of Medicine, Department of Pathology, New Haven, Connecticut, United States of America.
Yale University, School of Public Health, Department of Biostatistics, New Haven, Connecticut, United States of America.
出版信息
PLoS One. 2014 Jun 26;9(6):e99131. doi: 10.1371/journal.pone.0099131. eCollection 2014.
BACKGROUND
We sought to determine the predictive value of in situ mRNA measurement compared to traditional methods on a cohort of trastuzumab-treated metastatic breast cancer patients.
METHODS
A tissue microarray composed of 149, classified as HER2-positive, metastatic breast cancers treated with various trastuzumab-containing chemotherapy regimens was constructed. HER2 intracellular domain(ICD), HER2 extracellular domain(ECD) and HER2 mRNA were assessed using AQUA. For HER2 protein evaluation, CB11 was used to measure ICD and SP3 to measure ECD of the HER2 receptor. In addition, HER2 mRNA status was assessed using RNAscope assay ERRB2 probe. Kaplan - Meier estimates were used for depicting time-to-event endpoints. Multivariate Cox regression models with backward elimination were used to assess the performance of markers as predictors of TTP and OS, after adjusting for important covariates.
RESULTS
HER2 mRNA was correlated with ICD HER2, as measured by CB11 HER2, with ECD HER2 as measured by SP3 (Pearson's Correlation Coefficient, r = 0.66 and 0.51 respectively) and with FISH HER2 (Spearman's Correlation Coefficient, r = 0.75). All markers, HER2 mRNA, ICD HER2 and ECD HER2, along with FISH HER2, were found prognostic for OS (Log-rank p = 0.007, 0.005, 0.009 and 0.043 respectively), and except for FISH HER2, they were also prognostic for TTP Log-rank p = 0.036, 0.068 and 0.066 respectively) in this trastuzumab- treated cohort. Multivariate analysis showed that in the presence of pre-specified set of prognostic factors, among all biomarkers only ECD HER2, as measured by SP3, is strong prognostic factor for both TTP (HR = 0.54, 95% CI: 0.31-0.93, p = 0.027) and OS (HR = 0.39, 95%CI: 0.22-0.70, p = 0.002).
CONCLUSIONS
The expression of HER2 ICD and ECD as well as HER2 mRNA levels was significantly associated with TTP and OS in this trastuzumab-treated metastatic cohort. In situ assessment of HER2 mRNA has the potential to identify breast cancer patients who derive benefit from Trastuzumab treatment.
背景
我们试图确定与传统方法相比，原位mRNA检测对一组接受曲妥珠单抗治疗的转移性乳腺癌患者的预测价值。
方法
构建了一个组织微阵列，其由149例经各种含曲妥珠单抗的化疗方案治疗的HER2阳性转移性乳腺癌组成。使用AQUA评估HER2细胞内结构域（ICD）、HER2细胞外结构域（ECD）和HER2 mRNA。对于HER2蛋白评估，使用CB11测量HER2的ICD，使用SP3测量HER2受体的ECD。此外，使用RNAscope检测ERRB2探针评估HER2 mRNA状态。采用Kaplan-Meier估计法描绘事件发生时间终点。在调整重要协变量后，使用带有向后消除的多变量Cox回归模型评估标志物作为TTP和OS预测指标的性能。
结果
HER2 mRNA与通过CB11测量的HER2 ICD、通过SP3测量的HER2 ECD相关（Pearson相关系数，r分别为0.66和0.51），并与FISH HER2相关（Spearman相关系数，r为0.75）。在这个接受曲妥珠单抗治疗的队列中，所有标志物，HER2 mRNA、HER2 ICD和HER2 ECD，以及FISH HER2，均被发现对OS具有预后意义（对数秩检验p分别为0.007、0.005、0.009和0.043），除FISH HER2外，它们对TTP也具有预后意义（对数秩检验p分别为0.036、0.068和0.066）。多变量分析表明，在存在预先指定的一组预后因素的情况下，在所有生物标志物中，只有通过SP3测量的HER2 ECD是TTP（HR = 0.54，95%CI：0.31 - 0.93，p = 0.027）和OS（HR = 0.39，95%CI：0.22 - 0.70，p = 0.002）的强预后因素。
结论
在这个接受曲妥珠单抗治疗的转移性队列中，HER2 ICD和ECD的表达以及HER2 mRNA水平与TTP和OS显著相关。HER2 mRNA的原位评估有可能识别出从曲妥珠单抗治疗中获益的乳腺癌患者。
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