signature=77cc23b870fcd46b1f7fb6615d734032,Abstract P6-09-49: Three-gene signature predictive of hig...-优快云博客

研究发现，尽管接受了辅助内分泌和化疗，部分ER阳性、HER2阴性的乳腺癌患者仍存在高复发风险。通过对多个基因表达数据集的分析，确定了一个由MX1、MBD4和ZWINT三个基因组成的标志物，这些基因的高表达可以识别出这类患者。在训练和验证队列中，这三个基因的表达水平与生存率显著相关，表明它们可能用于预测化疗后的高复发风险。在多变量分析中，这一三基因标志物在两个队列中都保持显著性，而淋巴结状态在验证队列中也具有显著性。这表明，这个三基因组合可能有助于识别出即使接受现有治疗后仍处于极高复发风险的患者。

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Abstract

Background: A proportion of ER-positive, HER2-negative patients treated with both adjuvant endocrine and chemotherapy continue to remain high risk for recurrence. These individuals are the ideal patient population for future adjuvant trials.

Methods: We used gene expression data from ER+/HER2- patients who received adjuvant endocrine and chemotherapy. We utilized a training cohort of multiple gene expression datasets (N=131; GSE16391, GSE21653, GSE17907, GSE19615, GSE16716, GSE45255) and a validation cohort (N=277; GSE25066) from similarly treated ER+ patients. All data sets were generated with Affymetrix HGU133 arrays. Cox proportional hazards regression was performed across all genes using all possible cutoff values between the lower and upper quartile. Genes were ranked according to the estimated hazard rates for relapse. The top three genes were combined into a final signature that used the mean expression of these genes as the predictive score. Statistical analyses were performed in the R environment.

Results: The final signature capable to predict survival consisted of three genes, MX1, MBD4, and ZWINT. Each of these genes achieved high significance in a univariate analysis: MX1 HR=5.7 (p=1.8E-04) and HR=4.7 (p=1.3E-03), MBD4 HR=3.4 (p=2.8E-04) and HR=4.3 (p=4.4E-04), and ZWINT HR=4.4 (p=1E-03) and HR=3.7 (p=8.5E-03) in the training and validation cohorts, respectively. Using the mean expression of the three genes, the estimated hazard rates for survival were 20.5 (p=2.5E-05) and 17.5 (p=1E-04) in the two cohorts, respectively. Only one patient relapsed in each cohort. In a multivariate analysis including grade and lymph node status as covariates (size was not available), the three-gene signature retained significance (HR=13.2, p=0.011; and HR=13.9, p=0.01 in the two cohorts, respectively), while only lymph node status (HR=3.6, p=0.007) was significant in the validation cohort and no clinical variable was significant in the training cohort.

Conclusions: High expression of a 3-gene signature can identify ER+ patients who remain at very high risk for recurrence despite current adjuvant endocrine and chemotherapy.

Citation Format: Györffy B, Ocana A, Herman P, Hatzis C, Pandiella A, Pusztai L. Three-gene signature predictive of high residual risk of recurrence after adjuvant chemotherapy in ER-positive HER2-negative breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-49.