Abstract Increased expression or amplification of HER2 receptor tyrosine kinase gene ERBB2 is well-known and widely used as a prognostic biomarker of breast cancer (BC) response to the targeted treatment with trastuzumab and its analogs. Considering that part of the BC patients overexpressing HER2 does not respond to trastuzumab, clinical trial NCT03521245 was initiated to identify additional gene expression and molecular pathway activation response biomarkers to trastuzumab treatment in HER2-positive BC. Using RNA sequencing gene expression in 23 formalin-fixed, paraffin embedded HER2 positive BC tissue blocks from patients who either responded or not responded to trastuzumab treatment was profiled. Differentially regulated genes and molecular pathways were identified in the groups of trastuzumab responders and non-responders. These results were next compared with the 42 previously published BC trastuzumab responder and non-responder RNA sequencing profiles from the clinical trials NCT00513292 and NCT00353483. No correlation was observed between the response status and the expression levels of ERBB2 gene in the HER2 positive BC samples. Analysis of the differentially expressed genes and molecular pathways in the combined dataset revealed 15/27 commonly up/down regulated genes and 15/25 pathways, respectively. However, only the intersection of molecular pathways upregulated in trastuzumab responders vs non-responders was statistically significantly enriched compared to the random expectation model. A classifier built using the most significantly upregulated molecular pathway – cAMP Pathway Protein Retention – demonstrated the best performance for prediction of the HER2 positive BC response to trastuzumab for both our experimental and previously reported data. This pathway also predicted time to recurrence in the combined dataset with Log-rank p -value 0.041.

中文翻译：

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分子通路激活标志物与曲妥珠单抗治疗转移性 HER2 阳性乳腺癌的疗效相关，优于个体基因表达水平

摘要 HER2 受体酪氨酸激酶基因 ERBB2 的表达增加或扩增是众所周知的，并广泛用作乳腺癌 (BC) 对曲妥珠单抗及其类似物靶向治疗反应的预后生物标志物。考虑到部分过度表达 HER2 的 BC 患者对曲妥珠单抗没有反应，启动临床试验 NCT03521245 以确定额外的基因表达和分子通路激活反应生物标志物，以在 HER2 阳性 BC 中进行曲妥珠单抗治疗。在 23 个福尔马林固定、石蜡包埋的 HER2 阳性 BC 组织块中使用 RNA 测序基因表达，这些组织块来自对曲妥珠单抗治疗有反应或无反应的患者。在曲妥珠单抗应答者和非应答者组中鉴定出差异调节的基因和分子途径。接下来将这些结果与来自临床试验 NCT00513292 和 NCT00353483 的 42 个先前公布的 BC 曲妥珠单抗反应者和非反应者 RNA 测序谱进行比较。在 HER2 阳性 BC 样品中未观察到反应状态与 ERBB2 基因表达水平之间的相关性。对组合数据集中差异表达的基因和分子途径的分析分别揭示了 15/27 常见的上调/下调基因和 15/25 途径。然而，与随机期望模型相比，只有在曲妥珠单抗响应者与非响应者中上调的分子途径的交叉点在统计学上显着丰富。使用最显着上调的分子途径（cAMP 途径蛋白质保留）构建的分类器在预测 HER2 对曲妥珠单抗的阳性 BC 反应方面具有最佳性能，无论是我们的实验数据还是之前报告的数据。该途径还预测了组合数据集中的复发时间，对数秩 p 值为 0.041。