Gene expression, molecular class changes, and pathway analysis after neoadjuvant systemic therapy for breast cancer.
Gene expression, molecular class changes, and pathway analysis after neoadjuvant systemic therapy for breast cancer.
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DOI：
10.1158/1078-0432.ccr-11-2762
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发表时间：
2012-02-15
期刊：
影响因子：
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通讯作者：
Pusztai L
中科院分区：
文献类型：
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作者：
Gonzalez-Angulo AM;Iwamoto T;Liu S;Chen H;Do KA;Hortobagyi GN;Mills GB;Meric-Bernstam F;Symmans WF;Pusztai L
研究乳腺癌NST前后标本的基因表达差异，并确定可能导致新的治疗见解的生物学变化。将化疗前细针穿刺标本的基因表达数据与NST 4-6个月后21例患者切除的残留癌进行比较。我们去除了基质相关基因，以尽量减少混杂效应。PAM 50用于分配分子类别。配对t检验和基因集分析用于鉴定差异表达的基因和通路。基于mRNA表达的ER和HER 2状态在除两例外的所有病例中保持稳定，并且增殖指标（Ki 67和PCNA表达）没有变化。8例（33.3%）分子分类改变，通常为正常样分类，与低残留癌细胞相关。200-600个探针组的表达在基线和NST后样品之间变化。在基底细胞样癌中，由PI 3 K、小G蛋白和CAMK 2的表达增加以及能量代谢驱动的途径被富集，而免疫细胞衍生的和音刺猬途径在残留癌中被耗尽。在非基底样乳腺癌中，notch信号传导和能量代谢（例如脂肪酸合成）富集，而在残留癌中，音刺猬信号传导和免疫相关途径被耗尽。上皮间质转化或癌症干细胞特征没有增加。我们的数据表明，能量代谢相关过程被上调，免疫相关信号在残留癌症中被耗尽。靶向这些生物过程可能代表残留癌患者有希望的辅助治疗策略。
To examine gene expression differences between pre- and post-NST specimens of breast cancers and identify biological changers that may lead to new therapeutic insights. Gene expression data from pre-chemotherapy fine needle aspiration specimens were compared to resected residual cancers in 21 patients after 4-6 months of NST. We removed stroma-associated genes to minimize confounding effects. PAM50 was used to assign molecular class. Paired t-test and gene set analysis were used to identify differentially expressed genes and pathways. The ER and HER2 status based on mRNA expression remained stable in all but two cases and there were no changes in proliferation metrics (Ki67 and PCNA expression). Molecular class changed in 8 cases (33.3%) usually to normal-like class and which was associated with low residual cancer cell cellularity. The expression of 200-600 probe sets changed between baseline and post-NST samples. In basal-like cancers, pathways driven by increased expression of PI3K, small G proteins and CAMK2 and energy metabolism were enriched while immune cell-derived and the sonic hedgehog pathways were depleted in residual cancer. In non-basal-like breast cancers, notch signaling and energy metabolism (e.g. fatty acid synthesis) were enriched and sonic hedgehog signaling and immune-related pathways were depleted in residual cancer. There was no increase in epithelial mesenchymal transition or cancer stem cell signatures. Our data indicates that energy metabolism related processes are up-regulated and immune related signals are depleted in residual cancers. Targeting these biological processes may represent promising adjuvant treatment strategies for patients with residual cancer.