Departments of Breast Medical Oncology, Systems Biology, Biostatistics, Surgical Oncology, and Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Clin Cancer Res. 2012 Feb 15;18(4):1109-19. doi: 10.1158/1078-0432.CCR-11-2762. Epub 2012 Jan 10.
To examine gene expression differences between pre- and post-neoadjuvant systemic therapy (NST) specimens of breast cancers and identify biologic changers that may lead to new therapeutic insights.
Gene expression data from prechemotherapy fine needle aspiration specimens were compared with resected residual cancers in 21 patients after 4 to 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 proliferating cell nuclear antigen expression). Molecular class changed in 8 cases (33.3%), usually to normal-like class, which was associated with low residual cancer cell cellularity. The expression of 200 to 600 probe sets changed between baseline and post-NST samples. In basal-like cancers, pathways driven by increased expression of phosphoinositide 3-kinase, small G proteins, and calmodulin-dependent protein kinase II and energy metabolism were enriched, whereas 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 indicate that energy metabolism related processes are upregulated and immune-related signals are depleted in residual cancers. Targeting these biologic processes may represent promising adjuvant treatment strategies for patients with residual cancer.
研究新辅助化疗（NST）前后乳腺癌标本的基因表达差异，寻找可能导致新治疗靶点的生物学变化。
对 21 例患者 NST 治疗 4-6 个月后切除的残留癌组织与化疗前细针穿刺标本的基因表达数据进行了比较。我们去除了基质相关基因，以尽量减少混杂效应。采用 PAM50 对分子亚型进行分类。采用配对 t 检验和基因集分析识别差异表达基因和通路。
除 2 例外，基于 mRNA 表达的 ER 和 HER2 状态在所有病例中均保持稳定，增殖指标（Ki67 和增殖细胞核抗原表达）无变化。8 例（33.3%）病例的分子亚型发生变化，通常向正常样型转变，与残留癌细胞数量低有关。基线和 NST 后样本之间有 200 到 600 个探针集的表达发生变化。在基底样乳腺癌中，磷酸肌醇 3-激酶、小 G 蛋白和钙调蛋白依赖性蛋白激酶 II 以及能量代谢驱动的通路表达增加，而残留癌中免疫细胞衍生和 Sonic Hedgehog 通路被耗尽。在非基底样乳腺癌中，Notch 信号和能量代谢（如脂肪酸合成）被富集，而 Sonic Hedgehog 信号和免疫相关通路在残留癌中被耗尽。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，能量代谢相关过程在残留癌中上调，免疫相关信号被耗尽。针对这些生物学过程可能是残留癌患者有前途的辅助治疗策略。
