The Role of Proliferation in Determining Response to Neoadjuvant Chemotherapy in Breast Cancer: A Gene Expression-Based Meta-Analysis.
The Role of Proliferation in Determining Response to Neoadjuvant Chemotherapy in Breast Cancer: A Gene Expression-Based Meta-Analysis.
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DOI：
10.1158/1078-0432.ccr-16-0471
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发表时间：
2016-12-15
期刊：
影响因子：
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通讯作者：
Selfors LM
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文献类型：
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作者：
Stover DG;Coloff JL;Barry WT;Brugge JS;Winer EP;Selfors LM
为了进一步了解增殖和其他细胞过程在化疗敏感性和耐药性中的作用，我们评估了乳腺癌中不同基因表达特征与新辅助化疗（NAC）反应的相关性。在17项研究中，1419例患者在NAC之前的原发性乳腺癌活检的表达数据被确定并使用常见的标准化程序进行汇总。收集临床病理学特征，包括对NAC的反应。计算每个肿瘤的125个先前发表的乳腺癌相关基因表达特征的评分。在每个基于受体的亚组或PAM 50亚型中，具有高增殖特征评分的乳腺肿瘤更有可能实现NAC的pCR。为了区分“增殖相关”和“增殖无关”的签名，我们使用了相关性和线性建模方法。与NAC应答相关的大多数特征是增殖相关的：ER+/HER 2-为90.5%（38/42），三阴性乳腺癌（TNBC）为63.3%（38/60）。在ER+/HER 2-乳腺癌中，预测NAC应答的非依赖性特征与免疫活性相关，而在TNBC中，这些特征包括一组不同的特征，包括免疫、DNA损伤、信号传导途径（PI 3 K、AKT、Ras、EGFR）和“干性”表型。增殖差异解释了ER+/HER 2-乳腺癌新辅助化疗敏感性中基因表达特征的绝大多数预测能力，并且在较小程度上解释了TNBC的预测能力。免疫激活特征是ER+/HER 2-乳腺癌中pCR的增殖非依赖性预测因子。在TNBC中，显著的增殖非依赖性特征包括代表一组不同细胞过程的基因组。
To provide further insight into the role of proliferation and other cellular processes in chemosensitivity and resistance, we evaluated the association of a diverse set of gene expression signatures with response to neoadjuvant chemotherapy (NAC) in breast cancer. Expression data from primary breast cancer biopsies for 1419 patients in 17 studies prior to NAC were identified and aggregated using common normalization procedures. Clinicopathologic characteristics including response to NAC were collected. Scores for 125 previously published breast cancer-related gene expression signatures were calculated for each tumor. Within each receptor-based subgroup or PAM50 subtype, breast tumors with high proliferation signature scores were significantly more likely to achieve pCR to NAC. To distinguish ‘proliferation-associated’ from ‘proliferation-independent’ signatures, we used correlation and linear modeling approaches. Most signatures associated with response to NAC were proliferation-associated: 90.5% (38/42) in ER+/HER2- and 63.3% (38/60) in triple-negative breast cancer (TNBC). Proliferation-independent signatures predictive of response to NAC in ER+/HER2- breast cancer were related to immune activity, while those in TNBC comprised a diverse set of signatures, including immune, DNA damage, signaling pathways (PI3K, AKT, Ras, EGFR), and ‘stemness’ phenotypes. Proliferation differences account for the vast majority of predictive capacity of gene expression signatures in neoadjuvant chemosensitivity for ER+/HER2- breast cancers and, to a lesser extent, TNBCs. Immune activation signatures are proliferation-independent predictors of pCR in ER+/HER2- breast cancers. In TNBCs, significant proliferation-independent signatures include gene sets that represent a diverse set of cellular processes.