Patterns of resistance and incomplete response to docetaxel by gene expression profiling in breast cancer patients
Patterns of resistance and incomplete response to docetaxel by gene expression profiling in breast cancer patients
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DOI：
10.1200/jco.2005.03.156
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发表时间：
2005-02-20
影响因子：
45.3
通讯作者：
O'Connell, P
中科院分区：
文献类型：
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作者：
Chang, JC;Wooten, EC;O'Connell, P
目的：可手术乳腺癌化疗可降低死亡风险。多西他赛是乳腺癌治疗中最有效的药物之一，但耐药或不完全反应是常见的。患者和方法24例患者在接受多西他赛新辅助治疗（4个周期，100 mg/m2，每3周1次）前获得核心活检，化疗后评估反应。新辅助化疗3个月后，获得手术标本（n = 13），并进行激光捕获显微切割（LCM; n = 8）以富集肿瘤细胞。从每个核心，手术，和LCM标本，提取足够的总RNA（3至6 μ g）的cDNA阵列分析使用的Affyoung HgU 95-Av 2基因芯片（Affyoung，圣克拉拉，CA）。然而，多西他赛治疗3个月后残留癌的分子模式惊人地相似，与初始敏感性或耐药性无关。在LCM和非LCM手术标本中均观察到治疗后的这种相对遗传同质性。在最初敏感的肿瘤中治疗后的残留肿瘤表明选择了残留和抗性细胞亚群。基因表达模式由参与细胞周期阻滞在G（2）M期的基因（如有丝分裂细胞周期蛋白和cdc 2）和涉及哺乳动物雷帕霉素靶蛋白的生存通路组成。结论多西他赛治疗后残留肿瘤中发现了特异性和一致性的基因表达模式。这些特征提供了可能导致改善治疗的治疗靶点。(C)2005年，美国临床肿瘤学会。
Purpose Chemotherapy for operable breast cancer decreases the risk of death. Docetaxel is one of the most active agents in breast cancer, but resistance or incomplete response is frequent.Patients and Methods Core biopsies from 24 patients were obtained before treatment with neoradjuvant docetaxel (four cycles, 100 mg/m(2) every 3 weeks), and response was assessed after chemotherapy. After 3 months of neoadjuvant chemotherapy, surgical specimens (n = 13) were obtained, and laser capture microdissection (LCM; n = 8) was performed to enrich for tumor cells. From each core, surgical, and LCM specimen, sufficient total RNA (3 to 6 mug) was extracted for cDNA array analysis using the Affymetrix HgU95-Av2 GeneChip (Affymetrix, Santa Clara, CA).Results From the initial core biopsies, differential patterns of expression of 92 genes correlated with docetaxel response (P = .001). However, the molecular patterns of the residual cancers after 3 months of docetaxel treatment were strikingly similar, independent of initial sensitivity or resistance. This relative genetic homogeneity after treatment was observed in both LCM and non-LCM surgical specimens. The residual tumor after treatment in tumors that were initially sensitive indicates selection of a residual and resistant subpopulation of cells. The gene expression pattern was populated by genes involved in cell cycle arrest at G(2)M (eg, mitotic cyclins and cdc2) and survival pathways involving the mammalian target of rapamycin.Conclusion A specific and consistent gene expression pattern was found in residual tumors after docetaxel treatment. These profiles provide therapeutic targets that could lead to improved treatment. (C) 2005 by American Society of Clinical Oncology.