Chang Jenny C, Wooten Eric C, Tsimelzon Anna, Hilsenbeck Susan G, Gutierrez M Carolina, Elledge Richard, Mohsin Syed, Osborne C Kent, Chamness Gary C, Allred D Craig, O'Connell Peter
Breast Center and the Departments of Medicine, Pathology, and Molecular and Cellular Biology, Baylor College of Medicine, and the Methodist Hospital, Houston, TX 77030, USA.
Lancet. 2003 Aug 2;362(9381):362-9. doi: 10.1016/S0140-6736(03)14023-8.
Systemic chemotherapy for operable breast cancer substantially decreases the risk of death. Patients often have de novo resistance or incomplete response to docetaxel, one of the most active agents in this disease. We postulated that gene expression profiles of the primary breast cancer can predict the response to docetaxel.
We took core biopsy samples from primary breast tumours in 24 patients before treatment and then assessed tumour response to neoadjuvant docetaxel (four cycles, 100 mg/m2 daily for 3 weeks) by cDNA analysis of RNA extracted from biopsy samples using HgU95-Av2 GeneChip.
From the core biopsy samples, we extracted sufficient total RNA (3-6 microg) for cDNA array analysis using HgU95-Av2 GeneChip. Differential patterns of expression of 92 genes correlated with docetaxel response (p=0.001). Sensitive tumours had higher expression of genes involved in cell cycle, cytoskeleton, adhesion, protein transport, protein modification, transcription, and stress or apoptosis; whereas resistant tumours showed increased expression of some transcriptional and signal transduction genes. In leave-one-out cross-validation analysis, ten of 11 sensitive tumours (90% specificity) and 11 of 13 resistant tumours (85% sensitivity) were correctly classified, with an accuracy of 88%. This 92-gene predictor had positive and negative predictive values of 92% and 83%, respectively. Correlation between RNA expression measured by the arrays and semiquantitative RT-PCR was also ascertained, and our results were validated in an independent set of six patients.
If validated, these molecular profiles could allow development of a clinical test for docetaxel sensitivity, thus reducing unnecessary treatment for women with breast cancer.
可手术乳腺癌的全身化疗可大幅降低死亡风险。患者对多西他赛（该疾病最有效的药物之一）常常存在原发性耐药或反应不完全的情况。我们推测原发性乳腺癌的基因表达谱可预测对多西他赛的反应。
我们在治疗前从24例患者的原发性乳腺肿瘤中获取了核心活检样本，然后通过使用HgU95-Av2基因芯片对从活检样本中提取的RNA进行cDNA分析，评估肿瘤对新辅助多西他赛（四个周期，每日100mg/m²，共3周）的反应。
从核心活检样本中，我们提取了足够的总RNA（3 - 6μg）用于使用HgU95-Av2基因芯片进行cDNA阵列分析。92个基因的差异表达模式与多西他赛反应相关（p = 0.001）。敏感肿瘤中参与细胞周期、细胞骨架、黏附、蛋白质转运、蛋白质修饰、转录以及应激或凋亡的基因表达较高；而耐药肿瘤中一些转录和信号转导基因的表达增加。在留一法交叉验证分析中，11例敏感肿瘤中的10例（特异性为90%）和13例耐药肿瘤中的11例（敏感性为85%）被正确分类，准确率为88%。这个92基因预测指标的阳性和阴性预测值分别为92%和83%。还确定了通过阵列测量的RNA表达与半定量RT-PCR之间的相关性，我们的结果在另一组6例独立患者中得到了验证。
如果得到验证，这些分子谱可用于开发多西他赛敏感性的临床检测方法，从而减少对乳腺癌女性的不必要治疗。
