Biomarker analysis of neoadjuvant Doxorubicin/Cyclophosphamide followed by Ixabepilone or Paclitaxel in early-stage breast cancer

A randomized, open-label, multicenter, phase II trial (NCT00455533) enrolled previously untreated women with histologically-confirmed primary invasive breast adenocarcinoma (T2–3, N0–3, M0, tumor size ≥2.0 cm), regardless of hormone receptor or HER2 expression status. Patients received sequential neoadjuvant therapy starting with 4 cycles of AC (doxorubicin 60 mg/m2 intravenously and cyclophosphamide 600 mg/m2 intravenously) given every 3 weeks, followed by 1:1 randomization to either ixabepilone (40 mg/m2 3-hour infusion) every 3 weeks for 4 cycles, or paclitaxel (80 mg/m2 1-hour infusion) weekly for 12 weeks. Fresh tumor biopsies at screening were a mandatory prerequisite for study entry for biomarker analyses. Gene expression profiling was performed by Affymetrix GeneChip to determine if pre-specified gene models could distinguish between the clinical activity of two microtubule stabilizing agents, ixabepilone and paclitaxel. Three core needle tumor tissue biopsies were obtained from all subjects before neoadjuvant therapy with AC and immediately combined in RNAlater® solution for subsequent RNA extraction, cRNA labeling and gene expression profiling. Pre-specified gene models were tested for their capacity to distinguish pathologic complete response rates between the AC followed by ixabepilone versus the AC followed by paclitaxel treatment regimens. All samples were collected prior to treatment. All subject received cyclophosphamide/doxorubicin (AC) prior to randomization to either Ixabepilone or Paclitaxel.

本研究为一项随机、开放标签、多中心II期临床试验（临床试验注册号：NCT00455533），纳入经组织学确认的初治女性原发性浸润性乳腺腺癌患者（T2~3期、N0~3期、M0期，肿瘤尺寸≥2.0cm），不考虑其激素受体或人表皮生长因子受体2（HER2）表达状态。
所有患者先接受序贯新辅助治疗：先予以每3周1次、共4个周期的AC方案（多柔比星60mg/m²静脉给药+环磷酰胺600mg/m²静脉给药），随后按1:1比例随机分组，分别接受每3周1次、共4个周期的伊沙匹隆（40mg/m²，3小时静脉输注），或每周1次、共12周的紫杉醇（80mg/m²，1小时静脉输注）。
筛查时获取新鲜肿瘤活检组织是入组生物标志物分析的强制性前提。本研究通过Affymetrix基因芯片开展基因表达谱分析，旨在验证预设基因模型能否区分两种微管稳定剂——伊沙匹隆与紫杉醇的临床活性。所有受试者在接受AC方案新辅助治疗前，均获取3份核心针穿刺肿瘤组织活检标本，并立即将标本混合置于RNAlater®储存液中，用于后续RNA提取、互补RNA（cRNA）标记及基因表达谱分析。
预设基因模型被用于验证其区分“AC序贯伊沙匹隆”与“AC序贯紫杉醇”两种治疗方案的病理完全缓解率差异的能力。所有样本均采集于治疗开始前。所有受试者在被随机分配至伊沙匹隆组或紫杉醇组前，均已接受AC方案治疗。