Harris Lyndsay N, You Fanglei, Schnitt Stuart J, Witkiewicz Agnes, Lu Xin, Sgroi Dennis, Ryan Paula D, Come Steven E, Burstein Harold J, Lesnikoski Beth-Ann, Kamma Madhavi, Friedman Paula N, Gelman Rebecca, Iglehart J Dirk, Winer Eric P
Dana-Farber Cancer Institute.
Clin Cancer Res. 2007 Feb 15;13(4):1198-207. doi: 10.1158/1078-0432.CCR-06-1304.
To assess pathologic complete response (pCR), clinical response, feasibility, safety, and potential predictors of response to preoperative trastuzumab plus vinorelbine in patients with operable, human epidermal growth factor receptor 2 (HER2)-positive breast cancer.
Forty-eight patients received preoperative trastuzumab and vinorelbine weekly for 12 weeks. Single and multigene biomarker studies were done in an attempt to identify predictors of response.
Eight of 40 (20%) patients achieved pCR (95% confidence interval, 9-36%). Of 9 additional patients recruited for protocol-defined toxicity analysis, 8 were evaluable; 42 of 48 (88%) patients had clinical response (16 patients, clinical complete response; 26 patients, clinical partial response). T(1) tumors more frequently exhibited clinical complete response (P = 0.05) and showed a trend to exhibit pCR (P = 0.07). Five (13%) patients experienced grade 1 cardiac dysfunction during preoperative treatment. Neither HER2 nor estrogen receptor status changed significantly after exposure to trastuzumab and vinorelbine. RNA profiling identified three top-level clusters by unsupervised analysis. Tumors with extremes of response [pCR (n = 3) versus nonresponse (n = 3)] fell into separate groups by hierarchical clustering. No predictive genes were identified in pCR tumors. Nonresponding tumors were more likely to be T(4) stage (P = 0.02) and express basal markers (P < 0.00001), growth factors, and growth factor receptors. Insulin-like growth factor-I receptor membrane expression was associated with a lower response rate (50% versus 97%; P = 0.001).
Preoperative trastuzumab plus vinorelbine is active and well tolerated in patients with HER2-positive, operable, stage II/III breast cancer. HER2-overexpressing tumors with a basal-like phenotype, or with expression of insulin-like growth factor-I receptor and other proteins involved in growth factor pathways, are more likely to be resistant to this regimen.
评估术前曲妥珠单抗联合长春瑞滨治疗可手术的人表皮生长因子受体2（HER2）阳性乳腺癌患者的病理完全缓解（pCR）、临床反应、可行性、安全性及反应的潜在预测因素。
48例患者接受术前曲妥珠单抗和长春瑞滨每周一次，共12周。进行单基因和多基因生物标志物研究以试图确定反应的预测因素。
40例患者中有8例（20%）达到pCR（95%置信区间，9 - 36%）。在另外9例纳入方案定义毒性分析的患者中，8例可评估；48例患者中有42例（88%）有临床反应（16例临床完全缓解；26例临床部分缓解）。T(1)期肿瘤更常表现出临床完全缓解（P = 0.05），且有表现出pCR的趋势（P = 0.07）。5例（13%）患者在术前治疗期间出现1级心脏功能障碍。暴露于曲妥珠单抗和长春瑞滨后，HER2和雌激素受体状态均无显著变化。RNA谱分析通过无监督分析确定了三个顶级聚类。反应极端的肿瘤 [pCR（n = 3）与无反应（n = 3）] 通过层次聚类分为不同组。在pCR肿瘤中未鉴定出预测基因。无反应的肿瘤更可能为T(4)期（P = 0.02）并表达基底标志物（P < 0.00001）、生长因子和生长因子受体。胰岛素样生长因子 - I受体膜表达与较低的反应率相关（50%对97%；P = 0.001）。
术前曲妥珠单抗联合长春瑞滨对HER2阳性、可手术的II/III期乳腺癌患者有效且耐受性良好。具有基底样表型、或表达胰岛素样生长因子 - I受体及其他参与生长因子途径的蛋白质的HER2过表达肿瘤更可能对该方案耐药。
