Predictors of resistance to preoperative trastuzumab and vinorelbine for HER2-positive early breast cancer
Predictors of resistance to preoperative trastuzumab and vinorelbine for HER2-positive early breast cancer
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DOI：
10.1158/1078-0432.ccr-06-1304
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发表时间：
2007-02-15
影响因子：
11.5
通讯作者：
Winer, Eric P.
中科院分区：
文献类型：
--
作者：
Harris, Lyndsay N.;You, Fanglei;Winer, Eric P.
目的：评估可手术的人表皮生长因子受体2(HER2)阳性乳腺癌患者术前对曲妥珠单抗和长春瑞滨的病理完全反应(PCR)、临床反应、可行性、安全性和潜在的预测因素。实验设计：48例患者术前每周接受曲妥珠单抗和长春瑞滨联合治疗，为期12周。单基因和多基因生物标记物研究试图确定应答的预测因素。结果：40名患者中有8名(20%)获得了聚合酶链式反应(95%可信区间，9-36%)。在另外招募的9名患者中，8名可评估；48名患者中有42名(88%)有临床反应(16名患者为临床完全缓解；26名患者为临床部分缓解)。T期肿瘤临床完全缓解更多(P=0.05)，有PCR型倾向(P=0.07)。5例(13%)患者在术前治疗期间发生了1级心功能不全。在接触曲妥珠单抗和长春瑞滨后，HER2和雌激素受体状态都没有明显改变。RNA图谱通过非监督分析确定了三个顶级簇。通过分级聚类，将反应极端的肿瘤[聚合酶链式反应(n=3)与无反应(n=3)]分为不同的组。在聚合酶链式反应肿瘤中没有发现预测基因。无反应的肿瘤更有可能是T-4期(P=0.02)，并且表达基本标志(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有效率相关(50%比97%；P=0.001)。结论：曲妥珠单抗联合长春瑞滨治疗HER2阳性、可手术的II/III期乳腺癌患者术前有效且耐受性良好。HER2过表达的肿瘤具有基底样表型，或表达胰岛素样生长因子-I受体和其他与生长因子途径有关的蛋白，更有可能对该方案耐药。
Purpose: 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.Experimental Design: 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.Results: 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, 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. Insulinlike growth factor-I receptor membrane expression was associated with a lower response rate (50% versus 97%; P = 0.001).Conclusions: 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.