Biomarker Analyses in CLEOPATRA: A Phase III, Placebo-Controlled Study of Pertuzumab in Human Epidermal Growth Factor Receptor 2-Positive, First-Line Metastatic Breast Cancer
Biomarker Analyses in CLEOPATRA: A Phase III, Placebo-Controlled Study of Pertuzumab in Human Epidermal Growth Factor Receptor 2-Positive, First-Line Metastatic Breast Cancer
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DOI：
10.1200/jco.2013.54.5384
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发表时间：
2014-11-20
影响因子：
45.3
通讯作者：
Swain, Sandra M.
中科院分区：
文献类型：
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作者：
Baselga, Jose;Cortes, Javier;Swain, Sandra M.
目的探讨人表皮生长因子受体2（HER 2）通路相关生物标志物在CLEOPATRA III期研究中的预后和/或预测价值，该研究比较了帕妥珠单抗+曲妥珠单抗+多西他赛与安慰剂+曲妥珠单抗+多西他赛作为HER 2阳性转移性乳腺癌患者的一线治疗。（N = 808; 58%至99.8%可评估），并使用适当的测定法评估双调蛋白、β细胞素、表皮生长因子（EGF）、转化生长因子α、EGF受体、HER 2、HER 3、胰岛素样生长因子1受体、PTEN、磷酸化AKT、PIK 3CA、CMYC、血清HER 2胞外结构域（sHER 2）和FC γ R。使用单变量考克斯回归研究了两种类型的相关性：预测作用（生物标志物与帕妥珠单抗无进展生存期[PFS]获益的定性相关性）和独立于治疗组的预后影响结果帕妥珠单抗始终显示PFS获益，与生物标志物亚组无关（危险比< 1.0），包括雌激素受体阴性和阳性亚组。高HER 2蛋白、高HER 2和HER 3 mRNA水平、野生型PIK 3CA和低sHER 2显示出显著更好的预后（P <0.05）。PIK 3CA显示出最大的预后效应，在对照组和对照组中，肿瘤表达野生型与突变型PIK 3CA的患者的中位PFS更长。（13.8 vs 8.6个月）和帕妥珠单抗组（21.8 v12.5个月）。结论通过全面的前瞻性分析，CLEOPATRA生物标志物数据表明，HER 2是适合曲妥珠单抗加帕妥珠单抗的患者选择的唯一标志物。HER 2阳性转移性乳腺癌的治疗方案。HER 2、HER 3和PIK 3CA是相关的预后因素。(C)2014年美国临床肿瘤学会
PurposeTo explore the prognostic and/or predictive value of human epidermal growth factor receptor 2 (HER2) pathway-related biomarkers in the phase III CLEOPATRA study of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel as first-line treatment for patients with HER2-positive metastatic breast cancer.Patients and MethodsMandatory tumor and serum samples were collected (N = 808; 58% to 99.8% were assessable), and amphiregulin, betacellulin, epidermal growth factor (EGF), transforming growth factor alpha, EGF receptor, HER2, HER3, insulin-like growth factor 1 receptor, PTEN, phosphorylated AKT, PIK3CA, CMYC, serum HER2 extracellular domain (sHER2), and FC gamma R were assessed using appropriate assays. Two types of correlations were investigated using univariable Cox regression: predictive effects (qualitative association of biomarkers with pertuzumab progression-free survival [PFS] benefit) and prognostic effects independent of treatment arm (relationship of each biomarker to clinical outcome in both arms pooled).ResultsPertuzumab consistently showed a PFS benefit, independent of biomarker subgroups (hazard ratio < 1.0), including estrogen receptor-negative and -positive subgroups. High HER2 protein, high HER2 and HER3 mRNA levels, wild-type PIK3CA, and low sHER2 showed a significantly better prognosis (P < .05). PIK3CA showed the greatest prognostic effect, with longer median PFS for patients whose tumors expressed wild-type versus mutated PIK3CA in both the control (13.8 v 8.6 months) and pertuzumab groups (21.8 v 12.5 months).ConclusionThrough comprehensive prospective analyses, CLEOPATRA biomarker data demonstrate that HER2 is the only marker suited for patient selection for the trastuzumab plus pertuzumab-based regimen in HER2-positive metastatic breast cancer. HER2, HER3, and PIK3CA were relevant prognostic factors.(C) 2014 by American Society of Clinical Oncology