Association between HER-2/neu and vascular endothelial growth factor expression predicts clinical outcome in primary breast cancer patients
Association between HER-2/neu and vascular endothelial growth factor expression predicts clinical outcome in primary breast cancer patients
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DOI：
10.1158/1078-0432.ccr-0951-3
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发表时间：
2004-03-01
影响因子：
11.5
通讯作者：
Pegram, MD
中科院分区：
文献类型：
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作者：
Konecny, GE;Meng, YG;Pegram, MD
目的：HER-2/neu的激活或过表达与体外人乳腺癌细胞中血管内皮生长因子（VEGF）的上调相关临床前实验表明，VEGF的表达增加可能部分介导HER-2/neu过表达的人乳腺癌的生物学侵袭性表型。本研究的目的是：（a）在原发性乳腺癌患者的大型临床队列中评估HER-2/neu和VEGF表达之间的关联;（B）比较VEGF同种型的预后意义;和（c）分析HER-2/neu和VEGF对临床结果的联合作用。HER-2/neu和VEGF在611例乳腺癌患者的原发性乳腺肿瘤组织裂解物中通过ELISA测定，中位临床随访时间为50个月。作为选择性剪接的结果，产生由121、145、165、183、189或206个氨基酸组成的至少六种VEGF同种型。VEGF（121-206）ELISA使用与VEGF（121）结合的抗体，并且因此检测具有121个和更多个氨基酸的所有VEGF同种型。VEGF（165-206）ELISA使用与VEGF（165）结合的抗体，并且因此检测具有165个和更多个氨基酸的所有VEGF同种型。将VEGF（121-206）和VEGF（165-206）作为连续变量和分类变量进行分析，使用可检测的表达作为阳性的截止值。确定HER-2/neu表达水平的细胞系被用来建立乳腺肿瘤样品中HER-2/neu过表达的临界点。结果：我们的研究结果表明HER-2/neu和VEGF表达之间存在显著的正相关。VEGF（121-206）和VEGF（165-206）在88例乳腺癌组织中均有表达。（77.2%）和100在HER-2/neu过表达的114例患者中，在497例非过度表达肿瘤患者中，VEGF（121-206）和VEGF（165-206）分别为54.5%和353例（71.0%）（卡方检验：P < 0.001）。VEGF（121-206）和VEGF（165-206）对非原发性乳腺癌患者的生存率具有相当的预后意义（单因素分析：VEGF（121-206），P = 0.0068; VEGF（165-206），P = 0.0046;多因素分析：VEGF（121-206），P = 0.1475; VEGF（165-206），P = 0.1483）。当分别对淋巴结阴性和淋巴结阳性患者进行分析时，VEGF（121-206）和VEGF（165-206）仅对淋巴结阳性患者的生存具有预后意义（单因素分析：VEGF（121-206），P = 0.0003; VEGF（165-206），P = 0.0038;多因素分析：VEGF（121-206），P = 0.0103; VEGF（165-206），P = 0.0150）。VEGF表达与存活率之间的生物浓度-效应关系（VEGF（121-206），P = 0.0280; VEGF（161-206），P = 0.0097）表明，通过ELISA测定的VEGF水平可能作为靶向VEGF的治疗策略的预测标志物是重要的。联合HER-2/neu和VEGF（121-206）/VEGF（165-206）可获得额外的生存预后信息（VEGF（121-206），P = 0-0133; VEGF（165-206），P = 0.0092）。结论：HER-2/ neu和VEGF表达之间的正相关性暗示VEGF在HER-2/neu过表达所表现的侵袭性表型中，并支持使用针对HER-2/neu和VEGF的联合疗法治疗过表达HER-2/neu的乳腺癌。
Purpose: Activation or overexpression of HER-2/neu is associated with up-regulation of vascular endothelial growth factor (VEGF) in human breast cancer cells in vitro. Preclinical experiments indicate that increased expression of VEGF may in part mediate the biologically aggressive phenotype of HER-2/neu-overexpressing human breast cancer. It was the purpose of this study to: (a) evaluate the association between HER-2/neu and VEGF expression in a large clinical cohort of primary breast cancer patients; (b) compare the prognostic significance of VEGF isoforms; and (c) analyze the combined effects of HER-2/neu and VEGF on clinical outcome.Experimental Design: HER-2/neu and VEGF were measured by ELISA in primary breast tumor tissue lysates from 611 unselected patients with a median clinical follow-up of 50 months. At least six VEGF isoforms consisting of 121, 145, 165, 183, 189, or 206 amino acids are generated as a result of alternative splicing. The VEGF(121-206) ELISA uses antibodies that bind to VEGF(121), and, therefore, detects all of the VEGF isoforms with 121 and more amino acids. The VEGF(165-206) ELISA uses antibodies that bind to VEGF(165), and, therefore, detects all of the VEGF isoforms with 165 and more amino acids. VEGF(121-206) and VEGF(165-206) were analyzed both as continuous and categorical variables, using detectable expression as a cutoff for positivity. Cell lines with defined HER-2/neu expression levels were used to establish a cutoff point for HER-2/neu overexpression in breast tumor samples.Results: Our findings indicate a significant positive association between HER-2/neu and VEGF expression. VEGF(121-206) and VEGF(165-206) expression was detectable in 88 (77.2%) and 100 (87.7%), respectively, of the 114 patients with HER-2/neu-overexpressing tumors, in contrast to 271 (54.5%) and 353 (71.0%), respectively, of the 497 patients with nonoverexpressing tumors (chi(2) test: P < 0.001 for both VEGF(121-206) and VEGF(165-206)). VEGF(121-206) and VEGF(165-206) demonstrate a comparable prognostic significance for survival in unselected primary breast cancer patients (univariate analysis: VEGF(121-206), P = 0.0068; VEGF(165-206), P = 0.0046; multivariate analysis: VEGF(121-206), P = 0.1475; VEGF(165-206), P = 0.1483). When the analyses were performed separately for node-negative and node-positive patients, VEGF(121-206) and VEGF(165-206) were of prognostic significance for survival only in node-positive patients (univariate analysis: VEGF(121-206), P = 0.0003; VEGF(165-206), P = 0.0038; multivariate analysis: VEGF(121-206), P = 0.0103; VEGF(165-206), P = 0.0150). A biological concentration-effect relationship between VEGF expression and survival (VEGF(121-206), P = 0.0280; VEGF(161-206), P = 0.0097) suggests that VEGF levels, as determined by ELISA, could be of importance as a predictive marker for therapeutic strategies that target VEGF. Combining HER-2/neu and VEGF(121-206)/VEGF(165-206) results in additional prognostic information for survival (VEGF(121-206), P = 0-0133; VEGF(165-206), P = 0.0092).Conclusion: The positive association between HER-2/ neu and VEGF expression implicates VEGF in the aggressive phenotype exhibited by HER-2/neu overexpression, and supports the use of combination therapies directed against both HER-2/neu and VEGF for treatment of breast cancers that overexpress HER-2/neu.