Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520-8040, USA.
Int J Radiat Oncol Biol Phys. 2011 Dec 1;81(5):1236-43. doi: 10.1016/j.ijrobp.2010.07.031. Epub 2010 Nov 17.
Vascular endothelial growth factor (VEGF) is an important protein involved in the process of angiogenesis that has been found to correlate with relapse-free and overall survival in breast cancer, predominantly in locally advanced and metastatic disease. A paucity of data is available on the prognostic implications of VEGF in early-stage breast cancer; specifically, its prognostic value for local relapse after breast-conserving therapy (BCT) is largely unknown. The purpose of our study was to assess VEGF expression in a cohort of early-stage breast cancer patients treated with BCT and to correlate the clinical and pathologic features and outcomes with overexpression of VEGF.
After obtaining institutional review board approval, the paraffin specimens of 368 patients with early-stage breast cancer treated with BCT between 1975 and 2005 were constructed into tissue microarrays with twofold redundancy. The tissue microarrays were stained for VEGF and read by a trained pathologist, who was unaware of the clinical details, as positive or negative according the standard guidelines. The clinical and pathologic data, long-term outcomes, and results of VEGF staining were analyzed.
The median follow-up for the entire cohort was 6.5 years. VEGF expression was positive in 56 (15%) of the 368 patients. Although VEGF expression did not correlate with age at diagnosis, tumor size, nodal status, histologic type, family history, estrogen receptor/progesterone receptor status, or HER-2 status, a trend was seen toward increased VEGF expression in the black cohort (26% black vs. 13% white, p=.068). Within the margin-negative cohort, VEGF did not predict for local relapse-free survival (RFS) (96% vs. 95%), nodal RFS (100% vs. 100%), distant metastasis-free survival (91% vs. 92%), overall survival (92% vs. 97%), respectively (all p>.05). Subset analysis revealed that VEGF was highly predictive of local RFS in node-positive, margin-negative patients (86% vs. 100%, p=.029) on univariate analysis, but it did not retain its significance on multivariate analysis (hazard ratio, 2.52; 95% confidence interval, 0.804-7.920, p=.113). No other subgroups were identified in which a correlation was found between VEGF expression and local relapse.
To our knowledge, our study is the first to assess the prognostic value of VEGF with the endpoint of local relapse in early-stage breast cancer treated with BCT, an important question given the recent increased use of targeted antiangiogenic agents in early-stage breast cancer. Our study results suggest that VEGF is not an independent predictor of local RFS after BCT, but additional, larger studies specifically analyzing the endpoint of VEGF and local relapse are warranted.
血管内皮生长因子（VEGF）是一种参与血管生成过程的重要蛋白，已发现其与乳腺癌的无复发生存和总生存相关，主要与局部晚期和转移性疾病相关。关于早期乳腺癌中 VEGF 的预后意义的数据很少；具体来说，VEGF 在保乳治疗（BCT）后局部复发的预后价值在很大程度上尚不清楚。我们研究的目的是评估 BCT 治疗的早期乳腺癌患者队列中 VEGF 的表达，并将临床和病理特征与 VEGF 的过表达相关联。
在获得机构审查委员会批准后，构建了 1975 年至 2005 年间接受 BCT 治疗的 368 例早期乳腺癌患者的石蜡标本组织微阵列，其具有两倍的冗余度。组织微阵列根据标准指南用 VEGF 染色，并由经过培训的病理学家进行染色，该病理学家不知道临床细节，根据标准指南将其读为阳性或阴性。分析了临床和病理数据、长期结果以及 VEGF 染色的结果。
整个队列的中位随访时间为 6.5 年。368 例患者中有 56 例（15%）VEGF 表达阳性。尽管 VEGF 表达与诊断时的年龄、肿瘤大小、淋巴结状态、组织学类型、家族史、雌激素受体/孕激素受体状态或 HER-2 状态无关，但在黑人队列中 VEGF 表达呈增加趋势（26%黑人与 13%白人，p=.068）。在切缘阴性的队列中，VEGF 未预测局部无复发生存率（RFS）（96%对 95%）、淋巴结 RFS（100%对 100%）、无远处转移生存率（91%对 92%）、总生存率（92%对 97%）（均 p>.05）。亚组分析显示，在单因素分析中，VEGF 对淋巴结阳性、切缘阴性的患者具有高度的局部 RFS 预测价值（86%对 100%，p=.029），但在多因素分析中无统计学意义（危险比，2.52；95%置信区间，0.804-7.920，p=.113）。在其他亚组中未发现 VEGF 表达与局部复发之间存在相关性。
据我们所知，我们的研究是第一个评估 VEGF 在 BCT 治疗的早期乳腺癌中的预后价值的研究，这是一个重要的问题，因为最近在早期乳腺癌中使用了靶向抗血管生成药物。我们的研究结果表明，VEGF 不是 BCT 后局部 RFS 的独立预测因子，但需要更大规模的研究来专门分析 VEGF 和局部复发的终点。
