Sáez Rosana, Molina Miguel A, Ramsey Elizabeth E, Rojo Federico, Keenan Edward J, Albanell Joan, Lluch Ana, García-Conde Javier, Baselga José, Clinton Gail M
Cell Biology Department, Faculty of Biological Sciences, University of Valencia, Burjasot, Valencia, Spain.
Clin Cancer Res. 2006 Jan 15;12(2):424-31. doi: 10.1158/1078-0432.CCR-05-1807.
The HER-2 receptor undergoes a proteolytic cleavage generating an NH(2)-terminally truncated fragment, p95HER-2, that is membrane-associated and tyrosine-phosphorylated. We have reported that p95HER-2, but not the full-length receptor, p185HER-2, correlated with the extent of lymph node involvement in patients with breast cancer and its expression was significantly enhanced in nodal metastatic tissue. These facts suggested an important role for p95HER-2 either as a marker or cause of metastasis and poor outcome in breast cancer. In this work, we have studied the prognostic value of p95HER-2 in breast cancer.
Primary breast tumor tissues (n = 483) were from surgical resections conducted in hospitals in two different countries: the U.S. (n = 334) and Spain (n = 149). HER-2 protein forms, including p185HER-2 and p95HER-2, were examined in extracts of primary breast tumors by Western blot analysis. The levels of the two forms (high or low) were tested for association with other clinicopathologic factors and for correlation with disease-free survival.
The median follow-up was 46 months. A high level of p95HER-2 in primary tumor tissue correlated with reduced 5-year disease-free survival (hazard ratio, 2.55; 95% confidence interval, 2.13-8.01; P < 0.0001). The median time for disease-free survival was 32 versus 139 months in patients with low levels of p95HER-2. In comparison, high levels of the full-length p185HER-2 did not significantly correlate with poor outcome (P > 0.1). Multivariate analysis revealed that high p95HER-2 was an independent predictor of disease-free survival (hazard ratio, 1.59; 95% confidence interval, 1.246-1.990; P = 0.0004).
p95HER-2 expression is an independent prognostic factor in breast cancer and defines a group of patients with HER-2-positive breast cancer with significantly worse outcome.
HER-2受体经历蛋白水解切割，产生一个氨基端截短的片段p95HER-2，该片段与膜相关且酪氨酸磷酸化。我们曾报道，p95HER-2而非全长受体p185HER-2与乳腺癌患者的淋巴结受累程度相关，且其在淋巴结转移组织中的表达显著增强。这些事实提示p95HER-2在乳腺癌转移及不良预后中作为标志物或原因发挥重要作用。在本研究中，我们探讨了p95HER-2在乳腺癌中的预后价值。
原发性乳腺肿瘤组织（n = 483）来自两个不同国家医院的手术切除标本：美国（n = 334）和西班牙（n = 149）。通过蛋白质印迹分析检测原发性乳腺肿瘤提取物中的HER-2蛋白形式，包括p185HER-2和p95HER-2。检测这两种形式的水平（高或低）与其他临床病理因素的关联以及与无病生存期的相关性。
中位随访时间为46个月。原发性肿瘤组织中p95HER-2高水平与5年无病生存期降低相关（风险比，2.55；95%置信区间，2.13 - 8.01；P < 0.0001）。p95HER-2水平低的患者无病生存期的中位时间为32个月，而高水平患者为139个月。相比之下，全长p185HER-2的高水平与不良预后无显著相关性（P > 0.1）。多因素分析显示，p95HER-2高水平是无病生存期的独立预测因素（风险比，1.59；95%置信区间，1.246 - 1.990；P = 0.0004）。
p95HER-2表达是乳腺癌的独立预后因素，定义了一组HER-2阳性乳腺癌患者，其预后明显更差。
