Isola J, Weitz S, Visakorpi T, Holli K, Shea R, Khabbaz N, Kallioniemi O P
Department of Biomedical Sciences, University of Tampere, Finland.
J Clin Oncol. 1993 Jan;11(1):36-43. doi: 10.1200/JCO.1993.11.1.36.
Increased expression of the lysosomal protease cathepsin D (CD) has been implicated in the metastatic progression of breast cancer. This study was designed to determine the prognostic significance of CD expression in axillary node-negative (ANN) breast cancer. The relationship of CD expression and onset of soft tissue recurrences and visceral metastatases was also studied.
We analyzed a population-based group of 262 ANN breast cancer patients, none of whom had received any adjuvant chemotherapy or endocrine therapy. An immunohistochemical method based on a new monoclonal antibody (1C11) with a distinct epitope specificity made it possible to study CD expression from archival paraffin-embedded specimens and to distinguish staining in tumor cells from the high-level expression found in tumor-infiltrating macrophages.
High-level CD expression, as defined by cytoplasmic immunoreactivity in greater than 10% of the cancer cells, was found in 95 cases (36%). High-level CD expression was associated with large primary tumor size (P = .014), but not with histologic grade, estrogen and progesterone receptors, DNA index, or S-phase fraction, or with c-erbB-2 and p53 overexpression. Patients with CD-positive tumors developed significantly more often both soft tissue recurrences and visceral metastases (P = .0007) and had a significantly shorter disease-free survival (P < .0001). Eight-year overall survival of patients with high-level CD expression was 64% as compared with 90% in those with low-level expression (relative risk, 2.97; 95% confidence interval [Cl], 1.6 to 4.4; P < .0001). According to a Cox multivariate model and a regression-tree analysis, high-level CD expression was an independent predictor of poor overall survival in conjunction with tumor size and S-phase fraction.
These results indicate that CD expression determined by immunohistochemistry is a powerful prognostic factor in ANN breast cancer. The most significant prognostic information was obtained when CD expression (predicting metastatic activity) was combined with estimate of cell-proliferation rate (S-phase fraction).
溶酶体蛋白酶组织蛋白酶D（CD）表达增加与乳腺癌的转移进展有关。本研究旨在确定CD表达在腋窝淋巴结阴性（ANN）乳腺癌中的预后意义。还研究了CD表达与软组织复发和内脏转移发生的关系。
我们分析了一组基于人群的262例ANN乳腺癌患者，他们均未接受过任何辅助化疗或内分泌治疗。基于具有独特表位特异性的新型单克隆抗体（1C11）的免疫组织化学方法，使得从存档的石蜡包埋标本中研究CD表达并区分肿瘤细胞中的染色与肿瘤浸润巨噬细胞中发现的高水平表达成为可能。
在95例（36%）患者中发现高水平CD表达，定义为超过10%的癌细胞胞质免疫反应阳性。高水平CD表达与原发肿瘤体积大相关（P = 0.014），但与组织学分级、雌激素和孕激素受体、DNA指数或S期分数，以及c-erbB-2和p53过表达无关。CD阳性肿瘤患者发生软组织复发和内脏转移的频率明显更高（P = 0.0007），无病生存期明显更短（P < 0.0001）。高水平CD表达患者的8年总生存率为64%，而低水平表达患者为90%（相对风险，2.97；95%置信区间[Cl]，1.6至4.4；P < 0.0001）。根据Cox多变量模型和回归树分析，高水平CD表达与肿瘤大小和S期分数一起是总生存期差的独立预测因素。
这些结果表明，免疫组织化学测定的CD表达是ANN乳腺癌中一个有力的预后因素。当CD表达（预测转移活性）与细胞增殖率估计值（S期分数）相结合时，可获得最显著的预后信息。
