Silvestrini R, Benini E, Daidone M G, Veneroni S, Boracchi P, Cappelletti V, Di Fronzo G, Veronesi U
Oncologia Sperimentale C, Istituto Nazionale Tumori, Milan, Italy.
J Natl Cancer Inst. 1993 Jun 16;85(12):965-70. doi: 10.1093/jnci/85.12.965.
At present, most decisions concerning the use of adjuvant therapy in lymph node-negative breast cancer patients are made on the basis of traditional factors such as tumor size, nodal status, and histopathologic features. However, prognostic factors are being investigated that could identify high-risk groups and that could better address treatment efforts for those patients. Identification of more accurate prognostic markers, such as the expression of the mutant p53 protein encoded by the p53 (also known as TP53) tumor suppressor gene, that are reproducible, easily assessable, and independent in predicting clinical outcome would have a beneficial impact on cancer treatment decisions.
Our purpose was to analyze the predictive relevance of mutant p53 protein expression on 6-year relapse-free and overall survival in node-negative breast cancer patients in relation to menopausal status, tumor size, cell kinetics, and estrogen receptor status.
Expression of mutant p53 protein was detected by an immunohistochemical technique using a 1:50 dilution of PAb1801 monoclonal antibody on paraffin-embedded tumor specimens obtained from 256 axillary lymph node-negative breast cancer patients, with long-term follow-up (median, 72 months). The [3H]thymidine labeling index, a measure of cell kinetics, was evaluated on histologic sections after fresh tumor tissue was labeled with [3H]thymidine. Estrogen receptor status was determined by the dextran-coated charcoal absorption technique. Statistical comparisons were made for levels of p53 protein expression, [3H]thymidine labeling index, estrogen receptor status, tumor size, and menopausal status with respect to 6-year relapse-free survival and overall survival.
Overexpression of the p53 protein, defined as the presence of more than 5% positive cells, was detected in 113 (44%) of 256 tumors. Odds ratios (ORs) for multiple regression analysis of 6-year relapse-free survival were significantly higher for p53 (OR = 3.24; 95% confidence limits [CL] = 2.01-5.23) and [3H]thymidine labeling index (OR = 1.92; 95% CL = 1.19-3.12), both of which appeared to be the most relevant indicators of relapse, than for tumor size (OR = 1.49; 95% CL = 0.94-2.38) and estrogen receptor status (OR = 0.91; 95% CL = 0.55-1.51). Overexpression was found to be unrelated to menopausal status.
Immunohistochemically detected p53 overexpression is an independent marker for shortened 6-year relapse-free and overall survival in node-negative patients with resectable breast cancers. Based on these findings, p53 overexpression should be used with other established prognostic factors, such as [3H]thymidine labeling index and estrogen receptor status, to further refine the prognostic assessment of node-negative breast cancer.
目前，大多数关于淋巴结阴性乳腺癌患者辅助治疗的决策是基于传统因素做出的，如肿瘤大小、淋巴结状态和组织病理学特征。然而，人们正在研究一些预后因素，这些因素可以识别高危人群，并能更好地针对这些患者进行治疗。识别更准确的预后标志物，如由p53（也称为TP53）肿瘤抑制基因编码的突变型p53蛋白的表达，具有可重复性、易于评估且能独立预测临床结果，这将对癌症治疗决策产生有益影响。
我们的目的是分析突变型p53蛋白表达对淋巴结阴性乳腺癌患者6年无复发生存率和总生存率的预测相关性，同时考虑绝经状态、肿瘤大小、细胞动力学和雌激素受体状态。
使用1:50稀释的PAb1801单克隆抗体，通过免疫组织化学技术在从256例腋窝淋巴结阴性乳腺癌患者获取的石蜡包埋肿瘤标本上检测突变型p53蛋白的表达，并进行长期随访（中位随访时间为72个月）。在用[3H]胸腺嘧啶核苷标记新鲜肿瘤组织后，在组织学切片上评估[3H]胸腺嘧啶核苷标记指数，作为细胞动力学的一项指标。通过葡聚糖包被活性炭吸收技术确定雌激素受体状态。对p53蛋白表达水平、[3H]胸腺嘧啶核苷标记指数、雌激素受体状态、肿瘤大小和绝经状态进行统计学比较，以分析其与6年无复发生存率和总生存率的关系。
在256例肿瘤中的113例（44%）检测到p53蛋白过表达，定义为阳性细胞超过5%。对于6年无复发生存率的多元回归分析，p53（比值比[OR]=3.24；95%置信区间[CL]=2.01 - 5.23）和[3H]胸腺嘧啶核苷标记指数（OR = 1.92；95% CL = 1.19 - 3.12）的比值比显著高于肿瘤大小（OR = 1.49；95% CL = 0.94 - 2.38）和雌激素受体状态（OR = 0.91；95% CL = 0.55 - 1.51），这两者似乎是复发的最相关指标。发现过表达与绝经状态无关。
免疫组织化学检测到的p53过表达是可切除乳腺癌淋巴结阴性患者6年无复发生存率和总生存率缩短的独立标志物。基于这些发现，p53过表达应与其他已确立的预后因素，如[3H]胸腺嘧啶核苷标记指数和雌激素受体状态一起使用，以进一步完善淋巴结阴性乳腺癌的预后评估。
