Wild Peter J, Reichle Albrecht, Andreesen Reinhard, Röckelein Georg, Dietmaier Wolfgang, Rüschoff Josef, Blaszyk Hagen, Hofstädter Ferdinand, Hartmann Arndt
Departments of Pathology and Hematology and Oncology, University of Regensburg, Regensburg, Germany.
Clin Cancer Res. 2004 Jan 15;10(2):556-64. doi: 10.1158/1078-0432.ccr-0601-03.
The purpose is to define molecular prognostic factors in patients with advanced breast cancer treated with high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT).
Thirty-nine patients with breast cancer and extensive lymph node (level III) and/or systemic metastases from a prospective single-center study of sequential HDCT/ASCT were studied. Microsatellite analysis was performed after laser microdissection using 15 markers selected for sensitive detection of microsatellite instability (MSI) in breast cancer. Exons 5-9 of the P53 gene were directly sequenced. Expression of P53, HER-2/neu, and the mismatch repair proteins hMSH2 and hMLH1 was evaluated by immunohistochemistry.
MSI of at least three markers was detected in 13 of 39 patients (33%) and was predominantly found at tetranucleotide markers. All MSI-positive tumors showed normal expression of hMSH2 and hMLH1. Complete sequence analysis of exons 5-9 of the P53 gene was successful in 34 cases; 18% (n = 6) revealed a mutation. Overexpression of HER-2/neu and P53 was observed in 7 (22%) and 12 (46%) of 26 evaluated cases, respectively. The presence of MSI strongly correlated with shorter overall survival (OS; P = 0.0004) and progression-free survival (PFS; P = 0.02). None of the other investigated clinical or molecular factors correlated with OS in univariate analyses, with the exception of menopausal status and previous adjuvant chemotherapy. Testing various multivariate Cox regression models, MSI remained a highly significant, independent, and adverse risk factor for OS.
MSI is frequent in advanced breast cancer and could be an indicator of chemotherapy resistance and poor prognosis in breast cancer patients treated with HDCT/ASCT.
本研究旨在确定接受大剂量化疗（HDCT）和自体干细胞移植（ASCT）治疗的晚期乳腺癌患者的分子预后因素。
对一项前瞻性单中心序贯HDCT/ASCT研究中的39例乳腺癌伴广泛淋巴结转移（Ⅲ级）和/或全身转移患者进行了研究。使用15个为灵敏检测乳腺癌微卫星不稳定性（MSI）而选择的标记物，在激光显微切割后进行微卫星分析。对P53基因的外显子5-9进行直接测序。通过免疫组织化学评估P53、HER-2/neu以及错配修复蛋白hMSH2和hMLH1的表达。
39例患者中有13例（33%）检测到至少三个标记物的MSI，且主要在四核苷酸标记物处发现。所有MSI阳性肿瘤均显示hMSH2和hMLH1表达正常。34例成功完成了P53基因外显子5-9的完整序列分析；18%（n = 6）显示有突变。在26例评估病例中，分别有7例（22%）和12例（46%）观察到HER-2/neu和P53的过表达。MSI的存在与较短的总生存期（OS；P = 0.0004）和无进展生存期（PFS；P = 0.02）密切相关。在单因素分析中，除绝经状态和既往辅助化疗外，其他研究的临床或分子因素均与OS无关。在测试各种多变量Cox回归模型时，MSI仍然是OS的一个高度显著、独立的不良风险因素。
MSI在晚期乳腺癌中很常见，可能是接受HDCT/ASCT治疗的乳腺癌患者化疗耐药和预后不良的一个指标。
