Nielsen Torsten O, Hsu Forrest D, Jensen Kristin, Cheang Maggie, Karaca Gamze, Hu Zhiyuan, Hernandez-Boussard Tina, Livasy Chad, Cowan Dave, Dressler Lynn, Akslen Lars A, Ragaz Joseph, Gown Allen M, Gilks C Blake, van de Rijn Matt, Perou Charles M
Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver Hospital & British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
Clin Cancer Res. 2004 Aug 15;10(16):5367-74. doi: 10.1158/1078-0432.CCR-04-0220.
Expression profiling studies classified breast carcinomas into estrogen receptor (ER)+/luminal, normal breast-like, HER2 overexpressing, and basal-like groups, with the latter two associated with poor outcomes. Currently, there exist clinical assays that identify ER+/luminal and HER2-overexpressing tumors, and we sought to develop a clinical assay for breast basal-like tumors.
To identify an immunohistochemical profile for breast basal-like tumors, we collected a series of known basal-like tumors and tested them for protein patterns that are characteristic of this subtype. Next, we examined the significance of these protein patterns using tissue microarrays and evaluated the prognostic significance of these findings.
Using a panel of 21 basal-like tumors, which was determined using gene expression profiles, we saw that this subtype was typically immunohistochemically negative for estrogen receptor and HER2 but positive for basal cytokeratins, HER1, and/or c-KIT. Using breast carcinoma tissue microarrays representing 930 patients with 17.4-year mean follow-up, basal cytokeratin expression was associated with low disease-specific survival. HER1 expression was observed in 54% of cases positive for basal cytokeratins (versus 11% of negative cases) and was associated with poor survival independent of nodal status and size. c-KIT expression was more common in basal-like tumors than in other breast cancers but did not influence prognosis.
A panel of four antibodies (ER, HER1, HER2, and cytokeratin 5/6) can accurately identify basal-like tumors using standard available clinical tools and shows high specificity. These studies show that many basal-like tumors express HER1, which suggests candidate drugs for evaluation in these patients.
表达谱研究将乳腺癌分为雌激素受体（ER）阳性/管腔型、正常乳腺样型、HER2过表达型和基底样型，后两种类型与不良预后相关。目前，已有临床检测方法可识别ER阳性/管腔型和HER2过表达型肿瘤，我们试图开发一种针对乳腺基底样型肿瘤的临床检测方法。
为了确定乳腺基底样型肿瘤的免疫组化特征，我们收集了一系列已知的基底样型肿瘤，并检测它们具有该亚型特征的蛋白质模式。接下来，我们使用组织微阵列研究这些蛋白质模式的意义，并评估这些发现的预后意义。
使用一组通过基因表达谱确定的21例基底样型肿瘤，我们发现该亚型通常雌激素受体和HER2免疫组化呈阴性，但基底细胞角蛋白、HER1和/或c-KIT呈阳性。使用代表930例患者、平均随访17.4年的乳腺癌组织微阵列，基底细胞角蛋白表达与较低的疾病特异性生存率相关。在基底细胞角蛋白阳性的病例中，54%观察到HER1表达（而阴性病例为11%），且HER1表达与生存不良相关，与淋巴结状态和肿瘤大小无关。c-KIT表达在基底样型肿瘤中比在其他乳腺癌中更常见，但不影响预后。
一组四种抗体（ER、HER1、HER2和细胞角蛋白5/6）可使用标准的现有临床工具准确识别基底样型肿瘤，且显示出高特异性。这些研究表明，许多基底样型肿瘤表达HER1，这提示了可在这些患者中评估的候选药物。
