Department of Pathology, Università Vita-Salute San Raffaele, San Raffaele Scientific Institute, Via Olgettina 60, Milan, Italy.
Adv Anat Pathol. 2011 Jan;18(1):53-9. doi: 10.1097/PAP.0b013e3182026d72.
Molecular therapies targeting HER2 are part of the established drug armamentarium in breast carcinoma. Now the ToGA trial, an international multicenter phase III clinical study, involving 24 countries globally, has shown that the anti-HER2 humanized monoclonal antibody Trastuzumab is effective in prolonging survival in HER2-positive carcinoma of the stomach and the gastroesophageal junction (GEJ). Similarly to breast carcinoma, >20% of gastric cancers show HER2 overexpression and/or amplification, and this percentage increases to 33% in GEJ tumors. Thus, as in breast carcinoma, pathologists are now asked to evaluate HER2 status in gastric carcinoma samples. As validated in the ToGA trial, the HER2 testing criteria that must be used in evaluating both gastric carcinoma biopsies and surgical specimens significantly differ from those routinely applied in breast carcinoma. The main variations with regard to the pattern of reactivity in HER2-expressing cells are as follows: the completeness of membrane staining is not a "conditio sine qua non" and the number of stained cells necessary to consider a case as positive is different. We must also take note of the much more frequent heterogeneity of HER2 positivity in gastric cancer compared with breast carcinoma and the less stringent correlation between HER2 amplification and protein overexpression that is observed in gastric carcinoma, where more than 20% of cases may carry HER2 amplification, although of low level, without HER2 expression. In these patients, in the ToGA trial, there was no apparent benefit from adding Trastuzumab to chemotherapy: for this reason the European Medicines Agency, while approving usage of Trastuzumab for metastatic adenocarcinoma treatment, indicated HER2 testing by immunohistochemistry as first evaluation assay, followed by fluorescence in situ hybridization in 2+ equivocal cases. HER2 testing in gastric carcinoma is a new field, opening several opportunities: for patients with gastric cancer, this is a new promising therapeutic option; for pathologists, strengthening our role in therapy selection and emphasizing our duty of providing accurate and reproducible HER2 testing results; for all interested in understanding the biology of gastric and GEJ cancer and in discovering new possible molecular therapy targets.
针对 HER2 的分子疗法是乳腺癌既定药物治疗手段的一部分。现在，一项全球性的国际多中心 III 期临床试验（ToGA 试验）表明，抗 HER2 人源化单克隆抗体曲妥珠单抗可延长 HER2 阳性胃癌和胃食管交界处（GEJ）癌患者的生存期。与乳腺癌类似，超过 20%的胃癌表现出 HER2 过表达和/或扩增，而在 GEJ 肿瘤中这一比例增加到 33%。因此，就像在乳腺癌中一样，病理学家现在被要求评估胃癌样本中的 HER2 状态。如 ToGA 试验所验证的那样，评估胃癌活检和手术标本 HER2 状态时必须使用的 HER2 检测标准与在乳腺癌中常规应用的标准有显著差异。针对 HER2 阳性细胞的反应模式，主要有以下几个方面的变化：膜染色的完整性不再是“必要条件”，并且需要考虑阳性病例的染色细胞数量也不同。我们还必须注意到，与乳腺癌相比，胃癌中 HER2 阳性的异质性更为常见，而且在胃癌中观察到的 HER2 扩增与蛋白过表达之间的相关性较弱，尽管超过 20%的病例可能存在 HER2 扩增，但水平较低，没有 HER2 表达。在这些患者中，在 ToGA 试验中，曲妥珠单抗联合化疗并没有明显获益：出于这个原因，欧洲药品管理局在批准曲妥珠单抗用于转移性腺癌治疗的同时，指示将免疫组织化学检测作为首次评估检测，在 2+可疑病例中进行荧光原位杂交检测。胃癌的 HER2 检测是一个新领域，带来了多个机会：对于胃癌患者，这是一种新的有前途的治疗选择；对于病理学家，这加强了我们在治疗选择中的作用，并强调了我们提供准确和可重复的 HER2 检测结果的责任；对于所有对了解胃和 GEJ 癌症生物学和发现新的可能分子治疗靶点感兴趣的人来说，也是如此。
