人类表皮生长因子受体2(HER2)表达的分类被优化以检测HER2扩增的乳腺癌(BC)。然而,新型HER2靶向药物对HER2水平低的BCs也有效.这就提出了一个问题,即目前的HER2检测指南是否具有足够的可重复性来鉴定HER2低BC。这项多中心国际研究的目的是评估在HER2结果阴性的情况下,特定HER2免疫组织化学评分的观察者之间的一致性(0,1+,或2+/原位杂交阴性)根据当前的美国临床肿瘤学会/美国病理学家学院(ASCO/CAP)指南。此外,我们评估了通过重新定义免疫组织化学(IHC)评分标准或添加荧光原位杂交(FISH)是否改善了一致性.我们对105个非扩增BCs进行了2轮研究。在第一次评估中,16位病理学家使用了最新版本的ASCO/CAP指南。在一次共识会议之后,相同的病理学家使用基于2007ASCO/CAP指南的改良IHC评分标准对相同的数字幻灯片进行评分,并添加了一个额外的“超低”类别。总的来说,在第一轮中,观察员之间的协议有限(占100%同意的案件的4.7%),但这通过聚类IHC类别得到了改善。在第二轮中,在比较IHC0与超低/1+/2+分组簇(74.3%的病例符合100%)时,观察到最高的可重复性.HER2-0和低HER2病例之间的FISH结果没有统计学差异,无论使用的IHC标准如何。总之,我们的研究表明,与2018年ASCO/CAP标准相比,改良的2007年ASCO/CAP标准在区分HER2-0和低HER2病例方面更具可重复性.然而,重现性仍然中等,添加FISH并没有改善。这可能导致对符合新型HER2靶向剂的患者的次优选择。如果HER2IHC0和1+之间的阈值是临床可操作的,需要更清楚,更可重复的IHC定义,培训,和/或开发更准确的方法来检测蛋白质表达水平的这种细微差异。
The classification of human epidermal growth factor receptor 2 (HER2) expression is optimized to detect HER2-amplified breast cancer (BC). However, novel HER2-targeting agents are also effective for BCs with low levels of HER2. This raises the question whether the current guidelines for HER2 testing are sufficiently reproducible to identify HER2-low BC. The aim of this multicenter international
study was to assess the interobserver agreement of specific HER2 immunohistochemistry scores in cases with negative HER2 results (0, 1+, or 2+/in situ hybridization negative) according to the current American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines. Furthermore, we evaluated whether the agreement improved by redefining immunohistochemistry (IHC) scoring criteria or by adding fluorescent in situ hybridization (FISH). We conducted a 2-round
study of 105 nonamplified BCs. During the first assessment, 16 pathologists used the latest version of the ASCO/CAP guidelines. After a consensus meeting, the same pathologists scored the same digital slides using modified IHC scoring criteria based on the 2007 ASCO/CAP guidelines, and an extra \"ultralow\" category was added. Overall, the interobserver agreement was limited (4.7% of cases with 100% agreement) in the first round, but this was improved by clustering IHC categories. In the second round, the highest reproducibility was observed when comparing IHC 0 with the ultralow/1+/2+ grouped cluster (74.3% of cases with 100% agreement). The FISH results were not statistically different between HER2-0 and HER2-low cases, regardless of the IHC criteria used. In conclusion, our
study suggests that the modified 2007 ASCO/CAP criteria were more reproducible in distinguishing HER2-0 from HER2-low cases than the 2018 ASCO/CAP criteria. However, the reproducibility was still moderate, which was not improved by adding FISH. This could lead to a suboptimal selection of patients eligible for novel HER2-targeting agents. If the threshold between HER2 IHC 0 and 1+ is to be clinically actionable, there is a need for clearer, more reproducible IHC definitions, training, and/or development of more accurate methods to detect this subtle difference in protein expression levels.