Baez-Navarro Ximena, van Bockstal Mieke R, van der Made Angelique, van Deurzen Carolien H M
From the Department of Pathology, Erasmus Medical Center, Rotterdam, the Netherlands (Baez-Navarro, van der Made, van Deurzen).
From the Department of Pathology, Cliniques Universitaires Saint-Luc, Brussels, Belgium (van Bockstal).
Arch Pathol Lab Med. 2025 Jul 1;149(7):635-642. doi: 10.5858/arpa.2024-0255-OA.
CONTEXT.—: Breast cancers (BCs) with low levels of human epidermal growth factor receptor 2 (HER2) expression (HER2-low) have become a targetable subset because of novel antibody-drug conjugates. HER2 immunohistochemistry (IHC) is the recommended assay for HER2 classification but is associated with limited interobserver agreement concerning HER2-low identification. OBJECTIVE.—: To investigate whether mRNA expression quantified via quantitative reverse transcription-polymerase chain reaction (RT-qPCR) could serve as a valuable complementary and more objective method to identify HER2-low BCs. DESIGN.—: We selected all cases from a previously published interobserver study, which included 105 needle biopsies from HER2 nonamplified BC cases. HER2 IHC was evaluated by 16 pathologists. For the current study, mRNA was extracted from microdissected invasive tumor cells. RT-qPCR was performed for quantitative evaluation of HER2, using the cutoff values of the MammaTyper assay. We compared the mRNA expression levels with the IHC scores of the majority agreement (IHC 0, IHC >0, <1+ [ultralow], 1+, 2+) and the following HER2 subcategories: HER2 0/ultralow and HER2-low (IHC 1+ and 2+/fluorescence in situ hybridization negative). RESULTS.—: In total, 88 nonamplified HER2 cases could be analyzed. Based on IHC, 17 cases were HER2 0/ultralow and 71 were HER2-low. The mean rank HER2 mRNA level was significantly higher in HER2-low cases than in the HER2 0/ultralow group (P < .001). However, 10 of 17 HER2 0/ultralow cases by IHC (58.8%) were classified as HER2-low by MammaTyper, 2 of 71 cases (2.8%) were HER2-low by IHC and HER2 0/ultralow by MammaTyper, and 2 (2.8%) were HER2-low by IHC and HER2-positive by RT-qPCR. CONCLUSIONS.—: Our findings indicate a strong agreement between mRNA expression quantified by RT-qPCR and HER2 IHC scores, although there was a substantial proportion of discordant HER2 results between both methods owing to overestimation of HER2 expression by MammaTyper compared to IHC. Future large-scale trials should determine which technique is best associated with clinical outcome.
背景：人表皮生长因子受体2（HER2）低表达的乳腺癌（BC）由于新型抗体药物偶联物已成为一个可靶向治疗的亚组。HER2免疫组织化学（IHC）是HER2分类的推荐检测方法，但在HER2低表达的识别方面观察者间一致性有限。 目的：研究通过定量逆转录聚合酶链反应（RT-qPCR）定量的mRNA表达是否可作为一种有价值的补充方法，更客观地识别HER2低表达的BC。 设计：我们从之前发表的一项观察者间研究中选取了所有病例，其中包括105例HER2非扩增BC病例的穿刺活检样本。16名病理学家对HER2 IHC进行了评估。在本研究中，从显微切割的浸润性肿瘤细胞中提取mRNA。使用MammaTyper检测的临界值进行RT-qPCR以定量评估HER2。我们将mRNA表达水平与多数一致的IHC评分（IHC 0、IHC>0，<1+[超低]、1+、2+）以及以下HER2亚组进行比较：HER2 0/超低和HER2低表达（IHC 1+和2+/荧光原位杂交阴性）。 结果：总共可以分析88例非扩增HER2病例。基于IHC，17例为HER2 0/超低，71例为HER2低表达。HER2低表达病例中HER2 mRNA水平的平均秩次显著高于HER2 0/超低组（P<.001）。然而，17例IHC检测为HER2 0/超低的病例中有10例（58.8%）被MammaTyper分类为HER2低表达；71例病例中有2例（2.8%）IHC检测为HER2低表达而MammaTyper检测为HER2 0/超低；2例（2.8%）IHC检测为HER2低表达而RT-qPCR检测为HER2阳性。 结论：我们的研究结果表明，通过RT-qPCR定量的mRNA表达与HER2 IHC评分之间有很强的一致性，尽管由于MammaTyper与IHC相比高估了HER2表达，两种方法之间存在相当比例的HER2结果不一致。未来的大规模试验应确定哪种技术与临床结果最相关。
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