Rost Sandra, Giltnane Jennifer, Bordeaux Jennifer M, Hitzman Chuck, Koeppen Hartmut, Liu Scot D
Department of Pathology, Genentech, South San Francisco, CA, USA.
Navigate BioPharma Services, Carlsbad, CA, USA.
Lab Invest. 2017 Aug;97(8):992-1003. doi: 10.1038/labinvest.2017.50. Epub 2017 May 29.
Part of developing therapeutics is the need to identify patients who will respond to treatment. For HER2-targeted therapies, such as trastuzumab, the expression level of HER2 is used to identify patients likely to receive benefit from therapy. Currently, chromogenic immunohistochemistry on patient tumor tissue is one of the methodologies used to assess the expression level of HER2 to determine eligibility for trastuzumab. However, chromogenic staining is fraught with serious drawbacks that influence scoring, which is additionally flawed due to the subjective nature of human/pathologist bias. Thus, to advance drug development and precision medicine, there is a need to develop technologies that are more objective and quantitative through the collection and integration of larger data sets. In proof of concept experiments, we show multiplexed ion beam imaging (MIBI), a novel imaging technology, can quantitate HER2 expression on breast carcinoma tissue with known HER2 status and those values correlate with pathologist-determined IHC scores. The same type of quantitative analysis using the mean pixel value of five individual cells and total pixel count of the entire image was extended to a blinded study of breast carcinoma samples of unknown HER2 scores. Here, a strong correlation between quantitation of HER2 by MIBI analysis and pathologist-derived HER2 IHC score was identified. In addition, a comparison between MIBI analysis and immunofluorescence-based automated quantitative analysis (AQUA) technology, an industry-accepted quantitation system, showed strong correlation in the same blind study. Further comparison of the two systems determined MIBI was comparable to AQUA analysis when evaluated against pathologist-determined scores. Using HER2 as a model, these data show MIBI analysis can quantitate protein expression with greater sensitivity and objectivity compared to standard pathologist interpretation, demonstrating its potential as a technology capable of advancing cancer and patient diagnostics.
开发治疗方法的一部分工作是需要识别出对治疗有反应的患者。对于曲妥珠单抗等HER2靶向治疗药物，HER2的表达水平用于确定可能从治疗中获益的患者。目前，对患者肿瘤组织进行显色免疫组织化学是用于评估HER2表达水平以确定是否适合使用曲妥珠单抗的方法之一。然而，显色染色存在严重缺陷，会影响评分，而且由于人为/病理学家偏差的主观性，评分还存在缺陷。因此，为了推进药物开发和精准医学，需要通过收集和整合更大的数据集来开发更客观、更定量的技术。在概念验证实验中，我们展示了多重离子束成像（MIBI）这一新型成像技术，它可以对已知HER2状态的乳腺癌组织中的HER2表达进行定量，并且这些值与病理学家确定的免疫组化评分相关。使用五个单个细胞的平均像素值和整个图像的总像素计数进行的同类型定量分析被扩展到对HER2评分未知的乳腺癌样本的盲法研究。在此，通过MIBI分析对HER2进行定量与病理学家得出的HER2免疫组化评分之间发现了很强的相关性。此外，在同一盲法研究中，MIBI分析与基于免疫荧光的自动定量分析（AQUA）技术（一种行业认可的定量系统）之间的比较显示出很强的相关性。对这两个系统的进一步比较确定，在与病理学家确定的评分进行评估时，MIBI与AQUA分析相当。以HER2为模型，这些数据表明，与标准的病理学家解释相比，MIBI分析能够以更高的灵敏度和客观性对蛋白质表达进行定量，证明了其作为一种能够推进癌症和患者诊断的技术的潜力。
