期刊
LABORATORY INVESTIGATION
卷 102, 期 10, 页码 1101-1108出版社
ELSEVIER SCIENCE INC
DOI: 10.1038/s41374-022-00804-9
关键词
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资金
- InviCRO/Konica/Minolta
- Breast Cancer Research Foundation (DLR)
- Yale Cancer Cancer [P30CA016359]
- Hellenic Society of Medical Oncologists (HESMO)
The efficacy of the antibody drug conjugate Trastuzumab deruxtecan (T-DXd) in HER2 low breast cancer patients suggests the need for revision of the conventional HER2 assays. In this study, an optimized dynamic range for unamplified HER2 detection in breast cancer was determined and a quantitative assay to stratify HER2 expression in unamplified cases was designed. The application of this assay to a large number of breast cancer cases demonstrated its potential for selecting optimal patients for T-DXd treatment.
The efficacy of the antibody drug conjugate (ADC) Trastuzumab deruxtecan (T-DXd) in HER2 low breast cancer patients suggests that the historical/conventional assays for HER2 may need revision for optimal patient care. Specifically, the conventional assay is designed to distinguish amplified HER2 from unamplified cases but is not sensitive enough to stratify the lower ranges of HER2 expression. Here we determine the optimal dynamic range for unamplified HER2 detection in breast cancer and then redesign an assay to increase the resolution of the assay to stratify HER2 expression in unamplified cases. We used the AQUA (TM) method of quantitative immunofluorescence to test a range of antibody concentrations to maximize the sensitivity within the lower range of HER2 expression. Then, using a cell line microarray with HER2 protein measured by mass spectrometry we determined the amount of HER2 protein in units of attomols/mm(2). Then by calculation of the limits of detection, quantification, and linearity of this assay we determined that low HER2 range expression in unamplified cell lines is between 2 and 20 attomol/mm(2). Finally, application of this assay to a serial collection of 364 breast cancer cases from Yale shows 67% of the population has HER2 expression above the limit of quantification and below the levels seen in HER2 amplified breast cancer. In the future, this assay could be used to determine the levels of HER2 required for response to T-DXd or similar HER2 conjugated ADCs. The antibody drug conjugate (ADC) Trastuzumab deruxtecan (T-DXd) has shown activity in breast cancer with low levels of HER2 expression. The historical/conventional assays for HER2 were designed separate high levels of HER2 from intermediate levels and show no expression in the low range. In this study, we determine the optimal dynamic range for unamplified HER2 detection in breast cancer and then design a quantitative assay to stratify HER2 expression in unamplified cases. Assessment of HER2 protein in the optimal dynamic range will ultimately help select the optimal patients for T-DXd and this work can serve as a model for other assays for ADCs where pathology reads may be less accurate that protein measurements.
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