Krueger, Juliane M. and Thomas, Marlene and Korn, Rene and Dietmann, Gabriele and Rutz, Christoph and Brockhoff, Gero and Specht, Katja and Hasmann, Max and Feuerhake, Friedrich (2013) Detection of Truncated HER2 Forms in Formalin-Fixed, Paraffin-Embedded Breast Cancer Tissue Captures Heterogeneity and Is Not Affected by HER2-Targeted Therapy. AMERICAN JOURNAL OF PATHOLOGY, 183 (2). pp. 336-343. ISSN 0002-9440, 1525-2191
Full text not available from this repository. (Request a copy)Abstract
Truncated forms of HER2, previously identified in subsets of HER2-positive breast cancer, originate from proteolytic extracellular domain (ECD) cleavage or alternative translation initiation. They Lack ECD but may retain intracellular domain functionality, potentially associated with unfavorable prognosis, metastasis, and decreased sensitivity to antibody-based HER2-targeted therapy. To study the distribution of truncated HER2 in breast cancer, we detected loss of membrane-bound ECD independently of its molecular origin in paraffin sections, combining multispectral unmixing of chromogenic duplex IHC for HER2 ECD and intracellular domain with advanced image analysis. HER2 C-terminal fragment 611-transfected MCF7 and 4-aminophenylmercuric acetate-treated SKBR3 cell lines were used as controls. Applying a prototype work flow to whole sections, paired surgical resection/core needle biopsy samples, and paired samples from 69 patients of a phase 2 neoadjuvant clinical trial, we observed unexpected heterogeneity of ECD loss at the single-cell level, and in different areas of individual tumors, indicating that extent and Localization of HER2 ECD Loss add relevant information to averaging truncated HER2 across whole sections. We show acceptable run-to-run variation (coefficient of variation, <0.15), image analysis results in moderate agreement with conventional slide assessment (Cohen's kappa = 0.59), and no obvious interference with previous HER2-ECD-targeted therapy. We conclude that duplex IHC and digital image processing extend current approaches of truncated HER2 detection.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CARBOXY-TERMINAL FRAGMENT; EXTRACELLULAR DOMAIN; OPEN-LABEL; TRASTUZUMAB; TRIAL; MICROENVIRONMENT; MULTICENTER; LAPATINIB; RECEPTOR; P95HER2; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Frauenheilkunde und Geburtshilfe (Schwerpunkt Frauenheilkunde) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 03 Apr 2020 13:16 |
| Last Modified: | 03 Apr 2020 13:16 |
| URI: | https://pred.uni-regensburg.de/id/eprint/16287 |
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