Mass-spectrometry-based quantitation of Her2 in gastroesophageal tumor tissue: comparison to IHC and FISH

被引:32
|
作者
Catenacci, Daniel V. T. [1 ]
Liao, Wei-Li [2 ,3 ]
Zhao, Lei [4 ]
Whitcomb, Emma [4 ]
Henderson, Les [1 ]
O'Day, Emily [1 ]
Xu, Peng [1 ]
Thyparambil, Sheeno [2 ,3 ]
Krizman, David [2 ,3 ]
Bengali, Kathleen [2 ,3 ]
Uzzell, Jamar [2 ]
Darfler, Marlene [2 ,3 ]
Cecchi, Fabiola [2 ,3 ]
Blackler, Adele [2 ,3 ]
Bang, Yung-Jue [5 ]
Hart, John [4 ]
Xiao, Shu-Yuan [4 ]
Lee, Sang Mee [6 ]
Burrows, Jon [2 ]
Hembrough, Todd [2 ,3 ]
机构
[1] Univ Chicago, Med Ctr, Dept Med, Sect Hematol Oncol, Chicago, IL 60637 USA
[2] OncoPlex Diagnost Inc, Rockville, MD USA
[3] NantOmics LLC, Culver City, CA USA
[4] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA
[5] Seoul Natl Univ, Coll Med, Seoul, South Korea
[6] Univ Chicago, Dept Publ Hlth Studies, Chicago, IL 60637 USA
关键词
Her2; expression; HER2 (ERBB2) amplification; Gastric; Esophageal; Gastroesophageal adenocarcinoma; Stomach cancer; SRM-MS; Selected reaction monitoring mass spectrometry; Companion diagnostic; Clinical biomarker assay; Multiplex protein expression analysis in FFPE tissue; ADVANCED GASTRIC-CANCER; BREAST-CANCER; GENE AMPLIFICATION; INTRATUMORAL HETEROGENEITY; EXPRESSION; LAPATINIB; TRASTUZUMAB; RECEPTOR; MET; SURVIVAL;
D O I
10.1007/s10120-015-0566-0
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Trastuzumab has shown a survival benefit in cases of Her2-positive gastroesophageal cancer (GEC). Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) currently determine eligibility for trastuzumab-based therapy. However, these low-throughput assays often produce discordant or equivocal results. We developed a targeted proteomic assay based on selected reaction monitoring mass spectrometry (SRM-MS) and quantified levels (amol/mu g) of Her2-SRM protein in cell lines (n = 27) and GEC tissues (n = 139). We compared Her2-SRM protein expression with IHC/FISH, seeking to determine optimal SRM protein expression cutoffs in order to identify HER2 gene amplification. After demonstrating assay development, precision, and stability, Her2-SRM protein measurement was observed to be highly concordant with the HER2/CEP17 ratio, particularly in a multivariate regression model adjusted for SRM expression of the covariates Met, Egfr, Her3, and HER2 heterogeneity, as well as their interactions (cell lines r (2) = 0.9842; FFPE r (2) = 0.7643). In GEC tissues, Her2-SRM protein was detected at any level in 71.2 % of cases. ROC curves demonstrated that Her2-SRM protein levels have a high specificity (100 %) at an upper-level cutoff of > 750 amol/A mu g and sensitivity of 75 % at a lower-level cutoff of < 450 amol/mu g for identifying HER2 FISH-amplified tumors. An "equivocal zone" of 450-750 amol/A mu g of Her2-SRM protein was analogous to IHC2+ but represented fewer cases (9-16 % of cases versus 36-41 %). Compared to IHC, targeted SRM-Her2 proteomics provided more objective and quantitative Her2 expression with excellent HER2/CEP17 FISH correlation and fewer equivocal cases. Along with its multiplex capability for other relevant oncoproteins, these results demonstrate a refined HER2 protein expression assay for clinical application.
引用
收藏
页码:1066 / 1079
页数:14
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