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. 2017 Jan 1;28(1):110-115.
doi: 10.1093/annonc/mdw442.

Quantitative Proteomic Analysis of HER2 Expression in the Selection of Gastric Cancer Patients for Trastuzumab Treatment

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Free PMC article

Quantitative Proteomic Analysis of HER2 Expression in the Selection of Gastric Cancer Patients for Trastuzumab Treatment

E An et al. Ann Oncol. .
Free PMC article

Abstract

Background: A wide range of response rates have been reported in HER2-positive gastric cancer (GC) patients treated with trastuzumab. Other HER2-targeted therapies for GC have yet to show efficacy in clinical trials. These findings raise question about the ability of standard HER2 diagnostics to accurately distinguish between GC patients who would and would not benefit from anti-HER2 therapies.

Patients and methods: GC patients (n = 237), including a subset from the Trastuzumab in GC (ToGA) trial were divided into three groups based on HER2 status and history of treatment with standard chemotherapy or chemotherapy plus trastuzumab. We applied mass spectrometry-based proteomic analysis to quantify HER2 protein expression in formalin-fixed tumor samples. Using HER2 expression as a continuous variable, we defined a predictive protein level cutoff to identify which patients would benefit from trastuzumab. We compared quantitated protein level with clinical outcome and HER2 status as determined by conventional HER2 diagnostics.

Results: Quantitative proteomics detected a 115-fold range of HER2 protein expression among patients diagnosed as HER2 positive by standard methods. A protein level of 1825 amol/µg was predicted to determine benefit from the addition of trastuzumab to chemotherapy. Trastuzumab treated patients with HER2 protein levels above this cutoff had twice the median overall survival (OS) of their counterparts below the cutoff (35.0 versus 17.5 months, P = 0.011). Conversely, trastuzumab-treated patients with HER2 levels below the cutoff had outcomes similar to HER2-positive patients treated with chemotherapy. (Progression-free survival = 7.0 versus 6.5 months: P = 0.504; OS = 17.5 versus 12.6 months: P = 0.520). HER2 levels were not prognostic for response to chemotherapy.

Conclusions: Proteomic analysis of HER2 expression demonstrated a quantitative cutoff that improves selection of GC patients for trastuzumab as compared with current diagnostic methods.

Keywords: HER2; gastric cancer; molecular characterization; proteomics; trastuzumab.

Figures

Figure 1.
Figure 1.
Quantitated HER2 protein levels according to HER2 assessment by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). (A) In each HER2 IHC category, a wide range of HER2 protein levels were quantitated. Among gastric cancer tumor samples diagnosed as IHC3+, 24/110 (21.8%) expressed low HER2 protein levels (<750 amol/µg) and thus may be falsely positive by IHC (green circles). Among samples with IHC scores of 0, 1, and 2+, 15/112 (3.4%) expressed high HER2 levels (>750 amol/µg) and may be falsely negative by IHC (pink circles). (B and C) Linear regression suggests that quantitative HER2 protein levels are loosely correlated with FISH. HER2 protein levels below the 750 amol/µg threshold were measured in tumors that had tested FISH-positive by HER2/CEP17 ratio (23/72; 31.9%) and by gene copy number (GCN) (12/49; 24.5%). These tumors may be false positive by FISH. Of tumors considered FISH-negative by GCN, 3/70 (4.3%) may be false negatives.
Figure 2.
Figure 2.
HER2 selected reaction monitoring (SRM) identifies gastric cancer patients who would benefit from trastuzumab. With conventional HER2 testing methods, HER2-positive patients selected for treatment with trastuzumab plus chemotherapy had better (A) progression-free survival and (B) overall survival than HER2-positive patients who received chemotherapy alone and HER2-negative patients who received chemotherapy. (C and D) The survival benefits are greater with HER2 assessment by quantitative proteomics. Trastuzumab-treated patients with HER2 protein expression above the cutoff (1825 amol/µg) have twice the overall survival of patients whose HER2 levels are below the cutoff. Trastuzumab-treated patients with HER2 levels below the cutoff had survival outcomes similar to patients treated with chemotherapy alone. P-value is for the log rank test. Tx, treatment; Tmab, trastuzumab; chemo, chemotherapy.

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