Eunkyung An (Presenter)
NantOmics
Bio: I am currently a Sr. Scientist at NantOmics. I had a Post doctoral fellowship at the NIH after graduating from the George Washington University with major in Biochemistry and Molecular Genomics.
Authorship: E. An (1,2), C.-Y. Ock (3), T.-Y. Kim (3), K.-H. Lee (3,4), S.-W. Han (3,4), S.-A. Im (3,4), T.-Y. Kim (3,4), W.-L. Liao (1,2), F. Cecchi (1,2), A. Blackler(1,2), S. Thyparambil(1,2), W. H. Kim(5) , J. Burrows(2) , T. Hembrough(1,2), D. Catenacci(6) , D.-Y. Oh(3,4), Y.-J. Bang(3.4)
(1)NantOmics, Rockville, MD, USA; (2)Oncoplex Diagnostics, Rockville, MD, USA; (3)Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea; (4)Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea; (5)Department of Pathology, Seoul National University Hospital, Seoul, Korea; (6)Department of Medicine, University of Chicago, Chicago, IL, USA.
| Short Abstract 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, raising doubt about the ability of standard HER2 diagnostics to accurately identify the GC patients most likely to benefit from anti-HER2 therapy. We applied mass spectrometry-based proteomic analysis to quantify HER2 protein expression in 237 formalin-fixed GC samples. A 115-fold range of HER2 protein expression was observed among patients diagnosed as HER2 positive by standard methods. Trastuzumab-treated patients with HER2 protein levels above a cutoff of 1,825 amol/ug had twice the median overall survival (OS) of their counterparts below the cutoff. A quantitative proteomic cutoff improves selection of GC patients for trastuzumab as compared to current diagnostic methods. |
Long Abstract
Introduction: Trastuzumab is the only targeted therapy approved for gastric cancer (GC). Eligibility is determined by routine testing for human epidermal growth factor 2 (HER2) protein overexpression or HER2 gene amplification. [1]. A wide range of response rates have been reported in HER2-positive GC patients treated with trastuzumab. In the Trastuzumab in GC (ToGA) trial, nearly one-quarter of patients (131/584) had HER2 gene amplification but did not overexpress HER2 protein by immunohistochemistry. These patients received moderate benefit from trastuzumab. Other HER2-targeted therapies that are approved for breast cancer have yet to show efficacy in clinical trials of GC [2-4]. Taken together, these findings raise questions about the ability of standard HER2 diagnostics to accurately identify the GC patients most likely to benefit from anti-HER2 therapies.
Methods: GC patients (N=237) including a subset from the ToGA trial were divided into 3 groups based on HER2 status and history of treatment with standard chemotherapy or chemotherapy plus trastuzumab. A pathologist marked the tumor areas of formalin-fixed tissue sections. The marked areas were laser microdissected and solubilized to tryptic peptides. In each liquefied tumor sample, multiple biomarkers including HER2 were quantified with a mass spectrometry-based proteomic assay [5]. 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 1,825 amol/ug 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 vs 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 vs. 6.5 months: p=0.504; OS=17.5 vs. 12.6 months: p=0.520). There was no apparent relationship between HER2 protein level and response to chemotherapy.
Conclusions: Proteomic analysis of HER2 expression demonstrated a quantitative cutoff that improves selection of GC patients for trastuzumab as compared to current diagnostic methods.
References & Acknowledgements:
1. Bang YJ et al. Lancet 2010; 376: 687-697.
2. Satoh T et al. J Clin Oncol 2014; 32: 2039-2049.
3. Hecht JR et al. J Clin Oncol 2016; 34: 443-451.
4. Kang Y et al. J Clin Oncol 34 2016 (suppl 4S; abstr 5) 2016.
5. Hembrough T et al. J Mol Diagn 2013; 15: 454-465.
| Description | Y/N | Source |
| Grants | no | |
| Salary | yes | NantOmics |
| Board Member | no | |
| Stock | yes | NantOmics |
| Expenses | no |
IP Royalty: no
| Planning to mention or discuss specific products or technology of the company(ies) listed above: | yes |