Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 9 (12)

Trastuzumab Specific Epitope Evaluation as a Predictive and Prognostic Biomarker in Gastric Cancer Patients

Affiliations

Trastuzumab Specific Epitope Evaluation as a Predictive and Prognostic Biomarker in Gastric Cancer Patients

Jiwon Koh et al. Biomolecules.

Abstract

While human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) antibodies bind to the intracellular domain, trastuzumab binds to the extracellular epitope of HER2 receptor: target of drug action. We aimed to evaluate clinical significance of the new IHC method assessing the target of trastuzumab in gastric cancer (GC) patients and compare with conventional methods. Sixty-nine trastuzumab-treated GC patients were enrolled from two different cohorts. Additionally, we enrolled 528 consecutive GC patients to evaluate prognostic implications of HER2 test methods. HER2 status was assessed by trastuzumab IHC, HER2 IHC (4B5), and HER2 silver in situ hybridization (SISH). HER2 IHC showed 3+ in 48/69 trastuzumab-treated patients (69.6%), however, trastuzumab IHC showed 3+ in 25 (36.2%). Patients with trastuzumab IHC ≥2+ had significantly better progression-free survival (PFS) and overall survival (OS) than their counterpart (p = 0.014). In univariate analysis, trastuzumab IHC ≥2+ and HER2 IHC 3+ were only significant predictive factors for OS in trastuzumab-treated patients. Of the 528 consecutive GCs, patients with trastuzumab IHC ≥2+ had shorter disease-free survival (DFS) and OS (p = 0.008 and 0.031, respectively), while conventional methods failed to reveal any significant survival differences. HER2 assessment by trastuzumab IHC was different from conventional HER2 test results. Trastuzumab IHC was suggested to be a significant predictive factor for trastuzumab responsiveness and prognostic factor for consecutive GCs.

Keywords: HER2; gastric cancer; prediction; prognosis; trastuzumab.

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Comparison between HER2 IHC and trastuzumab IHC. Within HER2 IHC 2+ or 3+ group, the results of trastuzumab IHC varied.
Figure 2
Figure 2
(a) Progression free survival (PFS) and (b) overall survival (OS) according to trastuzumab IHC results.
Figure 3
Figure 3
Results of HER2 IHC, HER2 silver in situ hybridization (SISH), and trastuzumab IHC in two cases among consecutive gastric cancer patients. Case 1 shows negativity by HER2 IHC, however, HER2 amplification was confirmed by SISH, and was 3+ by trastuzumab IHC. Case 2 showed 3+ by both HER2 and trastuzumab IHC, and HER2 gene amplification was observed as well.
Figure 4
Figure 4
Disease-free survival (DFS) and overall survival (OS) of consecutive gastric cancer patients according to various HER2 assessment methods. Kaplan–Meier survival curves for both DFS and OS according to various subgroups are shown. (a) Trastuzumab IHC ≥2+ was associated with better survival with statistical significance. (bd) Other HER2 assessment methods were not able to discriminate significant survival differences between subgroups.
Figure 5
Figure 5
(a) Schematic illustration of different targets of HER2 IHC and trastuzumab IHC within HER2 protein. Widely-used antibodies for HER2 IHC bind to the intracellular region of HER2 protein near the C-terminal, while trastuzumab is designed to bind to the extracellular epitope. (b) When HER2 protein undergoes in vivo proteolytic cleavage, the extracellular domain is lost, therefore, trastuzumab cannot bind to HER2; however, theoretically antibodies for HER2 IHC can bind to the intracellular domain, producing positive IHC results.

Similar articles

See all similar articles

References

    1. Jemal A., Center M.M., DeSantis C., Ward E.M. Global Patterns of Cancer Incidence and Mortality Rates and Trends. Cancer Epidemiol. Biomark. Prev. 2010;19:1893–1907. doi: 10.1158/1055-9965.EPI-10-0437. - DOI - PubMed
    1. Nashimoto A., Akazawa K., Isobe Y., Miyashiro I., Katai H., Kodera Y., Tsujitani S., Seto Y., Furukawa H., Oda I., et al. Gastric cancer treated in 2002 in Japan: 2009 annual report of the JGCA nationwide registry. Gastric Cancer. 2012;16:1–27. doi: 10.1007/s10120-012-0163-4. - DOI - PMC - PubMed
    1. Digklia A., Wagner A.D. Advanced gastric cancer: Current treatment landscape and future perspectives. World J. Gastroenterol. 2016;22:2403–2414. doi: 10.3748/wjg.v22.i8.2403. - DOI - PMC - PubMed
    1. Sanford M. Trastuzumab: A Review of Its Use in HER2-Positive Advanced Gastric Cancer. Drugs. 2013;73:1605–1615. doi: 10.1007/s40265-013-0119-y. - DOI - PubMed
    1. Choi Y.Y., Noh S.H., Cheong J.-H. Molecular Dimensions of Gastric Cancer: Translational and Clinical Perspectives. J. Pathol. Transl. Med. 2016;50:1–9. doi: 10.4132/jptm.2015.09.10. - DOI - PMC - PubMed
Feedback