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Targeted Oncology

, Volume 12, Issue 3, pp 341–351 | Cite as

Detection of HER2 Amplification in Circulating Tumor Cells of HER2-Negative Gastric Cancer Patients

  • Yuji Mishima
  • Satoshi Matsusaka
  • Keisho Chin
  • Mariko Mikuniya
  • Sayuri Minowa
  • Tomoko Takayama
  • Harumi Shibata
  • Ryoko Kuniyoshi
  • Mariko Ogura
  • Yasuhito Terui
  • Nobuyuki Mizunuma
  • Kiyohiko Hatake
Original Research Article

Abstract

A key to the successful use of targeted cancer therapy is the ability to preselect patients who are likely to benefit from the treatment according to molecular markers. Assessment for predicting therapy response is mostly done using tumor biopsies. However, these might not truly represent all of the patient’s malignant cells because of tumor heterogeneity and/or clonal evolution during disease progression. One potential strategy that can complement primary tumor biopsy is the analysis of circulating tumor cells (CTCs). In this study, we analyzed CTCs of patients with gastric cancer (GC) to find those who were likely to benefit from trastuzumab therapies. We developed an imaging-based method that enabled CTC identification simultaneously with evaluation of HER2 gene amplification (the 3D–IF-FISH method). Then we performed a study enrolling 101 GC patients in whom we analyzed CTCs by both 3D–IF-FISH and an FDA-approved CellSearch system. As compared with the CellSearch system, 3D–IF-FISH methods identified a higher number of patients whose primary tumors were HER2- but who had HER2+ CTCs, suggesting that the 3D–IF-FISH method is effective in preselecting patients for trastuzumab therapies. To demonstrate this, we performed an exploratory clinical study to evaluate the clinical benefits of trastuzumab treatment for advanced GC patients (n = 15) whose primary tumors were HER2-, but whose CTCs showed HER2 amplification. An interim evaluation after the first stage showed that these preselected patients had response rates comparable to those reported in the trastuzumab-plus-chemotherapy arm of the ToGA study. The present study offers a new, non-invasive strategy to select patients who are likely to benefit from trastuzumab-based therapies, despite their primary biopsy being HER2-negative. (UMIN ID: UMIN000008622).

Keywords

Gastric Cancer Trastuzumab Overall Response Rate EpCAM Expression CellSearch System 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

CTCs

Circulating tumor cells

FISH

Fluorescent in situ hybridization

GC

Gastric cancer

HER2

Human epidermal growth factor receptor 2

IF

Immunofluorescence

IHC

Immunocytochemistry

CTCs

Circulating tumor cells

GEL

Gastroesophageal junction

CEP17

Centromere on chromosome 17

ECOG

Eastern Cooperative Oncology Group

ORR

Overall response rate

PFS

Progression-free survival

OS

Overall survival

EpCAM

Epithelial cell adhesion molecule

CR

Complete response

PR

Partial response

SD

Stable disease

PD

Progressive disease

CK

Cytokeratin

Notes

Acknowledgements

We received technical support from Dr. Abe T, Ms. Asakura H, and Dr. Kojima K from Olympus corporation. We thank Ms. Suitsu C, Ms. Horikie Y, Ms. Yago M, and Ms. Kobayasi K for management of clinical samples and data collection. We also thank Dr. Dovie Wylie, of On-site English Inc. (Palo Alto, CA, USA) for English editing assistance.

Compliance with Ethical Standards

Funding

This study was supported in part by a Grant-in-Aid for Scientific Research (grant number 23501320; to YM), and a grant from the Kobayashi Institute for Innovative Cancer Chemotherapy (to SM).

Conflict of Interest Statement

The authors have no conflict of interest.

Supplementary material

11523_2017_493_MOESM1_ESM.pdf (2.2 mb)
ESM 1 (PDF 2271 kb)

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Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  • Yuji Mishima
    • 1
  • Satoshi Matsusaka
    • 2
  • Keisho Chin
    • 2
  • Mariko Mikuniya
    • 1
  • Sayuri Minowa
    • 1
  • Tomoko Takayama
    • 1
  • Harumi Shibata
    • 1
  • Ryoko Kuniyoshi
    • 1
  • Mariko Ogura
    • 2
  • Yasuhito Terui
    • 1
    • 2
  • Nobuyuki Mizunuma
    • 2
  • Kiyohiko Hatake
    • 1
    • 2
  1. 1.Clinical Chemotherapy, Cancer Chemotherapy CenterJapanese Foundation for Cancer ResearchTokyoJapan
  2. 2.Cancer Institute Hospital of the Japanese Foundation for Cancer ResearchTokyoJapan

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