Loss of HER2 positivity after anti-HER2 chemotherapy in HER2-positive gastric cancer patients: results of the GASTric cancer HER2 reassessment study 3 (GASTHER3)

  • Seyoung Seo
  • Min-Hee Ryu
  • Young Soo Park
  • Ji Yong Ahn
  • Yangsoon Park
  • Sook Ryun Park
  • Baek-Yeol Ryoo
  • Gin Hyug Lee
  • Hwoon-Young Jung
  • Yoon-Koo KangEmail author
Original Article



Although discordance in HER2 positivity between primary and metastatic lesions is well established, changes in HER2 positivity after anti-HER2 therapy have not been well evaluated in gastric cancer. We aimed to evaluate whether HER2 expression in gastric cancer is affected by trastuzumab therapy.


We enrolled 48 HER2-positive advanced gastric cancer patients treated with trastuzumab-containing first-line chemotherapy and had paired biopsies at baseline and after progression.


At baseline, HER2 was positive, with immunohistochemistry (IHC) 2+ and in situ hybridization (ISH)+ in five patients, and with IHC 3+ in 43 patients. Fourteen patients (29.1%) exhibited loss of HER2 positivity on post-progression biopsy: 10 with IHC 0 or 1+, and four with IHC 2+/ISH−. HER2 remained positive on second biopsy in 34 patients: four with IHC 2+/ISH+, and 30 with IHC 3+. Median H-scores decreased from 225 to 175 (p = 0.047). HER2 genetic heterogeneity was defined in one of 34 ISH-assessable patients (2.9%) at baseline and seven of 32 (21.9%) at second biopsy. Among 13 patients who received second-line trastuzumab emtansine, three showed HER2-negative conversion; they had no objective response and short progression-free survival (1.2, 1.3, and 3.4 months). Patients with stable HER2 status had a 44% response rate and median progression-free survival of 2.7 (0.4–36.8) months.


A substantial portion of HER2-positive patients showed HER2-negative conversion with increased HER2 genetic heterogeneity after failure of trastuzumab-containing chemotherapy. Loss of HER2 positivity could be predictive of second-line anti-HER2 treatment, suggesting a need to reexamine HER2 status before initiating second-line anti-HER2 therapy.


HER2 Advanced gastric cancer Heterogeneity Trastuzumab T-DM1 


Compliance with ethical standards

Conflict of interest

Y-K Kang discloses a consultant role for Ono, Taiho, Daehwa, Roche, Novartis, Bayer, Blueprint, and Merck. The remaining authors declare no conflict of interest.

Research involving human and/or animal rights

All procedures followed were in accordance with the ethical standards of the Institutional Review Board of Asan Medical Center and with the Helsinki Declaration of 1964 and later versions.

Informed consent

Informed consent or a substitute for it was obtained from all patients included in the study.

Supplementary material

10120_2018_891_MOESM1_ESM.pdf (284 kb)
Supplementary material 1 (PDF 284 KB)


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Copyright information

© The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2018

Authors and Affiliations

  • Seyoung Seo
    • 1
  • Min-Hee Ryu
    • 1
  • Young Soo Park
    • 2
  • Ji Yong Ahn
    • 3
  • Yangsoon Park
    • 2
  • Sook Ryun Park
    • 1
  • Baek-Yeol Ryoo
    • 1
  • Gin Hyug Lee
    • 3
  • Hwoon-Young Jung
    • 3
  • Yoon-Koo Kang
    • 1
    Email author
  1. 1.Department of Oncology, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea
  2. 2.Department of Pathology, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea
  3. 3.Department of Gastroenterology, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea

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