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 Su Park, Ji Yong Ahn, Yangsoon Park, Sook Ryun Park, Baek Yeol Ryoo, Gin Hyug Lee, Hwoon Young Jung, Yoon Koo Kang

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)527-535
Number of pages9
JournalGastric Cancer
Volume22
Issue number3
DOIs
StatePublished - 1 May 2019

Keywords

  • Advanced gastric cancer
  • HER2
  • Heterogeneity
  • T-DM1
  • Trastuzumab

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