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©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
HER2 heterogeneity is a poor prognosticator for HER2-positive gastric cancer
Akio Kaito, Takeshi Kuwata, Masanori Tokunaga, Kohei Shitara, Reo Sato, Tetsuo Akimoto, Takahiro Kinoshita
Akio Kaito, Masanori Tokunaga, Reo Sato, Takahiro Kinoshita, Department of Gastric Surgery, National Cancer Center Hospital East, Kashiwa 277-8577, Japan
Akio Kaito, Takeshi Kuwata, Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa 277-8577, Japan
Akio Kaito, Kohei Shitara, Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan
Takeshi Kuwata, Kohei Shitara, Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center Hospital East, Kashiwa 277-8577, Japan
Tetsuo Akimoto, Juntendo University Graduate School of Medicine, Tokyo 163-8001, Japan
Tetsuo Akimoto, Department of Radiation Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan
Author contributions: Kaito A and Kuwata T contributed equally to this work in study conception, study design, data acquisition, quality control of data and algorithms, and data analysis and interpretation; Kaito A contributed to statistical analysis and manuscript preparation; All authors contributed equally to manuscript editing and manuscript review.
Institutional review board statement: This study was approved by the Institutional Review Board of the National Cancer Center, Japan, No. 2017-164, approval date: Oct. 11, 2017.
Informed consent statement: Comprehensive informed consent including publication without personally identifiable information was obtained from all of the subjects prior to study enrollment. Thus, specified informed consent for this study is not required. The public document of this study was published on our website: https://www.ncc.go.jp/jp/about/research_promotion/study/list/2017-164.pdf. Informed consent statement could not be obtained because most of the participants were deceased.
Conflict-of-interest statement: The authors have no conflict of interest to declare.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Takeshi Kuwata, MD, PhD, Doctor, Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa 277-8577, Japan.
tkuwata@east.ncc.go.jp
Telephone: +81-4-71331111 Fax: +81-4-71300190
Received: April 13, 2019
Peer-review started: April 15, 2019
First decision: May 16, 2019
Revised: June 16, 2019
Accepted: June 26, 2019
Article in press: June 27, 2019
Published online: August 6, 2019
Processing time: 115 Days and 8.2 Hours
BACKGROUND
The clinical significance of intratumoral human epidermal growth factor receptor 2 (HER2) heterogeneity is unclear for HER2-positive gastric cancer, although it has been reported to be a significant prognosticator for HER2-positive breast cancer, which has received trastuzumab-based chemotherapy.
AIM
To clarify the clinical significance of intratumoral HER2 heterogeneity for HER2-positive gastric cancer, which has received trastuzumab-based chemotherapy.
METHODS
Patients with HER2-positive unresectable or metastatic gastric cancer who received trastuzumab-based chemotherapy as a first line treatment were included. The patients were classified into two groups according to their intratumoral HER2 heterogeneity status examined by immunohistochemistry (IHC) on endoscopic biopsy specimens before treatment, and their clinical response to chemotherapy and survival were compared.
RESULTS
A total of 88 patients were included in this study, and HER2 heterogeneity was observed in 23 (26%) patients (Hetero group). The overall response rate was significantly better in patients without HER2 heterogeneity (Homo group) (Homo vs Hetero: 79.5% vs 35.7%, P = 0.002). Progression-free survival of trastuzumab-based chemotherapy was significantly better in the Homo group (median, 7.9 vs 2.5 mo, HR: 1.905, 95%CI: 1.109-3.268). Overall survival was also significantly better in the Homo group (median survival time, 25.7 vs 12.5 mo, HR: 2.430, 95%CI: 1.389-4.273). Multivariate analysis revealed IHC HER2 heterogeneity as one of the independent poor prognostic factors (HR: 3.115, 95%CI: 1.610-6.024).
CONCLUSION
IHC of HER2 heterogeneity is the pivotal predictor for trastuzumab-based chemotherapy. Thus, HER2 heterogeneity should be considered during the assessment of HER2 expression.
Core tip: Although intratumoral human epidermal growth factor receptor 2 (HER2) heterogeneity has been reported as an important predictor of trastuzumab-based chemotherapy for HER2-positive breast cancer, the clinical significance of HER2 heterogeneity for gastric cancer had been unclear. We defined intratumoral HER2 heterogeneity as biopsy specimens were taken from two or more different portions of the tumor that showed different HER2 positivity by immunohistochemistry, and HER2 heterogeneity based on this definition was a pivotal poor predictor of tumor shrinkage and poor prognosticator. Thus, intratumoral HER2 heterogeneity should be included in the assessment of HER2 positivity.
