HER2 transmembrane domain mutation: comprehensive characteristics and real-world evidence of treatment response in Chinese lung adenocarcinoma

Ziqi Jia; Jiahua Xing; Ji Li; Weiwei Wang; Yadong Wang; Yang Song; Xiaoying Yang; Jianchao Xue; Junyi Ye; Bing Li; Han Han-Zhang; Jiaxing Zhao; Xiaochun Zhang; Feng Peng; Fengxia Chen; Xueqin Chen; Yan Lu; Shenpeng Ying; Dongping Wu; Xinwei Zhang; Caixia Ma; Lipeng Lai; Songling Ma; Dianjing Liang; Peng Liu; Xiaoguang Li; Naixin Liang; Shanqing Li

doi:10.21037/tlcr-21-107

HER2 transmembrane domain mutation: comprehensive characteristics and real-world evidence of treatment response in Chinese lung adenocarcinoma

Transl Lung Cancer Res. 2021 Mar;10(3):1383-1396. doi: 10.21037/tlcr-21-107.

Authors

Ziqi Jia^{1

2}, Jiahua Xing³, Ji Li⁴, Weiwei Wang¹, Yadong Wang¹, Yang Song¹, Xiaoying Yang^{1

2}, Jianchao Xue¹, Junyi Ye⁵, Bing Li⁵, Han Han-Zhang⁶, Jiaxing Zhao⁶, Xiaochun Zhang⁷, Feng Peng⁸, Fengxia Chen⁹, Xueqin Chen¹⁰, Yan Lu¹¹, Shenpeng Ying¹², Dongping Wu¹³, Xinwei Zhang¹⁴, Caixia Ma¹⁵, Lipeng Lai¹⁵, Songling Ma¹⁵, Dianjing Liang¹⁶, Peng Liu¹⁷, Xiaoguang Li¹⁸, Naixin Liang¹, Shanqing Li¹

Affiliations

¹ Department of Thoracic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
² Eight-Year MD Program, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
³ School of Medicine, Nankai University, Tianjin, China.
⁴ Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.
⁵ Department of Biostatistics, Burning Rock Biotech Co. Ltd., Guangzhou, China.
⁶ Department of Medicine, Burning Rock Biotech Co. Ltd., Guangzhou, China.
⁷ Precision Medicine Center of Cancer, The Affiliated Hospital of Qingdao University, Qingdao, China.
⁸ Department of Thoracic Cancer, Cancer Center, West China Hospital, S.C.U., Chengdu, China.
⁹ Department of Thoracic Surgery, Hainan General Hospital, Haikou, China.
¹⁰ Department of Oncology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
¹¹ Department of Oncology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
¹² Department of Radiotherapy, Taizhou Central Hospital, Affiliated Hospital of Taizhou University, Taizhou, China.
¹³ Department of Radiation Oncology, Shaoxing People's Hospital, Shaoxing Hospital of Zhejiang University, Shaoxing, China.
¹⁴ Department of Biotherapy, Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China.
¹⁵ XtalPi, XtalPi AI Research Center, Beijing, Chinal.
¹⁶ Institute of Physics, Humboldt University of Berlin, Berlin, Germany.
¹⁷ Medical Research Center, Central Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.
¹⁸ Minimally Invasive Tumor Therapies Center, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.

Abstract

Background: HER2 transmembrane domain (TMD) mutation has been reported as a rare driver mutation associated with advanced stage disease and a poor prognosis in patients with lung adenocarcinoma (LUAD). We aimed to comprehensively profile the genetic landscape and treatment response information of HER2 TMD-mutant LUAD.

Methods: An in-house database of 7,812 LUAD patients was screened for mutation prevalence. A multi-center cohort of 16 HER2 V659E-mutant patients and an external cohort of 38 HER2-mutant patients from cBioPortal with overall survival (OS) data were analyzed. Eight patients from the in-house cohort were included in the real-world study of treatment response. Molecular docking simulation and binding affinity prediction were performed.

Results: In Chinese LUAD, the prevalence of HER2 TMD mutation was 0.18% (14/7,812), and 0.14% (11/7,812) for the HER2 V659E mutation. The most recurrent co-alteration was TP53 mutation (n=4, 25%) and HER2 amplification (n=2, 12.5%). TMD-mutant patients were diagnosed at more advance stages (P<0.001) and had poorer OS (median OS 10.0 vs. 61.6 months, HR =7.9, 95% CI: 1.0-61.0, P<0.001) than non-TMD mutations. The overall response rate of targeted therapy, chemo-based therapy, and immunotherapy was 57.1%, 22.2%, and 0%, respectively. We postulated to challenge the resistance of tyrosine kinase inhibitor (TKI) with another with stronger binding energy to HER2 and supported the conclusion with a successful case. Additionally, we demonstrated a three-month response to the off-label use of pyrotinib in fifth-line therapy.

Conclusions: Comapred with non-TMD mtuations, HER2 TMD mutation is a rare driver mutation with poorer prognosis in LUAD. Targeted therapy is the dominant choice for patients harboring this targetable mutation and longer OS could possibly be achieved through rechallenge with TKI of stronger binding affinity. Response to fifth-line pyrotinib was observed.

Keywords: HER2 mutation; lung adenocarcinoma (LUAD); prognosis; pyrotinib; treatment response.