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Clinical characterization of ERBB2 exon 20 insertions and heterogeneity of outcomes responding to afatinib in Chinese lung cancer patients

Authors Liu Z, Wu L, Cao J, Yang Z, Zhou C, Cao L, Wu H, Shen H, Jin M, Zhang Y, Mao X, Xiang J, Ma K, Li B, Zhang T, Hu Y

Received 7 May 2018

Accepted for publication 7 August 2018

Published 23 October 2018 Volume 2018:11 Pages 7323—7331


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Tohru Yamada

Zhefeng Liu,1,* Lin Wu,2,* Jun Cao,3 Zhe Yang,4 Chengzhi Zhou,5 Liming Cao,6 Hao Wu,7 Haibo Shen,8 Meiling Jin,9 Yong Zhang,1 Xinru Mao,10 Jianxing Xiang,10 Ke Ma,10 Bing Li,11 Tengfei Zhang,10 Yi Hu1

1Department of Oncology, Chinese PLA General Hospital, Beijing, People’s Republic of China; 2Department of the Second Chest Medicine, Hunan Cancer Hospital, Changsha, Hunan, People’s Republic of China; 3Department of Oncology, Hunan Cancer Hospital, Changsha, Hunan, People’s Republic of China; 4Department of Radiotherapy, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People’s Republic of China; 5State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 6Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 7Department of Thoracic Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong, People’s Republic of China; 8Department of Thoracic Surgery, Ningbo No 2 Hospital, Ningbo, Zhejiang, People’s Republic of China; 9Department of Respiratory Medicine, Zhongshan Hospital Affiliated with Fudan University, Shanghai, People’s Republic of China; 10Department of Medicine, Burning Rock Biotech, Guangzhou, Guangdong, People’s Republic of China; 11Department of Bioinformatics, Burning Rock Biotech, Guangzhou, Guangdong, People’s Republic of China

*These authors contributed equally to this work

Purpose: ERBB2 exon 20 insertions (20ins) have been identified as oncogenic drivers in lung cancers. Lung cancer patients with 20ins benefit from afatinib. However, response heterogeneity was observed in patients harboring different 20ins subtypes. In this study, we interrogated clinical characteristics in ERBB2-mutated Chinese lung cancer and investigated the clinical outcomes of specific ERBB2 20ins in response to afatinib.
Experimental design: In this study, we retrospectively collected genomic profiling data of 7,520 lung cancer patients sequenced using next-generation sequencing in a Clinical Laboratory Improvement Amendments-certified laboratory. We analyzed the clinical and molecular features of patients harboring ERBB2 20ins and evaluated clinical outcomes of 19 patients with clinical records after afatinib treatment.
Results: ERBB2 20ins were identified in 2.27% (171/7,520) of this lung cancer cohort. It occurred with a high proportion in females with adenocarcinoma histology. ERBB2 20ins was mutually exclusive with other well-established lung cancer oncogenic driver mutations. The most frequently appearing subtype was Y772_A775dup (69.6%) and several novel insertion subtypes were also identified. The correlations of specific 20ins subtypes and survival were investigated. The presence of a glycine at position 778 in ERBB2 was suggested to be a common feature of drug sensitivity mutations. Patients harboring G778_P780dup (G778) subtype achieved longer median progression-free survival and median overall survival than other 20ins (non-G778) subtypes (median progression-free survival, 10 vs 3.3 months, P=0.32; median overall survival, 19.7 vs 7 months, P=0.16). Moreover, we presented the first clinical case of a lung squamous cell carcinoma patient harboring ERBB2 20ins who achieved partial response to afatinib.
Conclusion: This study interrogated the characteristics of ERBB2 20ins in a large cohort from single ethnicity and demonstrated the response heterogeneity to afatinib among different ERBB2 20ins subtypes. Further studies in a larger cohort are needed to investigate the underlying molecular mechanisms and clinical response of different ERBB2 20ins subtypes.

Keywords: ERBB2, lung cancer, afatinib, survival, heterogeneity

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