AUTHOR=Yuan Bo , Zhao Jun , Zhou Chengzhi , Wang Xiumei , Zhu Bo , Zhuo Minglei , Dong Xilin , Feng Jiemei , Yi Cuihua , Yang Yunpeng , Zhang Hua , Zhou Wangyan , Chen Zhengtang , Yang Sheng , Ai Xinghao , Chen Kehe , Cui Xuefan , Liu Difa , Shi Chunmei , Wu Wei , Zhang Yanjun , Chang Lianpeng , Li Jin , Chen Rongrong , Yang Shuanying 

TITLE=Co-Occurring Alterations of ERBB2 Exon 20 Insertion in Non-Small Cell Lung Cancer (NSCLC) and the Potential Indicator of Response to Afatinib

JOURNAL=Frontiers in Oncology

VOLUME=10

YEAR=2020

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.00729

DOI=10.3389/fonc.2020.00729

ISSN=2234-943X

ABSTRACT=<p><bold>Background:</bold> Human epidermal growth factor receptor 2 (ERBB2, HER-2) exon 20 insertion (ERBB2ex20ins) remains a refractory oncogenic driver in lung cancer. So far there is limited data showing the co-occurring mutation background of ERBB2ex20ins in Chinese lung cancer and its relationship with response to afatinib.</p><p><bold>Patients and Methods:</bold> A total of 112 Chinese patients with ERBB2ex20ins identified by next-generation sequencing from 17 hospitals were enrolled. The clinical outcomes of 18 patients receiving afatinib treatment were collected.</p><p><bold>Results:</bold> Among the 112 patients, insertion-site subtypes comprised of A775ins (71%; 79/112), G776indel (17%; 19/112), and P780ins (12%; 14/112). There were 66.1% (74/112) of patients carrying TP53 co-mutation and FOXA1 was the most prevalent co-amplified gene (5.5%, 3/55). The co-occurring genomic feature was similar among three insertional-site subtypes and had an overall strong concordance with the western population from the MSKCC cohort (<italic>R</italic><sup>2</sup> = 0.74, <italic>P</italic> &lt; 0.01). For the prognosis, patients with co-occurring mutation in cell-cycle pathway especially TP53 showed shorter OS than patients without [median OS: 14.5 m (95% CI:12.7–16.3 m) vs. 30.3 m (95% CI: not reached), <italic>p</italic> = 0.04], while the OS was comparable among three subtypes. For the response to afatinib, ERBB2ex20ins as a subclonal variant was an independent factor relating to shorter PFS [median PFS: 1.2 m (95% CI: 0.8–1.6 m) vs. 4.3 m (95% CI: 3.3–5.3 m), <italic>p</italic> &lt; 0.05].</p><p><bold>Conclusion:</bold> Our data revealed co-occurring TP53 represent an unfavorable prognosis of patients with ERBB2ex20ins, emphasizing the more valuable role of the co-mutation patterns than insertion-site subtypes in predicting prognosis of this group of patients. Moreover, the clonality status of ERBB2ex20ins was identified as a potential indicator for response to afatinib.</p>