Mutation Variants and Co-Mutations as Genomic Modifiers of Response to Afatinib in HER2 -Mutant Lung Adenocarcinoma

The oncologist

article

Wenfeng Fang¹  Yang Yang³  Xiaoyan Ma²  Minghui Wang⁴  Wenjing Wang⁵  Songhui Zhao⁵  Kai Wang⁵  Song Gao²  Li Zhang¹  Shen Zhao¹  Ying Liang¹  Yunpeng Yang¹  Lin Yang⁶  Xiaorong Dong⁷  Li Zhang⁸  Yong Tang⁹  Shoufeng Wang^1,10 

[1] Department of Medical Oncology, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center;State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center;The First Affiliated Hospital of Guangxi University of Chinese Medicine;Department of Thoracic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University;OrigiMed;Department of Thoracic Surgery, Shenzhen People's Hospital, 2nd Clinical Medical College of Jinan University;Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology;Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology;Department of Thoracic Surgery, General Hospital of Guangzhou Military Command of PLA;Department of Thoracic Surgery, Guangxi Medical University Affiliated Tumor Hospital

关键词: Lung cancer;    ERBB2;    Mutation variant;    Concomitant mutation;    Intrinsic resistance;   

DOI  :  10.1634/theoncologist.2019-0547

学科分类：地质学

来源: AlphaMed Press Incorporated

【 摘 要 】

Background Human epidermal growth factor receptor 2 ( HER2 )-mutant lung cancer remains an orphan of specific targeted therapy. The variable responses to anti-HER2 therapies in these patients prompt us to examine impact of HER2 variants and co-mutations on responses to anti-HER2 treatments in lung cancer. Patients and Methods Patients with stage IV/recurrent HER2 -mutant lung cancers identified through next-generation sequencings were recruited from seven hospitals. The study comprised a cohort A to establish the patterns of HER2 variants and co-mutations in lung cancer and a cohort B to assess associations between HER2 variants, co-mutations, and clinical outcomes. Results The study included 118 patients (cohort A, n = 86; cohort B, n = 32). Thirty-one HER2 variants and 35 co-mutations were detected. Predominant variants were A775_G776insYVMA (49/118, 42%), G778_P780dup (11/118, 9%), and G776delinsVC (9/118, 8%). TP53 was the most common co-mutation (61/118, 52%). In cohort B, objective response rates with afatinib were 0% (0/14, 95% confidence interval [CI], 0%–26.8%), 40% (4/10, 14.7%–72.6%), and 13% (1/8, 0.7%–53.3%) in group 1 ( A775_G776insYVMA , n = 14), group 2 ( G778_P780dup , G776delinsVC , n = 10), and group 3 (missense mutation, n = 8), respectively ( p = .018). Median progression-free survival in group 1 (1.2 months; 95% CI, 0–2.4) was shorter than those in group 2 (7.6 months, 4.9–10.4; hazard ratio [HR], 0.009; 95% CI, 0.001–0.079; p < .001) and group 3 (3.6 months, 2.6–4.5; HR, 0.184; 95% CI, 0.062–0.552; p = .003). TP53 co-mutations (6.317; 95% CI, 2.180–18.302; p = .001) and PI3K/AKT/mTOR pathway activations (19.422; 95% CI, 4.098–92.039; p < .001) conferred additional resistance to afatinib. Conclusion G778_P780dup and G776delinsVC derived the greatest benefits from afatinib among HER2 variants. Co-mutation patterns were additional response modifiers. Refining patient population based on patterns of HER2 variants and co-mutations may help improve the efficacy of anti-HER2 treatment in lung cancer. Implications for Practice Human epidermal growth factor receptor 2 ( HER2 )-mutant lung cancers are a group of heterogenous diseases with up to 31 different variants and 35 concomitant genomic aberrations. Different HER2 variants exhibit divergent sensitivities to anti-HER2 treatments. Certain variants, G778_P780dup and G776delinsVC , derive sustained clinical benefits from afatinib, whereas the predominant variant, A775_G776insYVMA , is resistant to most anti-HER2 treatments. TP53 is the most common co-mutation in HER2 -mutant lung cancers. Co-mutations in TP53 and the PI3K/AKT/mTOR pathway confer additional resistance to anti-HER2 treatments in lung cancer. The present data suggest that different HER2 mutations in lung cancer, like its sibling epidermal growth factor receptor, should be analyzed independently in future studies.

【 授权许可】

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