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  • Taken together this study provides

    2021-10-14

    Taken together, this study provides the proof of concept that our novel heterologous human/rat HER2-specific T cell vaccine HuRt-TEXO, which is capable of stimulating both humoral and CTL responses leading to potent antitumor immunity through the circumvention of HER2 tolerance in double transgenic HLA-A2/HER2 mice, may provide a new therapeutic vaccine for patients with HER2+ breast cancer, especially for patients with trastuzumab-resistant HER2+ breast cancer tumors.
    Introduction Research into the molecular basis of lung cancers has led to an improved understanding of pathways that are deregulated in the process of tumourigenesis. These key biological pathways are often deregulated through single-gene alterations, including mutations, amplifications, rearrangements or fusions, and this process has been described as an oncogene addiction model [1]. This model is well characterised in lung adenocarcinomas with approved targeted therapies for certain driver oncogenes including EGFR, ALK, ROS1 and BRAF. Human epidermal growth factor 2 (HER2) has been identified as an additional key oncogenic driver in approximately 1–3% of lung adenocarcinomas [2], [3], [4]. HER2 is a member of the ErbB receptor tyrosine kinase family and acts through downstream effectors in the phosphoinositide 3-kinase-AKT and MEK-extracellular signal-regulated kinase pathways [5]. Most HER2 mutations in lung cancer involve a 12–base pair (bp) in-frame insertion in MHC class II antigen (45-57) [Homo sapiens] 20, known as the YVMA mutation, which leads to constitutive activation of downstream effectors through the AKT and MEK pathways [6], [7], [8]. This mutation is most often found in female patients, never smokers and in patients with adenocarcinomas [6], [9], [10]. Overall, patients with HER2-mutant lung adenocarcinomas have previously been reported to have a median overall survival (OS) of 1.6–1.9 years from the date of metastatic or recurrent disease diagnosis and carry a poorer prognosis compared with other oncogenic drivers [2], [3], [10]. Treatment responses to both chemotherapy and HER2-targeted therapies have been reported, but there are no approved agents for HER2-mutant lung cancers, and there are limited data available to guide optimal treatments. Afatinib is an irreversible ErbB family inhibitor that has been demonstrated to have preclinical activity in human lung cancer cell lines with an exon 20 insertion in HER2 [11], [12]. Along with other HER2-targeted agents including dacomitinib and trastuzumab, afatinib has been reported to have clinical activity in patients with HER2-mutant lung adenocarcinomas, although conclusions and recommendations for its clinical use are not possible because of the small sample size of these series [10], [13], [14], [15], [16], [17]. To increase our sample size and to improve our understanding of the clinical activity of afatinib in this subset of patients with lung adenocarcinomas, we combined data from seven institutions. In this article, we present the results of our international multicentre study on clinical outcomes of patients with HER2-mutant lung adenocarcinomas who were treated with afatinib.
    Material and methods
    Results
    Discussion To the best of our knowledge, our study represents one of the largest single cohort of patients with HER2-mutant lung adenocarcinomas treated with afatinib. Although there are limitations in our retrospective series, it is one of the largest international efforts to date to assess the activity of afatinib in this uncommon molecular subset of lung cancers. Our patient characteristics were similar to prior series of HER2-mutant lung cancers, including a similar median age of 63 years, primarily never smokers, and exclusively adenocarcinomas [6], [10], [17], [19]. However, there were two key differences: our patients were predominantly male compared with predominantly female in previous studies and heavy smokers with up to 60 pack years were identified. Our study highlights that molecular testing for HER2 mutations should be considered in all adenocarcinomas, even if patients do not fit the usual clinical profile of female and never smokers. Comparable to prior studies, most of our patients were found to have mutations involving exon 20 insertions in HER2, with the most common being the YVMA mutation.