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    • br Funding This study was supported by grants in aid

    2022-07-22


    Funding This study was supported by grants-in-aid for scientific research from the Japan Society for Promotion of Science (grant 16K186462 to Dr. Tomizawa, grant 16K19989 to Dr. Kobayashi, and grant 16H05433 to Dr. Mitsudomi) and a research grant from Boehringer-Ingelheim (to T. Mitsudomi).
    Conflict of interest
    Acknowledgements
    Introduction Lung cancer remains the leading cause of cancer death worldwide, accounting for 1.69 million deaths in 2015 and approximately 19% of the total cancer death toll according to the World Health Organization [1]. In the United States, the American Cancer Society estimated that 222,500 new cases of lung cancer will be diagnosed in 2017, with an estimated mortality of 70% (155,870 deaths) among both sexes [2]. Of the two main types of lung cancer, non-small cell lung cancer comprises 80 to 85% of lung cancers and histologically, 40% of these are adenocarcinomas [3]. The discovery of the epidermal growth factor receptor gene (EGFR) mutation in patients with lung adenocarcinomas in 2004 [[4], [5], [6]] and the Cy7.5 NHS ester (non-sulfonated) of genomic sequencing and targeted therapy have resulted in the further subclassification of lung adenocarcinomas based on the presence of driver oncogenes. The human epidermal growth factor receptor 2 gene (HER2/ERBB2) is an important driver oncogene for lung adenocarcinomas. HER2, the protein encoded by this gene, is a tyrosine kinase receptor of the ErbB family. HER2 has no direct activating ligand; it serves as the preferred and most stable hetero-dimerization partner for all the other family receptors, especially EGFR. HER2 dysregulation presents itself as HER2 protein overexpression in 6% to 35% of non-small cell lung cancer, gene amplification in 10% to 20%, and HER2 mutations in 2% to 4% [7, 8], resulting in constitutive activation of intracellular signaling through the PI3K/AKT/mTOR and MEK/ERK pathways, and subsequently promoting cellular mitosis and proliferation [9, 10]. As new drug development for HER2-mutant lung cancers is accelerating, it is increasingly important to study the unique characteristics of this group of patients [7, 11, 12]. Radiogenomics is the study of the radiological appearance of tumors in association with genomic alterations, including driver oncogenes [13]. It is highly promising for the follow-up assessment of tailored targeted therapies. Rizzo et al. has noted a preponderance for air bronchograms, pleural retractions, small lesion size, and absence of fibrosis for EGFR-mutant lung adenocarcinomas; and a round lesion shape for KRAS-mutant adenocarcinomas in addition to presence of nodules in non-tumor lobes [14]. As such the goal of this study was to identify the radiologic characteristics of HER2-mutant lung adenocarcinomas in comparison with other non-small cell lung cancer subtypes, specifically KRAS- and EGFR-mutant lung adenocarcinomas.
    Materials and methods
    Results
    Discussion HER2 gene dysregulation is a known driver of tumor growth and has been identified in several human malignancies, mainly breast, stomach and lung cancers [[19], [20], [21]]. In lung cancer, cancers harboring HER2 mutations can be aggressive, portending a poor prognosis [9, 22]. Mazières et al. described three major types of HER2 dysregulation in patients with non-small cell lung cancer that may increase oncogenic signaling independent from EGFR and KRAS mutations, and ALK fusions. The most common dysregulation is HER2 protein overexpression (6–35%), followed by HER2 gene amplification (2–5%) and HER2 gene mutation (2–4%) [7, 8]. At the same time, however, these cancers might benefit from existing and emergent therapies targeting HER2, especially when combined with conventional chemotherapy [11]. Novel HER2-targeted drugs are being tested and encouraging activity has been seen [16, 23]. A phase II trial in HER2 exon 20 insertion-containing lung cancers showed single agent activity of dacomitinib, a pan-HER inhibitor that binds irreversibly to HER2, HER1 (EGFR), and HER4 tyrosine kinases receptors [12]. A more recent phase II trial of ado-trastuzumab emtansine was declared positive after demonstrating 44% partial response rate in patients with HER2-mutant lung cancers [24]. Lately, radiogenomics has taken radiology a step beyond its conventional descriptive role. The power to see the genomic characteristics of various tumors plays a pivotal role in engineering an adequate targeted therapy in various cancers including lung adenocarcinoma [[25], [26], [27], [28], [29]], and predicting their response to treatment [32]. To our knowledge, our study is the first to describe the CT characteristics of HER2-mutant lung adenocarcinomas. Several other studies have examined the radiologic characteristics of NSCLCs associated with other driver oncogenes. A similar study conducted by Yano et al. for EGFR-mutant NSCLC found a predilection for solid nature [30] and others found a correlation between the size of the primary tumor, its ground glass component, and the probability of harboring EGFR mutation [31].