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    • br Funding This study was supported by grants

    2021-09-07


    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 Amiloride HCl 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].