• 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2020-03
  • 2020-07
  • 2020-08
  • Our NGS approach on ctDNA was very promising showing a


    Our NGS approach on ctDNA was very promising, showing a high technical success rate (98%), a strong concordance between EGFR sensitizing mutations in tissue samples at diagnosis and in plasma at progression (92%), and a high detection rate of plasma T790 M at progression (71%) with a concordance rate between standard methods and NGS of 94%. These results are in line with previously reported data, giving further credibility to the application of in-house non-invasive molecular profiling of lung cancer patients [26,27]. Among the EGFR T790 M positive patients who received osimertinib, four showed progressive disease. In two of them a dissociated radiological response was observed. The tissue biopsies of the progressive lesions were EGFR T790 M negative and MET gene amplification positive, providing additional evidence of NSCLC tumor heterogeneity as already documented in both autopsy and ctDNA-based studies [28]. Our data also support the use of a targeted multigene panel NGS assay for a more informative characterization of the most common mechanisms, other than T790 M mutation, involved in the resistance to third-generation EGFR-TKI [[29], [30], [31]], such as C797S EGFR mutation allelic conformation. The Ko 143 20 EGFR C797S represents an acquired resistance mechanism to third-generation TKIs as it prevents their binding to the EGFR active site. Such occurrences can be found either in the same (in cis) T790M-mutated allele or in the other allele (in trans) and, both in vitro and in vivo studies reported that, when C797S emerged in trans of the T790 M allele, tumors remain sensitive to first- and third generation EGFR-TKI combinations, whereas tumors remain broadly resistant if C797S emerged in the cis position of T790 M allele [32,33]. NGS genotyping of ctDNA at progression identified also additional tumor associated alterations in genes such as TP53, PIK3CA, KRAS, ROS1, BRAF, ALK, NRAS, ERBB2, and MP2K1. These data deserve further investigation in larger data sets, as they can contribute to better define the co-occurring genetic alteration role in affecting the response to TKI EGFR inhibitors. Indeed, heterogeneous resistance mechanisms of T790M-mutant subclones coexisting with subclones harboring different acquired alterations, including KRAS mutations have been described [28,34,35]. Further, distinct combinations of TP53 mutations with other gene alterations were proved to be major determinants of the tumor immune profile and of the expression of PD-L1 by malignant cells in lung cancer [36]. In particular mutations of genes such as TP53 may alter the immune landscape via the generation of neoantigens which have been proposed as biomarkers to predict therapeutic effects of immune checkpoint blockade therapy and as potential targets for cancer immunotherapy [37]. Among the various mechanisms that lead to acquired resistance to TKIs therapies, the histologic transformation from adenocarcinoma to SCLC has been observed in 3–20% of patients. This resistance mechanism can be formally proved only by recurrence biopsy. Nevertheless, TP53 and RB1 alterations can be used as an indication of this resistance mechanism. In fact, though the molecular basis of this histology transformation are not fully understood, TP53 and RB1 gene inactivation has been described in SCLC and therefore associated to histology transformation from adenocarcinoma to SCLC [38,39].
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    Introduction Lung cancer is the most common cause of cancer related mortality worldwide [1,2]. At present, adenocarcinoma is the most common histological type of lung cancer [3]. In 2011, a new multidisciplinary classification for lung adenocarcinoma (LUAD) was proposed by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society, which classified lung invasive adenocarcinoma into five main pathological subtypes, including: acinar, solid, micropapillary, papillary, and lepidic [4]. Among the five pathological subtypes, the acinar-predominant subtype accounts for the highest percentage [5,6], and this subtype demonstrates significant heterogeneity in prognosis [7]. One of the main reasons for different prognoses seen with acinar-predominant LUAD is related to histological heterogeneity [8]. According to the 2015 World Health Organization (WHO) classification of the lung cancer, a distinctive histological pattern named cribriform component, which has been included in acinar-predominant adenocarcinoma [9]. Several studies have demonstrated that the cribriform component may further stratify survival in acinar-predominant LUADs [[10], [11], [12], [13], [14]].