Efficacy of tyrosine kinase inhibitors against lung cancer with EGFR exon 18 deletion: Case report and pooled analysis.

BACKGROUND: Within the exon 18 of EGFR, a complex, in-frame deletion-delE709_T710ins-has been described among pulmonary adenocarcinomas with an estimated prevalence of 0.3%. Available evidences suggest that some EGFR tyrosine kinase inhibitors (TKI) have activity against this cancer. However, due to the rarity of this mutation, it remains unclear which TKI is the most effective. METHODS: We reported our experience using afatinib followed by osimertinib in a patient with this mutation. We performed a systematic review of literature and conducted a pooled analysis to compare the outcomes of treatment with first generation TKIs vs. afatinib. Cases with compound mutations were excluded. RESULTS: Our patient achieved a partial response to afatinib with a progression-free survival of 11 months. Upon disease progression, osimertinib failed to control the disease. Literature review identified 14 cases being reported: 8 received first generation TKI and 6 received afatinib. Among those with tumor response assessed, partial response occurred in 2 out of 7 patients (28.6%) treated with first generation TKI compared with 6 out of 6 patients (100%) treated with afatinib, p = 0.03. The median progression-free survival (PFS) was 3.1 months vs. 7.0 months, respectively, p = 0.005. Insufficient evidences were available to assess for the efficacy of osimertinib. CONCLUSION: Based on currently available data, afatinib was associated with a greater tumor response rate and a longer PFS than the first generation TKIs.

Correction: Opportunities to implement a sustainable genomic medicine program: lessons learned from the IGNITE Network.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Opportunities to implement a sustainable genomic medicine program: lessons learned from the IGNITE Network.

PURPOSE: While there is growing scientific evidence for and significant advances in the use of genomic technologies in medicine, there is a significant lag in the clinical adoption and sustainability of genomic medicine. Here we describe the findings from the National Human Genome Research Institute's (NHGRI) Implementing GeNomics In pracTicE (IGNITE) Network in identifying key constructs, opportunities, and challenges associated with driving sustainability of genomic medicine in clinical practice. METHODS: Network members and affiliates were surveyed to identify key drivers associated with implementing and sustaining a genomic medicine program. Tallied results were used to develop and weigh key constructs/drivers required to support sustainability of genomic medicine programs. RESULTS: The top three driver-stakeholder dyads were (1) genomic training for providers, (2) genomic clinical decision support (CDS) tools embedded in the electronic health record (EHR), and (3) third party reimbursement for genomic testing. CONCLUSION: Priorities may differ depending on healthcare systems when comparing the current state of key drivers versus projected needs for supporting genomic medicine sustainability. Thus we provide gap-filling guidance based on IGNITE members' experiences. Although results are limited to findings from the IGNITE network, their implementation, scientific, and clinical experience may be used as a road map by others considering implementing genomic medicine programs.

Correction: Opportunities to implement a sustainable genomic medicine program: lessons learned from the IGNITE Network.

The original version of this Article contained an error in the spelling of the author Geoffrey S. Ginsburg, which was incorrectly given as Geoffrey Ginsburg. This has now been corrected in both the PDF and HTML versions of the Article.

Multiple configurations of EGFR exon 20 resistance mutations after first- and third-generation EGFR TKI treatment affect treatment options in NSCLC.

After sequential treatment with first- and third-generation EGFR tyrosine kinase inhibitors (TKIs), EGFR-mutant non-small cell lung cancers frequently harbor multiple resistance mutations in exon 20 of EGFR including T790M, mediating resistance to first-generation TKIs, and at codons 792, 796, or 797 mediating resistance to third-generation TKIs. However, whether these resistance mutations are in cis or trans has therapeutic implications for patients. We analyzed a cohort of 29 patients with NSCLC harboring EGFR mutations at codons 792, 796, or 797 to establish the configuration of these mutations. We performed hybrid capture-based, next-generation sequencing on formalin-fixed paraffin-embedded biopsy tissue or liquid biopsy. 27 samples had both a T790M mutation and a mutation at codons 792, 796, or 797. In all of these cases, the mutations were found in the cis configuration; the trans configuration was not observed. Two patients' samples harbored a mutation at codon 797 but no T790M mutation. In these two cases, longitudinal analysis showed earlier biopsies harbored EGFR T790M, which was undetectable following osimertinib treatment. Treatment of one these patients with both first- and third-generation EGFR TKIs resulted in a mixed response. Here we describe multiple configurations of EGFR T790M and third-generation TKI resistance mutations at codons 792, 796, and 797. These mutations are most commonly found in cis, which confers resistance to all current EGFR TKIs. We also describe two patients that exhibited T790M loss with acquisition of a mutation at codon 797. In addition, one of these patients, with an EGFR C797S in a lung biopsy was subsequently found to have EGFR C797N in a later biopsy of pleural fluid, highlighting the dynamic multiclonal nature of advanced NSCLC.

Reactive oxygen nitrogen species decrease cystic fibrosis transmembrane conductance regulator expression and cAMP-mediated Cl- secretion in airway epithelia.

We investigated putative mechanisms by which nitric oxide modulates cystic fibrosis transmembrane conductance regulator (CFTR) expression and function in epithelial cells. Immunoprecipitation followed by Western blotting, as well as immunocytochemical and cell surface biotinylation measurements, showed that incubation of both stably transduced (HeLa) and endogenous CFTR expressing (16HBE14o-, Calu-3, and mouse tracheal epithelial) cells with 100 microm diethylenetriamine NONOate (DETA NONOate) for 24-96 h decreased both intracellular and apical CFTR levels. Calu-3 and mouse tracheal epithelial cells, incubated with DETA NONOate but not with 100 microm 8-bromo-cGMP for 96 h, exhibited reduced cAMP-activated short circuit currents when mounted in Ussing chambers. Exposure of Calu-3 cells to nitric oxide donors resulted in the nitration of a number of proteins including CFTR. Nitration was augmented by proteasome inhibition, suggesting a role for the proteasome in the degradation of nitrated proteins. Our studies demonstrate that levels of nitric oxide that are likely to be encountered in the vicinity of airway cells during inflammation may nitrate CFTR resulting in enhanced degradation and decreased function. Decreased levels and function of normal CFTR may account for some of the cystic fibrosis-like symptoms that occur in chronic inflammatory lung diseases associated with increased NO production.