Prevalence of Epidermal Growth Factor Receptor Exon 20 Insertion Mutations in Non-small-Cell Lung Cancer in Europe: A Pragmatic Literature Review and Meta-analysis

Sanden, Suzy Van; Murton, Molly; Bobrowska, Anna; Rahhali, Nora; Sermon, Jan; Rodrigues, Bernardo; Goff-Leggett, D.; Chouaïd, C.; Sebastian, Martin; Greystoke, Alastair

doi:10.1007/s11523-022-00868-z

Cited by 17 publications

(17 citation statements)

References 34 publications

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“…In this real‐world analysis using three US NGS genomic datasets, EGFR ex20ins variants account for ~ 1% of all NSCLC cases in each of the three databases. The estimated frequency of ex20ins was ~ 7–8% of all EGFRm lung adenocarcinomas, which is consistent with the range (up to 12%) reported in the literature from other US‐based databases [ 13 ] and globally [ 2 , 17 , 18 , 19 , 20 ]. The near loop was the most frequent insertion region of EGFR ex20ins, where ~ 70% of all insertions were found.…”

Section: Discussionsupporting

confidence: 88%

Frequency, underdiagnosis, and heterogeneity of epidermal growth factor receptor exon 20 insertion mutations using real‐world genomic datasets

Viteri¹,

Minchom

Bazhenova

et al. 2022

Molecular Oncology

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Epidermal growth factor receptor (EGFR) exon 20 insertion mutations (ex20ins) account for ≤ 12% of all EGFR-mutant nonsmall cell lung cancers. We analysed real-world datasets to determine the frequency of ex20ins variants, and the ability of polymerase chain reaction (PCR) and nextgeneration sequencing (NGS) to identify them. Three real-world United States NGS databases were used: GENIE, FoundationInsights, and GuardantINFORM. Mutation profiles consistent with in-frame EGFR ex20ins were summarized. GENIE, FoundationInsights, and Guardant-INFORM datasets identified 180, 627, and 627 patients with EGFR ex20ins respectively. The most frequent insertion region of exon 20 was the near loop (~70%), followed by the far loop (~30%) and the helical (~3-6%) regions. GENIE, FoundationInsights, and GuardantINFORM datasets identified 41, 102, and 96 unique variants respectively. An analysis of variants projected that ~50% of EGFR ex20ins identified by NGS would have been missed by PCR-based assays. Given the breadth of EGFR ex20ins identified in the real-world US datasets, the ability of PCR to identify these mutations is limited. NGS platforms are more appropriate to identify patients likely to benefit from EGFR ex20ins-targeted therapies.

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Section: Discussionsupporting

confidence: 88%

Frequency, underdiagnosis, and heterogeneity of epidermal growth factor receptor exon 20 insertion mutations using real‐world genomic datasets

Viteri¹,

Minchom

Bazhenova

et al. 2022

Molecular Oncology

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“…Insertional mutations, that is, mutations in the DNA strand caused by the insertion of additional nucleotides or DNA fragments [ 30 ]. Insertion mutations occur from time to time, and in humans, exon 20 insertion mutations lead to an increased prevalence of non-small-cell lung cancer (NSCLC) [ 31 ]; in the medaka fish ( Oryzias latipes ), intra-exon insertion of an additional 1.9 kb fragment resulted in oculocutaneous albinism [ 32 ]; in human neonatal fetuses, we found that FGFR3 insertions resulted in shortened extremities, curved femurs, and narrowed thorax. This mutation also leads to overexpression of Fgfr3 in zebrafish, resulting in downstream signaling and overactivation of the dorsal embryo [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of Male-Specific Molecular Markers by Recombination of RhoGEF10 Gene in Spotted Knifejaw (Oplegnathus punctatus)

Xiao

et al. 2022

Genes

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The spotted knifejaw (Oplegnathus punctatus) is a marine economic fish with high ecological value, food value, and fishing value, and its growth has obvious sex dimorphism. The rapid identification of its sex is beneficial to the development of sex determination and breeding. In this study, the method of comparative genomics and PCR amplification was used to further establish a rapid detection method for the recombinant RhoGEF10 gene in O. punctatus, which can quickly, accurately, and efficiently identify the sex of the O. punctatus to be tested. The homologous comparison results of male and female individuals showed that the DNA fragment length of the RhoGEF10 gene on the X1 chromosome was 326 bp, and the DNA fragment length on the Y chromosome was 879 bp. Therefore, it can be concluded that there is an insert fragment of 553 bp on the Y chromosome. PCR amplification results showed that the two DNA fragments of 879 bp and 326 bp were amplified in the Y chromosome and X1 chromosome of the male O. punctatus (X1X2Y), respectively, and the 879 bp fragment was a unique marker fragment of the recombinant RhoGEF10 gene; The female O. punctatus (X1X1X2X2) only a single DNA fragment of 326 bp was amplified. At the same time, the inserted fragment of the male individual resulted in partial inactivation of the RhoGEF10 protein, which in turn resulted in a slowing of peripheral nerve conduction velocity and thinning of the myelin sheath in male O. punctatus. The method shortens the time for accurate identification of the O. punctatus RhoGEF10 gene recombination and improves the detection efficiency. It is of great significance and application value in the research of nerve conduction and myelin development, male and female sex identification, the preparation of high male seedlings, and family selection based on the RhoGEF10 gene in the O. punctatus.

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“…Preclinical studies suggested that CLN-081 was a more selective inhibitor in comparison with poziotinib and osimertinib in vitro [53]. A multicenter, phase I/IIa trial accessed 73 evaluable patients and the interim results revealed an ORR of 38.4% (28/73),a DCR of 95.9% (70/73), and a median PFS of 10 months (6)(7)(8)(9)(10)(11)(12). Of note, CLN-081 presented encouraging efficacy in patients who received prior EGFR exon 20 insertion inhibitors, as two patients obtained partial response and two patients obtained stable disease.…”

Section: Cln-081 (Tas6417)mentioning

confidence: 99%

Targeting exon 20 insertion mutations in lung cancer

Yang

Wang

2022

Current Opinion in Oncology

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Purpose of reviewThe application of tyrosine kinase inhibitor (TKI) has successfully changed the standard of care in epidermal growth factor receptor (EGFR) positive non-small cell lung cancer. However, clinical survivals for patients with EGFR exon 20 insertions have failed to improve over the long period and the mutation appeared resistant to EGFR-TKIs. This overview focused on the current treatment strategies, summarized the emerging regimens for patients with EGFR exon 20 insertions, and demonstrated historical challenges and future development.Recent findingCurrent clinical trials suggested that several regimens selectively-targeted EGFR exon 20 insertions presented potent antitumor activity, like mobocertinib and the bispecific anti-EGFR-MET monoclonal antibody amivantamab and were approved by Food and Drug Administration (FDA) in patients progressed beyond first-line treatment. Novel treatments, including DZD9008, CLN-081, revealed modest clinical efficacy as well and clinical trials are underway, which may lead to improvement of survival outcomes.SummaryRecent clinical evidence indicates that targeted therapies could improve survival benefits to some extent. More efforts on drug development are underway to bring higher response rates both extracranial and intracranial, sustained clinical remission, and better survival benefits.

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Prevalence of Epidermal Growth Factor Receptor Exon 20 Insertion Mutations in Non-small-Cell Lung Cancer in Europe: A Pragmatic Literature Review and Meta-analysis

Cited by 17 publications

References 34 publications

Frequency, underdiagnosis, and heterogeneity of epidermal growth factor receptor exon 20 insertion mutations using real‐world genomic datasets

Frequency, underdiagnosis, and heterogeneity of epidermal growth factor receptor exon 20 insertion mutations using real‐world genomic datasets

Identification of Male-Specific Molecular Markers by Recombination of RhoGEF10 Gene in Spotted Knifejaw (Oplegnathus punctatus)

Targeting exon 20 insertion mutations in lung cancer

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