EGFR Exon 19 Insertions: A New Family of Sensitizing EGFR Mutations in Lung Adenocarcinoma

Abstract

Purpose EGFR genotyping is now standard in the management of advanced lung adenocarcinoma, as this biomarker predicts marked benefit from treatment with EGFR tyrosine kinase inhibitors (TKIs). EGFR exon 19 insertions are a poorly described family of EGFR mutations, and their association with EGFR TKI-sensitivity in lung adenocarcinoma is uncertain. Experimental Design Patients with lung cancers harboring EGFR exon 19 insertions were studied. The predicted effects of the insertions on the structure of the EGFR protein were examined, and EGFR exon 19 insertions were introduced into Ba/F3 cells to assess oncogenicity and in vitro sensitivity to EGFR TKIs. In patients receiving TKI, response magnitude was assessed with serial computed tomography (CT) measurement. Results Twelve tumors harboring EGFR exon 19 insertions were identified; patients were predominately female (92%) and never-smokers (75%). The 11 specimens available for full sequencing all demonstrated an 18 bp insertion that resulted in the substitution of a Pro for Leu at residue 747. The mutant EGFR transformed the Ba/F3 cells, which were then sensitive to EGFR TKI. Six patients with measurable disease received TKI and 5 had a response on serial CT. Conclusions EGFR exon 19 insertions are a newly appreciated family of EGFR TKI-sensitizing mutations, and patients with tumors harboring these mutations should be treated with EGFR-TKI. While these mutations may be missed through the use of some mutation-specific assays, the addition of PCR product size analysis to multi-gene assays allows sensitive detection of both exon 19 insertion and deletion mutations.

BGB-283, a Novel RAF Kinase and EGFR Inhibitor, Displays Potent Antitumor Activity in BRAF-Mutated Colorectal Cancers

“…Ba/F3 cells normally grow in an IL3-dependent manner (29), but their growth can be rendered IL3 independent by overexpression of EGFR exon 19 deletion or EGFR L858R mutant (30,31). In accordance with its EGFR inhibition effect, BGB-283 was found to block the proliferation of Ba/F3 cells that express EGFR exon 19 deletion or EGFR L858R mutants, suggesting that BGB-283 could inhibit EGFR-driven cell proliferation (Table 2A and Supplementary Fig.…”

Liquid biopsy - emergence of a new era in personalized cancer care

“…L747 participates in a key hydrophobic core that stabilizes the inactive form of EGFR. Therefore, leucine to proline substitution would disfavor the formation of this hydrophobic core, thereby leading to constitutive activation of the mutant EGFR [55] and could explain resistance to EGFR inhibitor. Chabon and colleagues [56] performed CAPP-Seq cfDNA analysis from 2 to 4 ml of plasma to identify mechanisms responsible for resistance to a third-generation EGFR inhibitor, rociletinib, in NSCLC patients.…”

Actualización de las recomendaciones para la determinación de biomarcadores en el carcinoma de pulmón avanzado de célula no pequeña. Consenso Nacional de la Sociedad Española de Anatomía Patológica y de la Sociedad Española de Oncología Médica

“…Aunque existe una tendencia creciente hacia la extensiva caracterización molecular de los tumores, se recomienda informar de las mutaciones poco habituales de forma separada, con un comentario acerca de su poco clara o incierta significación clínica. Algunas publicaciones recientes pueden ayudar a entender el significado clínico de algunas de estas mutaciones raras 20,21 . con la sonda comercial Vysis ® ALK Break-Apart FISH Probe Kit (Abbott Molecular, Inc.), que recibió la aprobación como prueba acompañante del fármaco crizotinib 22 .…”