Clinical Outcomes in Non–Small Cell Lung Cancers Harboring Different Exon 19 Deletions in EGFR

Chung, Kuei-Pin; Wu, Shang‐Gin; Wu, Jo‐Hsuan; Yang, James Chih‐Hsin; Yu, Chong‐Jen; Wei, Pin-Fei; Shih, Jin‐Yuan; Yang, Pan‐Chyr

doi:10.1158/1078-0432.ccr-11-2353

Cited by 62 publications

(71 citation statements)

References 28 publications

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“…17 Supporting the importance of this residue, exon 19 deletions that do not include a substitution at 747 have been found to have poorer outcomes when treated with TKI. 27 The lack of structural consistency among the exon 20 insertions may indicate a particularly varied biology among this family of mutations. Indeed, cell line studies have recently indicated that one variant of exon 20 insertions, A763_Y764insFQEA, is actually sensitive to treatment with erlotinib.…”

Section: Discussionmentioning

confidence: 99%

Natural History and Molecular Characteristics of Lung Cancers Harboring EGFR Exon 20 Insertions

Oxnard

Nishino

et al. 2013

Journal of Thoracic Oncology

284

244

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Introduction Exon 20 insertions are the third most common family of EGFR mutations found in non-small cell lung cancer (NSCLC). Little is known about cancers harboring these mutations aside from their lack of response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, impairing the development of effective targeted therapies. Methods NSCLC patients with EGFR genotyping were studied using an IRB-approved mechanism. Cancers with exon 20 insertions were indentified, sequences were characterized, and effectiveness of different treatment regimens was reviewed retrospectively. Clinical characteristics and survival were compared with cancers harboring common EGFR mutations and cancers with wild-type EGFR. Results 1086 patients underwent EGFR genotyping from 2004 to 2012. Twenty seven (2.5%) harbored exon 20 insertions, making up 9.2% of all cancers with documented EGFR mutations. Compared to wild-type cancers, those with exon 20 insertions were more commonly found in never-smokers and Asian patients. Insertion sequences were highly variable, with the most common variant (V769_D770insASV) making up only 22% of cases. Median survival of patients with exon 20 insertions was 16 months, similar to the survival of wild-type cancers and shorter than the survival of cancers with common EGFR mutations. Conclusions Patients with EGFR exon 20 insertions have similar clinical characteristics to those with common EGFR mutations but a poorer prognosis. The prevalence of this subset of NSCLC is similar to that of other genotype-defined subsets of lung adenocarcinoma (e.g. those with BRAF mutations, HER2 insertions, ROS1 rearrangements) and is a population of interest for trials of new targeted therapies.

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Section: Discussionmentioning

confidence: 99%

Natural History and Molecular Characteristics of Lung Cancers Harboring EGFR Exon 20 Insertions

Oxnard

Nishino

et al. 2013

Journal of Thoracic Oncology

284

244

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“…Most of the deletions in exon 19 encompass the amino acids from codons L747-750 (LRE fragment) which activate EGFR and respond to EGFR-TKI, while the other deletions which do not involve any of the LRE fragment are reported to have a worse response (2). This may be because that the LRE deletion mutation can significantly change the conformation of a protein in this region from the initial to the "active dimer" state and can keep the state longer (3).…”

Section: Discussionmentioning

confidence: 99%

Exon 19 L747P mutation presented as a primary resistance to EGFR-TKI: a case report

Wang¹,

Ning²,

Li³

et al. 2016

J. Thorac. Dis.

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Active mutations of the EGFR gene have been proved to predict the activity of EGFR-TKI. The most common mutations are the exon 19 deletion and exon 21 point mutation, both of which are sensitive to EGFR-TKI. However, rare EGFR mutations or complex mutations still exist, and data of which are scarce and controversial. Their response to EGFR-TKI remains uncertain. We presented a patient diagnosed with stage IV lung adenocarcinoma who was found to have the EGFR mutation in exon 19 (L747P) before any treatment. The disease progressed 2 months after the chemotherapy containing cisplatin and pemetrexed, and erlotinib was administered, but there was no response found. This EGFR-TKI naïve patient failed to achieve the desired effect with the therapy of EGFR-TKI. L747P may be associated with primary resistance to EGFR-TKI in this case.

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“…evaluated the phosphorylation of this mutation variant using a phospho‐Y1092‐specific antibody and an anti‐phosphotyrosine antibody; phosphorylation was at a low level compared to WT EGFR or L858R. Although it is unclear why only del747–752 is not as highly phosphorylated at Y1092, patients with del747–752 mutation benefit from EGFR‐TKI treatment . A possible hypothesis is that this EGFR mutation may be activated by heterodimerization with HER2 or human epidermal growth factor receptor type 3 (HER3).…”

Section: Discussionmentioning

confidence: 99%

Sensitivity and kinase activity of epidermal growth factor receptor (EGFR) exon 19 and others to EGFR‐tyrosine kinase inhibitors

et al. 2013

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The presence of epidermal growth factor receptor (EGFR) somatic mutations in non-small-cell lung cancer patients is associated with response to treatment with EGFR-tyrosine kinase inhibitors, such as gefitinib and erlotinib. More than 100 mutations in the kinase domain of EGFR have been identified. In particular there are many variations of deletion mutations in exon 19. In this study, using yellow fluorescent protein-tagged fragments of the EGFR intracellular domain, we examined the differences in sensitivity to gefitinib, erlotinib and afatinib between several exon 19 mutants and other common EGFR mutations. We also used serum of patients undergoing treatment with EGFR-tyrosine kinase inhibitors in this system. In addition, we examined the relative kinase activity of these mutants by measuring relative fluorescent intensity after immunofluorescence staining. We found that both sensitivity to EGFR-tyrosine kinase inhibitors and relative kinase activity differed among several EGFR mutations found in the same region of the kinase domain. This study underscores the importance of reporting the clinical outcome of treatment in relation to different EGFR mutations. (Cancer Sci 2013; 104: 584-589)

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Clinical Outcomes in Non–Small Cell Lung Cancers Harboring Different Exon 19 Deletions in EGFR

Cited by 62 publications

References 28 publications

Natural History and Molecular Characteristics of Lung Cancers Harboring EGFR Exon 20 Insertions

Natural History and Molecular Characteristics of Lung Cancers Harboring EGFR Exon 20 Insertions

Exon 19 L747P mutation presented as a primary resistance to EGFR-TKI: a case report

Sensitivity and kinase activity of epidermal growth factor receptor (EGFR) exon 19 and others to EGFR‐tyrosine kinase inhibitors

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