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The Impact of Variant Allele Frequency in EGFR Mutated NSCLC Patients on Targeted Therapy

EGFR mutations represent the most common currently targetable oncogenic driver in non-small cell lung cancer. There has been tremendous progress in targeting this alteration over the course of the last decade, and third generation tyrosine kinase inhibitors offer previously unseen survival rates amo...

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Autores principales: Friedlaender, Alex, Tsantoulis, Petros, Chevallier, Mathieu, De Vito, Claudio, Addeo, Alfredo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044828/
https://www.ncbi.nlm.nih.gov/pubmed/33869038
http://dx.doi.org/10.3389/fonc.2021.644472
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author Friedlaender, Alex
Tsantoulis, Petros
Chevallier, Mathieu
De Vito, Claudio
Addeo, Alfredo
author_facet Friedlaender, Alex
Tsantoulis, Petros
Chevallier, Mathieu
De Vito, Claudio
Addeo, Alfredo
author_sort Friedlaender, Alex
collection PubMed
description EGFR mutations represent the most common currently targetable oncogenic driver in non-small cell lung cancer. There has been tremendous progress in targeting this alteration over the course of the last decade, and third generation tyrosine kinase inhibitors offer previously unseen survival rates among these patients. Nonetheless, a better understanding is still needed, as roughly a third of patients do not respond to targeted therapy and there is an important heterogeneity among responders. Allelic frequency, or the variant EGFR allele frequency, corresponds to the fraction of sequencing reads harboring the mutation. The allelic fraction is influenced by the proportion of tumor cells in the sample, the presence of copy number alterations but also, most importantly, by the proportion of cells within the tumor that carry the mutation. Mutations that occur early in tumor evolution, often called clonal or truncal, have a higher allelic frequency than late, subclonal mutations, and are more often drivers of cancer evolution and attractive therapeutic targets. Most, but not all, EGFR mutations are clonal. Although an exact estimate of clonal proportion is hard to derive computationally, the allelic frequency is readily available to clinicians and could be a useful surrogate. We hypothesized that tumors with low allelic frequency of the EGFR mutation will respond less favorably to targeted treatment.
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spelling pubmed-80448282021-04-15 The Impact of Variant Allele Frequency in EGFR Mutated NSCLC Patients on Targeted Therapy Friedlaender, Alex Tsantoulis, Petros Chevallier, Mathieu De Vito, Claudio Addeo, Alfredo Front Oncol Oncology EGFR mutations represent the most common currently targetable oncogenic driver in non-small cell lung cancer. There has been tremendous progress in targeting this alteration over the course of the last decade, and third generation tyrosine kinase inhibitors offer previously unseen survival rates among these patients. Nonetheless, a better understanding is still needed, as roughly a third of patients do not respond to targeted therapy and there is an important heterogeneity among responders. Allelic frequency, or the variant EGFR allele frequency, corresponds to the fraction of sequencing reads harboring the mutation. The allelic fraction is influenced by the proportion of tumor cells in the sample, the presence of copy number alterations but also, most importantly, by the proportion of cells within the tumor that carry the mutation. Mutations that occur early in tumor evolution, often called clonal or truncal, have a higher allelic frequency than late, subclonal mutations, and are more often drivers of cancer evolution and attractive therapeutic targets. Most, but not all, EGFR mutations are clonal. Although an exact estimate of clonal proportion is hard to derive computationally, the allelic frequency is readily available to clinicians and could be a useful surrogate. We hypothesized that tumors with low allelic frequency of the EGFR mutation will respond less favorably to targeted treatment. Frontiers Media S.A. 2021-03-30 /pmc/articles/PMC8044828/ /pubmed/33869038 http://dx.doi.org/10.3389/fonc.2021.644472 Text en Copyright © 2021 Friedlaender, Tsantoulis, Chevallier, De Vito and Addeo https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Friedlaender, Alex
Tsantoulis, Petros
Chevallier, Mathieu
De Vito, Claudio
Addeo, Alfredo
The Impact of Variant Allele Frequency in EGFR Mutated NSCLC Patients on Targeted Therapy
title The Impact of Variant Allele Frequency in EGFR Mutated NSCLC Patients on Targeted Therapy
title_full The Impact of Variant Allele Frequency in EGFR Mutated NSCLC Patients on Targeted Therapy
title_fullStr The Impact of Variant Allele Frequency in EGFR Mutated NSCLC Patients on Targeted Therapy
title_full_unstemmed The Impact of Variant Allele Frequency in EGFR Mutated NSCLC Patients on Targeted Therapy
title_short The Impact of Variant Allele Frequency in EGFR Mutated NSCLC Patients on Targeted Therapy
title_sort impact of variant allele frequency in egfr mutated nsclc patients on targeted therapy
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044828/
https://www.ncbi.nlm.nih.gov/pubmed/33869038
http://dx.doi.org/10.3389/fonc.2021.644472
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