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Genomic Analyses for Predictors of Response to Chemoradiation in Stage III Non-Small Cell Lung Cancer

BACKGROUND: Radiation with platinum-based chemotherapy is the standard of care for unresectable stage III non-small cell lung cancer (NSCLC). Despite aggressive treatment, progression-free survival and overall survival remain poor. It is unclear whether any tumor genetic mutations are associated wit...

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Autores principales: Luo, Leo Y., Samstein, Robert M., Dick-Godfrey, Rosalind, Sidiqi, Baho, Wang, Chunyu, Oro, Federica, Sonnick, Mark, Paik, Paul K., Chaft, Jamie E., Shaverdian, Narek, Gomez, Daniel R., Rimner, Andreas, Wu, Abraham J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897765/
https://www.ncbi.nlm.nih.gov/pubmed/33665490
http://dx.doi.org/10.1016/j.adro.2020.10.027
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author Luo, Leo Y.
Samstein, Robert M.
Dick-Godfrey, Rosalind
Sidiqi, Baho
Wang, Chunyu
Oro, Federica
Sonnick, Mark
Paik, Paul K.
Chaft, Jamie E.
Shaverdian, Narek
Gomez, Daniel R.
Rimner, Andreas
Wu, Abraham J.
author_facet Luo, Leo Y.
Samstein, Robert M.
Dick-Godfrey, Rosalind
Sidiqi, Baho
Wang, Chunyu
Oro, Federica
Sonnick, Mark
Paik, Paul K.
Chaft, Jamie E.
Shaverdian, Narek
Gomez, Daniel R.
Rimner, Andreas
Wu, Abraham J.
author_sort Luo, Leo Y.
collection PubMed
description BACKGROUND: Radiation with platinum-based chemotherapy is the standard of care for unresectable stage III non-small cell lung cancer (NSCLC). Despite aggressive treatment, progression-free survival and overall survival remain poor. It is unclear whether any tumor genetic mutations are associated with response to chemoradiation therapy. METHODS: We retrospectively reviewed clinical outcomes of patients with stage III NSCLC treated with definitive radiation who had undergone tumor molecular profiling through a next-generation DNA sequencing platform. Cox proportional hazards model was used to investigate associations between clinical outcomes and genetic mutations detected by next-generation sequencing. RESULTS: 110 patients were identified with stage III NSCLC and underwent definitive radiation between 2013 and 2017 and tumor molecular profiling. Concurrent or sequential chemotherapy was given in 104 patients (95%). Unbiased genomic analyses revealed a significant association between AKT2 mutations and decreased local-regional tumor control and overall survival (hazard ratios [HR] 12.5 and 13.7, P = .003 and P = .003, respectively). Analyses restricted to loss-of-function mutations identified KMT2C and KMT2D deleterious mutations as negative prognostic factors for overall survival (HR 13.4 and 7.0, P < .001 and P < .001, respectively). Deleterious mutations in a panel of 38 DNA damage response and repair pathway genes were associated with improved local-regional control (HR 0.32, P = .049). CONCLUSIONS: This study coupled multiplexed targeted sequencing with clinical outcome and identified mutations in AKT2, KMT2C, and KMT2D as negative predictors of local-regional control and survival, and deleterious mutations in damage response and repair pathway genes were associated with improved local-regional disease control after chemoradiation therapy. These findings will require validation in a larger cohort of patients with prospectively collected and detailed clinical information.
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spelling pubmed-78977652021-03-03 Genomic Analyses for Predictors of Response to Chemoradiation in Stage III Non-Small Cell Lung Cancer Luo, Leo Y. Samstein, Robert M. Dick-Godfrey, Rosalind Sidiqi, Baho Wang, Chunyu Oro, Federica Sonnick, Mark Paik, Paul K. Chaft, Jamie E. Shaverdian, Narek Gomez, Daniel R. Rimner, Andreas Wu, Abraham J. Adv Radiat Oncol Scientific Article BACKGROUND: Radiation with platinum-based chemotherapy is the standard of care for unresectable stage III non-small cell lung cancer (NSCLC). Despite aggressive treatment, progression-free survival and overall survival remain poor. It is unclear whether any tumor genetic mutations are associated with response to chemoradiation therapy. METHODS: We retrospectively reviewed clinical outcomes of patients with stage III NSCLC treated with definitive radiation who had undergone tumor molecular profiling through a next-generation DNA sequencing platform. Cox proportional hazards model was used to investigate associations between clinical outcomes and genetic mutations detected by next-generation sequencing. RESULTS: 110 patients were identified with stage III NSCLC and underwent definitive radiation between 2013 and 2017 and tumor molecular profiling. Concurrent or sequential chemotherapy was given in 104 patients (95%). Unbiased genomic analyses revealed a significant association between AKT2 mutations and decreased local-regional tumor control and overall survival (hazard ratios [HR] 12.5 and 13.7, P = .003 and P = .003, respectively). Analyses restricted to loss-of-function mutations identified KMT2C and KMT2D deleterious mutations as negative prognostic factors for overall survival (HR 13.4 and 7.0, P < .001 and P < .001, respectively). Deleterious mutations in a panel of 38 DNA damage response and repair pathway genes were associated with improved local-regional control (HR 0.32, P = .049). CONCLUSIONS: This study coupled multiplexed targeted sequencing with clinical outcome and identified mutations in AKT2, KMT2C, and KMT2D as negative predictors of local-regional control and survival, and deleterious mutations in damage response and repair pathway genes were associated with improved local-regional disease control after chemoradiation therapy. These findings will require validation in a larger cohort of patients with prospectively collected and detailed clinical information. Elsevier 2020-11-14 /pmc/articles/PMC7897765/ /pubmed/33665490 http://dx.doi.org/10.1016/j.adro.2020.10.027 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Scientific Article
Luo, Leo Y.
Samstein, Robert M.
Dick-Godfrey, Rosalind
Sidiqi, Baho
Wang, Chunyu
Oro, Federica
Sonnick, Mark
Paik, Paul K.
Chaft, Jamie E.
Shaverdian, Narek
Gomez, Daniel R.
Rimner, Andreas
Wu, Abraham J.
Genomic Analyses for Predictors of Response to Chemoradiation in Stage III Non-Small Cell Lung Cancer
title Genomic Analyses for Predictors of Response to Chemoradiation in Stage III Non-Small Cell Lung Cancer
title_full Genomic Analyses for Predictors of Response to Chemoradiation in Stage III Non-Small Cell Lung Cancer
title_fullStr Genomic Analyses for Predictors of Response to Chemoradiation in Stage III Non-Small Cell Lung Cancer
title_full_unstemmed Genomic Analyses for Predictors of Response to Chemoradiation in Stage III Non-Small Cell Lung Cancer
title_short Genomic Analyses for Predictors of Response to Chemoradiation in Stage III Non-Small Cell Lung Cancer
title_sort genomic analyses for predictors of response to chemoradiation in stage iii non-small cell lung cancer
topic Scientific Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897765/
https://www.ncbi.nlm.nih.gov/pubmed/33665490
http://dx.doi.org/10.1016/j.adro.2020.10.027
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