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BRCA1 Expression and Outcome in Patients With EGFR-Mutant NSCLC Treated With Gefitinib Alone or in Combination With Olaparib
INTRODUCTION: DNA repair capacity, as exemplified by BRCA1 gene expression, is related with outcome to EGFR tyrosine kinase inhibitors in patients with EGFR-mutant NSCLC. Olaparib, a PARP inhibitor, reduces BRCA1 expression. Olaparib was tested in combination with gefitinib versus gefitinib single a...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474244/ https://www.ncbi.nlm.nih.gov/pubmed/34589994 http://dx.doi.org/10.1016/j.jtocrr.2020.100113 |
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author | Karachaliou, Niki Arrieta, Oscar Giménez-Capitán, Ana Aldeguer, Erika Drozdowskyj, Ana Chaib, Imane Reguart, Noemí Garcia-Campelo, Rosario Chen, Jing-Hua Molina-Vila, Miguel Angel Rosell, Rafael |
author_facet | Karachaliou, Niki Arrieta, Oscar Giménez-Capitán, Ana Aldeguer, Erika Drozdowskyj, Ana Chaib, Imane Reguart, Noemí Garcia-Campelo, Rosario Chen, Jing-Hua Molina-Vila, Miguel Angel Rosell, Rafael |
author_sort | Karachaliou, Niki |
collection | PubMed |
description | INTRODUCTION: DNA repair capacity, as exemplified by BRCA1 gene expression, is related with outcome to EGFR tyrosine kinase inhibitors in patients with EGFR-mutant NSCLC. Olaparib, a PARP inhibitor, reduces BRCA1 expression. Olaparib was tested in combination with gefitinib versus gefitinib single agent, as a first-line therapy for patients with EGFR-mutant NSCLC in the GOAL study (trial registration: NCT01513174). Here, we report the results of the biomarker-related prespecified secondary objectives of the GOAL study. METHODS: We evaluated the impact of BRCA1 mRNA expression in 91 patients with EGFR-mutant NSCLC. Of those 91 patients, 51 were randomized to treatment with gefitinib and 40 were randomized to treatment with gefitinib plus olaparib. We explored in vitro whether BRCA1 mRNA levels are related with outcome to gefitinib plus olaparib. The expression levels of 53BP1, CtIP, and AXL were also explored and correlated with the treatment outcome. RESULTS: Overall, as what happened in the GOAL study, no statistically significant difference was observed in median progression-free survival (PFS) between the two treatment arms, for the 91 patients of the present study (p = 0.2419). For patients with high BRCA1 mRNA expression (BRCA1-high group), median PFS was 12.9 months in the gefitinib plus olaparib arm, compared with 9.2 months in the gefitinib arm (p = 0.0449). In the gefitinib arm, median PFS was 9.1 months for the BRCA1-high group and 10.2 months for the BRCA1-low group (p = 0.0193). We observed a more pronounced synergism of gefitinib plus olaparib in cells with higher BRCA1 compared with those with low BRCA1 mRNA expression. CONCLUSIONS: High BRCA1 mRNA expression identified patients with NSCLC who benefited from gefitinib plus olaparib in the GOAL phase 2 clinical trial. |
format | Online Article Text |
id | pubmed-8474244 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-84742442021-09-28 BRCA1 Expression and Outcome in Patients With EGFR-Mutant NSCLC Treated With Gefitinib Alone or in Combination With Olaparib Karachaliou, Niki Arrieta, Oscar Giménez-Capitán, Ana Aldeguer, Erika Drozdowskyj, Ana Chaib, Imane Reguart, Noemí Garcia-Campelo, Rosario Chen, Jing-Hua Molina-Vila, Miguel Angel Rosell, Rafael JTO Clin Res Rep Original Article INTRODUCTION: DNA repair capacity, as exemplified by BRCA1 gene expression, is related with outcome to EGFR tyrosine kinase inhibitors in patients with EGFR-mutant NSCLC. Olaparib, a PARP inhibitor, reduces BRCA1 expression. Olaparib was tested in combination with gefitinib versus gefitinib single agent, as a first-line therapy for patients with EGFR-mutant NSCLC in the GOAL study (trial registration: NCT01513174). Here, we report the results of the biomarker-related prespecified secondary objectives of the GOAL study. METHODS: We evaluated the impact of BRCA1 mRNA expression in 91 patients with EGFR-mutant NSCLC. Of those 91 patients, 51 were randomized to treatment with gefitinib and 40 were randomized to treatment with gefitinib plus olaparib. We explored in vitro whether BRCA1 mRNA levels are related with outcome to gefitinib plus olaparib. The expression levels of 53BP1, CtIP, and AXL were also explored and correlated with the treatment outcome. RESULTS: Overall, as what happened in the GOAL study, no statistically significant difference was observed in median progression-free survival (PFS) between the two treatment arms, for the 91 patients of the present study (p = 0.2419). For patients with high BRCA1 mRNA expression (BRCA1-high group), median PFS was 12.9 months in the gefitinib plus olaparib arm, compared with 9.2 months in the gefitinib arm (p = 0.0449). In the gefitinib arm, median PFS was 9.1 months for the BRCA1-high group and 10.2 months for the BRCA1-low group (p = 0.0193). We observed a more pronounced synergism of gefitinib plus olaparib in cells with higher BRCA1 compared with those with low BRCA1 mRNA expression. CONCLUSIONS: High BRCA1 mRNA expression identified patients with NSCLC who benefited from gefitinib plus olaparib in the GOAL phase 2 clinical trial. Elsevier 2020-10-23 /pmc/articles/PMC8474244/ /pubmed/34589994 http://dx.doi.org/10.1016/j.jtocrr.2020.100113 Text en © 2020 The Authors https://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 | Original Article Karachaliou, Niki Arrieta, Oscar Giménez-Capitán, Ana Aldeguer, Erika Drozdowskyj, Ana Chaib, Imane Reguart, Noemí Garcia-Campelo, Rosario Chen, Jing-Hua Molina-Vila, Miguel Angel Rosell, Rafael BRCA1 Expression and Outcome in Patients With EGFR-Mutant NSCLC Treated With Gefitinib Alone or in Combination With Olaparib |
title | BRCA1 Expression and Outcome in Patients With EGFR-Mutant NSCLC Treated With Gefitinib Alone or in Combination With Olaparib |
title_full | BRCA1 Expression and Outcome in Patients With EGFR-Mutant NSCLC Treated With Gefitinib Alone or in Combination With Olaparib |
title_fullStr | BRCA1 Expression and Outcome in Patients With EGFR-Mutant NSCLC Treated With Gefitinib Alone or in Combination With Olaparib |
title_full_unstemmed | BRCA1 Expression and Outcome in Patients With EGFR-Mutant NSCLC Treated With Gefitinib Alone or in Combination With Olaparib |
title_short | BRCA1 Expression and Outcome in Patients With EGFR-Mutant NSCLC Treated With Gefitinib Alone or in Combination With Olaparib |
title_sort | brca1 expression and outcome in patients with egfr-mutant nsclc treated with gefitinib alone or in combination with olaparib |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474244/ https://www.ncbi.nlm.nih.gov/pubmed/34589994 http://dx.doi.org/10.1016/j.jtocrr.2020.100113 |
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