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High lymphocyte population-related predictive factors for a long-term response in non-small cell lung cancer patients treated with pemetrexed: a retrospective observational study

BACKGROUND: Regimens combining pemetrexed (PEM) and immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) or programmed death-ligand 1 (PD-L1) are widely used for the treatment of advanced non-squamous non-small-cell lung cancer (NSq-NSCLC). Recently, PEM was shown to induce i...

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Autores principales: Sumiyoshi, Issei, Okabe, Takahiro, Togo, Shinsaku, Takagi, Haruhi, Motomura, Hiroaki, Ochi, Yusuke, Shimada, Naoko, Haraguchi, Mizuki, Shibayama, Rina, Fujimoto, Yuichi, Watanabe, Junko, Iwai, Moe, Kadoya, Kotaro, Iwakami, Shin-ichiro, Takahashi, Kazuhisa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916269/
https://www.ncbi.nlm.nih.gov/pubmed/33639962
http://dx.doi.org/10.1186/s12967-021-02761-1
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author Sumiyoshi, Issei
Okabe, Takahiro
Togo, Shinsaku
Takagi, Haruhi
Motomura, Hiroaki
Ochi, Yusuke
Shimada, Naoko
Haraguchi, Mizuki
Shibayama, Rina
Fujimoto, Yuichi
Watanabe, Junko
Iwai, Moe
Kadoya, Kotaro
Iwakami, Shin-ichiro
Takahashi, Kazuhisa
author_facet Sumiyoshi, Issei
Okabe, Takahiro
Togo, Shinsaku
Takagi, Haruhi
Motomura, Hiroaki
Ochi, Yusuke
Shimada, Naoko
Haraguchi, Mizuki
Shibayama, Rina
Fujimoto, Yuichi
Watanabe, Junko
Iwai, Moe
Kadoya, Kotaro
Iwakami, Shin-ichiro
Takahashi, Kazuhisa
author_sort Sumiyoshi, Issei
collection PubMed
description BACKGROUND: Regimens combining pemetrexed (PEM) and immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) or programmed death-ligand 1 (PD-L1) are widely used for the treatment of advanced non-squamous non-small-cell lung cancer (NSq-NSCLC). Recently, PEM was shown to induce immunogenic cell death (ICD) and to enhance immune-regulatory genes. Some patients demonstrate an extremely long-term response to PEM. It is possible that the continued response in these patients is dependent on not only the pharmacological induction of cytotoxic cell death but also antitumor immunity. However, factors that can predict outcomes associated with long-term PEM administration using blood test results have not yet been elucidated. We investigated the clinical characteristics and predictive factors in patients with advanced NSq-NSCLC who underwent long-term PEM maintenance therapy. METHODS: In total, 504 patients with advanced NSq-NSCLC who received PEM combination therapy/monotherapy (n = 414) or paclitaxel (PTX) combination therapy (n = 90) between January 2010 and November 2019 were recruited; 381 patients were retained for the final analysis. Patients treated with PEM (n = 301) were divided into subgroups according to the total cycles of PEM (≥ 17 [n = 25] for the long-term administration group and ≤ 16 [n = 276] for the intermediate/short-term group) and compared with another population (n = 80) treated with PTX combination regimen. We investigated clinical features and predictive biomarkers, focusing on immune-regulatory factors, absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), and PD-1 and PD-L1 expression, to predict long-term response to PEM. RESULTS: The long-term PEM administration group exhibited a higher ALC and a lower NLR than the shorter-term group did. Both these markers displayed greater association with progression-free survival and overall survival in the PEM combination therapy group than in the PTX combination therapy group. Increased PD-1 lymphocytes were associated with the long-term PEM response group, as PD-L1 expression in tumors was associated with a high incidence of immune-related adverse effects following ICI administration. CONCLUSIONS: ALC, NLR, and PD-1 expression are PEM-mediated predictive biomarkers that are indirectly related to tumor immunity and can provide useful predictive information on the long-term response to PEM in patients with NSq-NSCLC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-021-02761-1.
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spelling pubmed-79162692021-03-02 High lymphocyte population-related predictive factors for a long-term response in non-small cell lung cancer patients treated with pemetrexed: a retrospective observational study Sumiyoshi, Issei Okabe, Takahiro Togo, Shinsaku Takagi, Haruhi Motomura, Hiroaki Ochi, Yusuke Shimada, Naoko Haraguchi, Mizuki Shibayama, Rina Fujimoto, Yuichi Watanabe, Junko Iwai, Moe Kadoya, Kotaro Iwakami, Shin-ichiro Takahashi, Kazuhisa J Transl Med Research BACKGROUND: Regimens combining pemetrexed (PEM) and immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) or programmed death-ligand 1 (PD-L1) are widely used for the treatment of advanced non-squamous non-small-cell lung cancer (NSq-NSCLC). Recently, PEM was shown to induce immunogenic cell death (ICD) and to enhance immune-regulatory genes. Some patients demonstrate an extremely long-term response to PEM. It is possible that the continued response in these patients is dependent on not only the pharmacological induction of cytotoxic cell death but also antitumor immunity. However, factors that can predict outcomes associated with long-term PEM administration using blood test results have not yet been elucidated. We investigated the clinical characteristics and predictive factors in patients with advanced NSq-NSCLC who underwent long-term PEM maintenance therapy. METHODS: In total, 504 patients with advanced NSq-NSCLC who received PEM combination therapy/monotherapy (n = 414) or paclitaxel (PTX) combination therapy (n = 90) between January 2010 and November 2019 were recruited; 381 patients were retained for the final analysis. Patients treated with PEM (n = 301) were divided into subgroups according to the total cycles of PEM (≥ 17 [n = 25] for the long-term administration group and ≤ 16 [n = 276] for the intermediate/short-term group) and compared with another population (n = 80) treated with PTX combination regimen. We investigated clinical features and predictive biomarkers, focusing on immune-regulatory factors, absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), and PD-1 and PD-L1 expression, to predict long-term response to PEM. RESULTS: The long-term PEM administration group exhibited a higher ALC and a lower NLR than the shorter-term group did. Both these markers displayed greater association with progression-free survival and overall survival in the PEM combination therapy group than in the PTX combination therapy group. Increased PD-1 lymphocytes were associated with the long-term PEM response group, as PD-L1 expression in tumors was associated with a high incidence of immune-related adverse effects following ICI administration. CONCLUSIONS: ALC, NLR, and PD-1 expression are PEM-mediated predictive biomarkers that are indirectly related to tumor immunity and can provide useful predictive information on the long-term response to PEM in patients with NSq-NSCLC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-021-02761-1. BioMed Central 2021-02-28 /pmc/articles/PMC7916269/ /pubmed/33639962 http://dx.doi.org/10.1186/s12967-021-02761-1 Text en © The Author(s) 2021 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Sumiyoshi, Issei
Okabe, Takahiro
Togo, Shinsaku
Takagi, Haruhi
Motomura, Hiroaki
Ochi, Yusuke
Shimada, Naoko
Haraguchi, Mizuki
Shibayama, Rina
Fujimoto, Yuichi
Watanabe, Junko
Iwai, Moe
Kadoya, Kotaro
Iwakami, Shin-ichiro
Takahashi, Kazuhisa
High lymphocyte population-related predictive factors for a long-term response in non-small cell lung cancer patients treated with pemetrexed: a retrospective observational study
title High lymphocyte population-related predictive factors for a long-term response in non-small cell lung cancer patients treated with pemetrexed: a retrospective observational study
title_full High lymphocyte population-related predictive factors for a long-term response in non-small cell lung cancer patients treated with pemetrexed: a retrospective observational study
title_fullStr High lymphocyte population-related predictive factors for a long-term response in non-small cell lung cancer patients treated with pemetrexed: a retrospective observational study
title_full_unstemmed High lymphocyte population-related predictive factors for a long-term response in non-small cell lung cancer patients treated with pemetrexed: a retrospective observational study
title_short High lymphocyte population-related predictive factors for a long-term response in non-small cell lung cancer patients treated with pemetrexed: a retrospective observational study
title_sort high lymphocyte population-related predictive factors for a long-term response in non-small cell lung cancer patients treated with pemetrexed: a retrospective observational study
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916269/
https://www.ncbi.nlm.nih.gov/pubmed/33639962
http://dx.doi.org/10.1186/s12967-021-02761-1
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