CDKN2A loss-of-function predicts immunotherapy resistance in non-small cell lung cancer

Abstract Immune checkpoint blockade (ICB) improves outcomes in non-small cell lung cancer (NSCLC) though most patients progress. There are limited data regarding molecular predictors of progression. In particular, there is controversy regarding the role of CDKN2A loss-of-function (LOF) in ICB resist...

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Autores principales:	Stanley I. Gutiontov, William Tyler Turchan, Liam F. Spurr, Sherin J. Rouhani, Carolina Soto Chervin, George Steinhardt, Angela M. Lager, Pankhuri Wanjari, Renuka Malik, Philip P. Connell, Steven J. Chmura, Aditya Juloori, Philip C. Hoffman, Mark K. Ferguson, Jessica S. Donington, Jyoti D. Patel, Everett E. Vokes, Ralph R. Weichselbaum, Christine M. Bestvina, Jeremy P. Segal, Sean P. Pitroda
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/82195ffa5c7b45b097938796d4698839
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spelling	oai:doaj.org-article:82195ffa5c7b45b097938796d46988392021-12-02T18:37:09ZCDKN2A loss-of-function predicts immunotherapy resistance in non-small cell lung cancer10.1038/s41598-021-99524-12045-2322https://doaj.org/article/82195ffa5c7b45b097938796d46988392021-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-99524-1https://doaj.org/toc/2045-2322Abstract Immune checkpoint blockade (ICB) improves outcomes in non-small cell lung cancer (NSCLC) though most patients progress. There are limited data regarding molecular predictors of progression. In particular, there is controversy regarding the role of CDKN2A loss-of-function (LOF) in ICB resistance. We analyzed 139 consecutive patients with advanced NSCLC who underwent NGS prior to ICB initiation to explore the association of CDKN2A LOF with clinical outcomes. 73% were PD-L1 positive (≥ 1%). 48% exhibited high TMB (≥ 10 mutations/megabase). CDKN2A LOF was present in 26% of patients and was associated with inferior PFS (multivariate hazard ratio [MVA-HR] 1.66, 95% CI 1.02–2.63, p = 0.041) and OS (MVA-HR 2.08, 95% CI 1.21–3.49, p = 0.0087) when compared to wild-type (WT) patients. These findings held in patients with high TMB (median OS, LOF vs. WT 10.5 vs. 22.3 months; p = 0.069) and PD-L1 ≥ 50% (median OS, LOF vs. WT 11.1 vs. 24.2 months; p = 0.020), as well as in an independent dataset. CDKN2A LOF vs. WT tumors were twice as likely to experience disease progression following ICB (46% vs. 21%; p = 0.021). CDKN2A LOF negatively impacts clinical outcomes in advanced NSCLC treated with ICB, even in high PD-L1 and high TMB tumors. This novel finding should be prospectively validated and presents a potential therapeutic target.Stanley I. GutiontovWilliam Tyler TurchanLiam F. SpurrSherin J. RouhaniCarolina Soto ChervinGeorge SteinhardtAngela M. LagerPankhuri WanjariRenuka MalikPhilip P. ConnellSteven J. ChmuraAditya JulooriPhilip C. HoffmanMark K. FergusonJessica S. DoningtonJyoti D. PatelEverett E. VokesRalph R. WeichselbaumChristine M. BestvinaJeremy P. SegalSean P. PitrodaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Stanley I. Gutiontov William Tyler Turchan Liam F. Spurr Sherin J. Rouhani Carolina Soto Chervin George Steinhardt Angela M. Lager Pankhuri Wanjari Renuka Malik Philip P. Connell Steven J. Chmura Aditya Juloori Philip C. Hoffman Mark K. Ferguson Jessica S. Donington Jyoti D. Patel Everett E. Vokes Ralph R. Weichselbaum Christine M. Bestvina Jeremy P. Segal Sean P. Pitroda CDKN2A loss-of-function predicts immunotherapy resistance in non-small cell lung cancer
description	Abstract Immune checkpoint blockade (ICB) improves outcomes in non-small cell lung cancer (NSCLC) though most patients progress. There are limited data regarding molecular predictors of progression. In particular, there is controversy regarding the role of CDKN2A loss-of-function (LOF) in ICB resistance. We analyzed 139 consecutive patients with advanced NSCLC who underwent NGS prior to ICB initiation to explore the association of CDKN2A LOF with clinical outcomes. 73% were PD-L1 positive (≥ 1%). 48% exhibited high TMB (≥ 10 mutations/megabase). CDKN2A LOF was present in 26% of patients and was associated with inferior PFS (multivariate hazard ratio [MVA-HR] 1.66, 95% CI 1.02–2.63, p = 0.041) and OS (MVA-HR 2.08, 95% CI 1.21–3.49, p = 0.0087) when compared to wild-type (WT) patients. These findings held in patients with high TMB (median OS, LOF vs. WT 10.5 vs. 22.3 months; p = 0.069) and PD-L1 ≥ 50% (median OS, LOF vs. WT 11.1 vs. 24.2 months; p = 0.020), as well as in an independent dataset. CDKN2A LOF vs. WT tumors were twice as likely to experience disease progression following ICB (46% vs. 21%; p = 0.021). CDKN2A LOF negatively impacts clinical outcomes in advanced NSCLC treated with ICB, even in high PD-L1 and high TMB tumors. This novel finding should be prospectively validated and presents a potential therapeutic target.
format	article
author	Stanley I. Gutiontov William Tyler Turchan Liam F. Spurr Sherin J. Rouhani Carolina Soto Chervin George Steinhardt Angela M. Lager Pankhuri Wanjari Renuka Malik Philip P. Connell Steven J. Chmura Aditya Juloori Philip C. Hoffman Mark K. Ferguson Jessica S. Donington Jyoti D. Patel Everett E. Vokes Ralph R. Weichselbaum Christine M. Bestvina Jeremy P. Segal Sean P. Pitroda
author_facet	Stanley I. Gutiontov William Tyler Turchan Liam F. Spurr Sherin J. Rouhani Carolina Soto Chervin George Steinhardt Angela M. Lager Pankhuri Wanjari Renuka Malik Philip P. Connell Steven J. Chmura Aditya Juloori Philip C. Hoffman Mark K. Ferguson Jessica S. Donington Jyoti D. Patel Everett E. Vokes Ralph R. Weichselbaum Christine M. Bestvina Jeremy P. Segal Sean P. Pitroda
author_sort	Stanley I. Gutiontov
title	CDKN2A loss-of-function predicts immunotherapy resistance in non-small cell lung cancer
title_short	CDKN2A loss-of-function predicts immunotherapy resistance in non-small cell lung cancer
title_full	CDKN2A loss-of-function predicts immunotherapy resistance in non-small cell lung cancer
title_fullStr	CDKN2A loss-of-function predicts immunotherapy resistance in non-small cell lung cancer
title_full_unstemmed	CDKN2A loss-of-function predicts immunotherapy resistance in non-small cell lung cancer
title_sort	cdkn2a loss-of-function predicts immunotherapy resistance in non-small cell lung cancer
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/82195ffa5c7b45b097938796d4698839
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CDKN2A loss-of-function predicts immunotherapy resistance in non-small cell lung cancer

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