PTEN is a predictive biomarker of trastuzumab resistance and prognostic factor in HER2-overexpressing gastroesophageal adenocarcinoma

Abstract Poor trastuzumab (Tmab) response of patients with human epidermal growth factor receptor 2-overexpressing gastric or gastroesophageal junction adenocarcinoma (HER2-GEA) is associated with the inhibition of phosphatase and tensin homolog (PTEN) expression. In this multicenter, retrospective...

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Autores principales:	Daiju Yokoyama, Shigeo Hisamori, Yasunori Deguchi, Tatsuto Nishigori, Hiroshi Okabe, Seiichiro Kanaya, Dai Manaka, Yoshio Kadokawa, Hiroaki Hata, Sachiko Minamiguchi, Shigeru Tsunoda, Kazutaka Obama, Yoshiharu Sakai
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/af698eef3b3f4acea1b3b7bfb6a09a48
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spelling	oai:doaj.org-article:af698eef3b3f4acea1b3b7bfb6a09a482021-12-02T13:40:50ZPTEN is a predictive biomarker of trastuzumab resistance and prognostic factor in HER2-overexpressing gastroesophageal adenocarcinoma10.1038/s41598-021-88331-32045-2322https://doaj.org/article/af698eef3b3f4acea1b3b7bfb6a09a482021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88331-3https://doaj.org/toc/2045-2322Abstract Poor trastuzumab (Tmab) response of patients with human epidermal growth factor receptor 2-overexpressing gastric or gastroesophageal junction adenocarcinoma (HER2-GEA) is associated with the inhibition of phosphatase and tensin homolog (PTEN) expression. In this multicenter, retrospective observational study, pathological samples of patients with HER2-GEA receiving Tmab-combined chemotherapy were immunohistochemically analyzed for PTEN expression. The primary endpoints were disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). We assessed the effect of conventional chemotherapy and Tmab alone or combined with PI3K pathway inhibitors in vitro in HER2-GEA cells with or without PTEN expression. Twenty-nine and 116 patients were in the PTEN-loss and PTEN-positive groups, respectively. In patients with the target region, DCR was significantly lower in PTEN-loss patients than in PTEN-positive patients (67% and 87%, respectively, p = 0.049). The multivariate analysis demonstrated that PTEN loss was significantly associated with shorter PFS (HR = 1.63, p = 0.035) and OS (HR = 1.83, p = 0.022). PTEN knockdown did not affect the cytostatic effect of 5-FU and cisplatin, whereas Tmab combined with the PI3K/mTOR inhibitor NPV-BEZ235 suppressed PTEN-knockdown cell proliferation. In patients with HER2-GEA, PTEN loss is a predictive biomarker of Tmab resistance and prognostic factor. Molecular-targeted therapy with a PI3K/mTOR inhibitor would be effective for HER2-GEA with PTEN loss.Daiju YokoyamaShigeo HisamoriYasunori DeguchiTatsuto NishigoriHiroshi OkabeSeiichiro KanayaDai ManakaYoshio KadokawaHiroaki HataSachiko MinamiguchiShigeru TsunodaKazutaka ObamaYoshiharu SakaiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Daiju Yokoyama Shigeo Hisamori Yasunori Deguchi Tatsuto Nishigori Hiroshi Okabe Seiichiro Kanaya Dai Manaka Yoshio Kadokawa Hiroaki Hata Sachiko Minamiguchi Shigeru Tsunoda Kazutaka Obama Yoshiharu Sakai PTEN is a predictive biomarker of trastuzumab resistance and prognostic factor in HER2-overexpressing gastroesophageal adenocarcinoma
description	Abstract Poor trastuzumab (Tmab) response of patients with human epidermal growth factor receptor 2-overexpressing gastric or gastroesophageal junction adenocarcinoma (HER2-GEA) is associated with the inhibition of phosphatase and tensin homolog (PTEN) expression. In this multicenter, retrospective observational study, pathological samples of patients with HER2-GEA receiving Tmab-combined chemotherapy were immunohistochemically analyzed for PTEN expression. The primary endpoints were disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). We assessed the effect of conventional chemotherapy and Tmab alone or combined with PI3K pathway inhibitors in vitro in HER2-GEA cells with or without PTEN expression. Twenty-nine and 116 patients were in the PTEN-loss and PTEN-positive groups, respectively. In patients with the target region, DCR was significantly lower in PTEN-loss patients than in PTEN-positive patients (67% and 87%, respectively, p = 0.049). The multivariate analysis demonstrated that PTEN loss was significantly associated with shorter PFS (HR = 1.63, p = 0.035) and OS (HR = 1.83, p = 0.022). PTEN knockdown did not affect the cytostatic effect of 5-FU and cisplatin, whereas Tmab combined with the PI3K/mTOR inhibitor NPV-BEZ235 suppressed PTEN-knockdown cell proliferation. In patients with HER2-GEA, PTEN loss is a predictive biomarker of Tmab resistance and prognostic factor. Molecular-targeted therapy with a PI3K/mTOR inhibitor would be effective for HER2-GEA with PTEN loss.
format	article
author	Daiju Yokoyama Shigeo Hisamori Yasunori Deguchi Tatsuto Nishigori Hiroshi Okabe Seiichiro Kanaya Dai Manaka Yoshio Kadokawa Hiroaki Hata Sachiko Minamiguchi Shigeru Tsunoda Kazutaka Obama Yoshiharu Sakai
author_facet	Daiju Yokoyama Shigeo Hisamori Yasunori Deguchi Tatsuto Nishigori Hiroshi Okabe Seiichiro Kanaya Dai Manaka Yoshio Kadokawa Hiroaki Hata Sachiko Minamiguchi Shigeru Tsunoda Kazutaka Obama Yoshiharu Sakai
author_sort	Daiju Yokoyama
title	PTEN is a predictive biomarker of trastuzumab resistance and prognostic factor in HER2-overexpressing gastroesophageal adenocarcinoma
title_short	PTEN is a predictive biomarker of trastuzumab resistance and prognostic factor in HER2-overexpressing gastroesophageal adenocarcinoma
title_full	PTEN is a predictive biomarker of trastuzumab resistance and prognostic factor in HER2-overexpressing gastroesophageal adenocarcinoma
title_fullStr	PTEN is a predictive biomarker of trastuzumab resistance and prognostic factor in HER2-overexpressing gastroesophageal adenocarcinoma
title_full_unstemmed	PTEN is a predictive biomarker of trastuzumab resistance and prognostic factor in HER2-overexpressing gastroesophageal adenocarcinoma
title_sort	pten is a predictive biomarker of trastuzumab resistance and prognostic factor in her2-overexpressing gastroesophageal adenocarcinoma
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/af698eef3b3f4acea1b3b7bfb6a09a48
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PTEN is a predictive biomarker of trastuzumab resistance and prognostic factor in HER2-overexpressing gastroesophageal adenocarcinoma

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