Large‐scale genomic sequencing reveals adaptive opportunity of targeting mutated‐PI3Kα in early and advanced HER2‐positive breast cancer

Abstract Background Few studies have discussed the contradictory roles of mutated‐PI3Kα in HER2‐positive (HER2+) breast cancer. Thus, we characterised the adaptive roles of PI3Kα mutations among HER2+ tumour progression. Methods We conducted prospective clinical sequencing of 1923 Chinese breast can...

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Autores principales:	Lin‐Wei Guo, Xiao‐Guang Li, Yun‐Song Yang, Xun‐Xi Lu, Xiang‐Chen Han, Guan‐Tian Lang, Li Chen, Zhi‐Ming Shao, Xin Hu
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	early and advanced HER2‐positive breast cancer library screening prospective sequencing shifty PI3Kα treatment strategy Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/95e5f690bc48412b8e7f6cd96e0d6269
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spelling	oai:doaj.org-article:95e5f690bc48412b8e7f6cd96e0d62692021-11-30T07:25:38ZLarge‐scale genomic sequencing reveals adaptive opportunity of targeting mutated‐PI3Kα in early and advanced HER2‐positive breast cancer2001-132610.1002/ctm2.589https://doaj.org/article/95e5f690bc48412b8e7f6cd96e0d62692021-11-01T00:00:00Zhttps://doi.org/10.1002/ctm2.589https://doaj.org/toc/2001-1326Abstract Background Few studies have discussed the contradictory roles of mutated‐PI3Kα in HER2‐positive (HER2+) breast cancer. Thus, we characterised the adaptive roles of PI3Kα mutations among HER2+ tumour progression. Methods We conducted prospective clinical sequencing of 1923 Chinese breast cancer patients and illustrated the clinical significance of PIK3CA mutations in locally advanced and advanced HER2+ cohort. A high‐throughput PIK3CA mutations‐barcoding screen was performed to reveal impactful mutation sites in tumour growth and drug responses. Results PIK3CA mutations acted as a protective factor in treatment‐naïve patients; however, advanced/locally advanced patients harbouring mutated‐PI3Kα exhibited a higher progressive disease rate (100% vs. 15%, p = .000053) and a lower objective response rate (81.7% vs. 95.4%, p = .0008) in response to trastuzumab‐based therapy. Meanwhile, patients exhibiting anti‐HER2 resistance had a relatively high variant allele fraction (VAF) of PIK3CA mutations; we defined the VAF > 12.23% as a predictor of poor anti‐HER2 neoadjuvant treatment efficacy. Pooled mutations screen revealed that specific PI3Kα mutation alleles mediated own biological effects. PIK3CA functional mutations suppressed the growth of HER2+ cells, but conferred anti‐HER2 resistance, which can be reversed by the PI3Kα‐specific inhibitor BYL719. Conclusions We proposed adaptive treatment strategies that the mutated PIK3CA and amplified ERBB2 should be concomitantly inhibited when exposing to continuous anti‐HER2 therapy, while the combination of anti‐HER2 and anti‐PI3Kα treatment was not essential for anti‐HER2 treatment‐naïve patients. These findings improve the understanding of genomics‐guided treatment in the different progressions of HER2+ breast cancer.Lin‐Wei GuoXiao‐Guang LiYun‐Song YangXun‐Xi LuXiang‐Chen HanGuan‐Tian LangLi ChenZhi‐Ming ShaoXin HuWileyarticleearly and advanced HER2‐positive breast cancerlibrary screeningprospective sequencingshifty PI3Kα treatment strategyMedicine (General)R5-920ENClinical and Translational Medicine, Vol 11, Iss 11, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	early and advanced HER2‐positive breast cancer library screening prospective sequencing shifty PI3Kα treatment strategy Medicine (General) R5-920
spellingShingle	early and advanced HER2‐positive breast cancer library screening prospective sequencing shifty PI3Kα treatment strategy Medicine (General) R5-920 Lin‐Wei Guo Xiao‐Guang Li Yun‐Song Yang Xun‐Xi Lu Xiang‐Chen Han Guan‐Tian Lang Li Chen Zhi‐Ming Shao Xin Hu Large‐scale genomic sequencing reveals adaptive opportunity of targeting mutated‐PI3Kα in early and advanced HER2‐positive breast cancer
description	Abstract Background Few studies have discussed the contradictory roles of mutated‐PI3Kα in HER2‐positive (HER2+) breast cancer. Thus, we characterised the adaptive roles of PI3Kα mutations among HER2+ tumour progression. Methods We conducted prospective clinical sequencing of 1923 Chinese breast cancer patients and illustrated the clinical significance of PIK3CA mutations in locally advanced and advanced HER2+ cohort. A high‐throughput PIK3CA mutations‐barcoding screen was performed to reveal impactful mutation sites in tumour growth and drug responses. Results PIK3CA mutations acted as a protective factor in treatment‐naïve patients; however, advanced/locally advanced patients harbouring mutated‐PI3Kα exhibited a higher progressive disease rate (100% vs. 15%, p = .000053) and a lower objective response rate (81.7% vs. 95.4%, p = .0008) in response to trastuzumab‐based therapy. Meanwhile, patients exhibiting anti‐HER2 resistance had a relatively high variant allele fraction (VAF) of PIK3CA mutations; we defined the VAF > 12.23% as a predictor of poor anti‐HER2 neoadjuvant treatment efficacy. Pooled mutations screen revealed that specific PI3Kα mutation alleles mediated own biological effects. PIK3CA functional mutations suppressed the growth of HER2+ cells, but conferred anti‐HER2 resistance, which can be reversed by the PI3Kα‐specific inhibitor BYL719. Conclusions We proposed adaptive treatment strategies that the mutated PIK3CA and amplified ERBB2 should be concomitantly inhibited when exposing to continuous anti‐HER2 therapy, while the combination of anti‐HER2 and anti‐PI3Kα treatment was not essential for anti‐HER2 treatment‐naïve patients. These findings improve the understanding of genomics‐guided treatment in the different progressions of HER2+ breast cancer.
format	article
author	Lin‐Wei Guo Xiao‐Guang Li Yun‐Song Yang Xun‐Xi Lu Xiang‐Chen Han Guan‐Tian Lang Li Chen Zhi‐Ming Shao Xin Hu
author_facet	Lin‐Wei Guo Xiao‐Guang Li Yun‐Song Yang Xun‐Xi Lu Xiang‐Chen Han Guan‐Tian Lang Li Chen Zhi‐Ming Shao Xin Hu
author_sort	Lin‐Wei Guo
title	Large‐scale genomic sequencing reveals adaptive opportunity of targeting mutated‐PI3Kα in early and advanced HER2‐positive breast cancer
title_short	Large‐scale genomic sequencing reveals adaptive opportunity of targeting mutated‐PI3Kα in early and advanced HER2‐positive breast cancer
title_full	Large‐scale genomic sequencing reveals adaptive opportunity of targeting mutated‐PI3Kα in early and advanced HER2‐positive breast cancer
title_fullStr	Large‐scale genomic sequencing reveals adaptive opportunity of targeting mutated‐PI3Kα in early and advanced HER2‐positive breast cancer
title_full_unstemmed	Large‐scale genomic sequencing reveals adaptive opportunity of targeting mutated‐PI3Kα in early and advanced HER2‐positive breast cancer
title_sort	large‐scale genomic sequencing reveals adaptive opportunity of targeting mutated‐pi3kα in early and advanced her2‐positive breast cancer
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/95e5f690bc48412b8e7f6cd96e0d6269
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Large‐scale genomic sequencing reveals adaptive opportunity of targeting mutated‐PI3Kα in early and advanced HER2‐positive breast cancer

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