The temporal mutational and immune tumour microenvironment remodelling of HER2-negative primary breast cancers

Abstract The biology of breast cancer response to neoadjuvant therapy is underrepresented in the literature and provides a window-of-opportunity to explore the genomic and microenvironment modulation of tumours exposed to therapy. Here, we characterised the mutational, gene expression, pathway enric...

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Autores principales: Leticia De Mattos-Arruda, Javier Cortes, Juan Blanco-Heredia, Daniel G. Tiezzi, Guillermo Villacampa, Samuel Gonçalves-Ribeiro, Laia Paré, Carla Anjos Souza, Vanesa Ortega, Stephen-John Sammut, Pol Cusco, Roberta Fasani, Suet-Feung Chin, Jose Perez-Garcia, Rodrigo Dienstmann, Paolo Nuciforo, Patricia Villagrasa, Isabel T. Rubio, Aleix Prat, Carlos Caldas
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Publicado: Nature Portfolio 2021
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spelling oai:doaj.org-article:206a008b2ff14604b0c18a4e4d55bbec2021-12-02T14:58:17ZThe temporal mutational and immune tumour microenvironment remodelling of HER2-negative primary breast cancers10.1038/s41523-021-00282-02374-4677https://doaj.org/article/206a008b2ff14604b0c18a4e4d55bbec2021-06-01T00:00:00Zhttps://doi.org/10.1038/s41523-021-00282-0https://doaj.org/toc/2374-4677Abstract The biology of breast cancer response to neoadjuvant therapy is underrepresented in the literature and provides a window-of-opportunity to explore the genomic and microenvironment modulation of tumours exposed to therapy. Here, we characterised the mutational, gene expression, pathway enrichment and tumour-infiltrating lymphocytes (TILs) dynamics across different timepoints of 35 HER2-negative primary breast cancer patients receiving neoadjuvant eribulin therapy (SOLTI-1007 NEOERIBULIN-NCT01669252). Whole-exome data (N = 88 samples) generated mutational profiles and candidate neoantigens and were analysed along with RNA-Nanostring 545-gene expression (N = 96 samples) and stromal TILs (N = 105 samples). Tumour mutation burden varied across patients at baseline but not across the sampling timepoints for each patient. Mutational signatures were not always conserved across tumours. There was a trend towards higher odds of response and less hazard to relapse when the percentage of subclonal mutations was low, suggesting that more homogenous tumours might have better responses to neoadjuvant therapy. Few driver mutations (5.1%) generated putative neoantigens. Mutation and neoantigen load were positively correlated (R 2 = 0.94, p = <0.001); neoantigen load was weakly correlated with stromal TILs (R 2 = 0.16, p = 0.02). An enrichment in pathways linked to immune infiltration and reduced programmed cell death expression were seen after 12 weeks of eribulin in good responders. VEGF was downregulated over time in the good responder group and FABP5, an inductor of epithelial mesenchymal transition (EMT), was upregulated in cases that recurred (p < 0.05). Mutational heterogeneity, subclonal architecture and the improvement of immune microenvironment along with remodelling of hypoxia and EMT may influence the response to neoadjuvant treatment.Leticia De Mattos-ArrudaJavier CortesJuan Blanco-HerediaDaniel G. TiezziGuillermo VillacampaSamuel Gonçalves-RibeiroLaia ParéCarla Anjos SouzaVanesa OrtegaStephen-John SammutPol CuscoRoberta FasaniSuet-Feung ChinJose Perez-GarciaRodrigo DienstmannPaolo NuciforoPatricia VillagrasaIsabel T. RubioAleix PratCarlos CaldasNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Breast Cancer, Vol 7, Iss 1, Pp 1-10 (2021)
institution DOAJ
collection DOAJ
language EN
topic Neoplasms. Tumors. Oncology. Including cancer and carcinogens
RC254-282
spellingShingle Neoplasms. Tumors. Oncology. Including cancer and carcinogens
RC254-282
Leticia De Mattos-Arruda
Javier Cortes
Juan Blanco-Heredia
Daniel G. Tiezzi
Guillermo Villacampa
Samuel Gonçalves-Ribeiro
Laia Paré
Carla Anjos Souza
Vanesa Ortega
Stephen-John Sammut
Pol Cusco
Roberta Fasani
Suet-Feung Chin
Jose Perez-Garcia
Rodrigo Dienstmann
Paolo Nuciforo
Patricia Villagrasa
Isabel T. Rubio
Aleix Prat
Carlos Caldas
The temporal mutational and immune tumour microenvironment remodelling of HER2-negative primary breast cancers
description Abstract The biology of breast cancer response to neoadjuvant therapy is underrepresented in the literature and provides a window-of-opportunity to explore the genomic and microenvironment modulation of tumours exposed to therapy. Here, we characterised the mutational, gene expression, pathway enrichment and tumour-infiltrating lymphocytes (TILs) dynamics across different timepoints of 35 HER2-negative primary breast cancer patients receiving neoadjuvant eribulin therapy (SOLTI-1007 NEOERIBULIN-NCT01669252). Whole-exome data (N = 88 samples) generated mutational profiles and candidate neoantigens and were analysed along with RNA-Nanostring 545-gene expression (N = 96 samples) and stromal TILs (N = 105 samples). Tumour mutation burden varied across patients at baseline but not across the sampling timepoints for each patient. Mutational signatures were not always conserved across tumours. There was a trend towards higher odds of response and less hazard to relapse when the percentage of subclonal mutations was low, suggesting that more homogenous tumours might have better responses to neoadjuvant therapy. Few driver mutations (5.1%) generated putative neoantigens. Mutation and neoantigen load were positively correlated (R 2 = 0.94, p = <0.001); neoantigen load was weakly correlated with stromal TILs (R 2 = 0.16, p = 0.02). An enrichment in pathways linked to immune infiltration and reduced programmed cell death expression were seen after 12 weeks of eribulin in good responders. VEGF was downregulated over time in the good responder group and FABP5, an inductor of epithelial mesenchymal transition (EMT), was upregulated in cases that recurred (p < 0.05). Mutational heterogeneity, subclonal architecture and the improvement of immune microenvironment along with remodelling of hypoxia and EMT may influence the response to neoadjuvant treatment.
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author Leticia De Mattos-Arruda
Javier Cortes
Juan Blanco-Heredia
Daniel G. Tiezzi
Guillermo Villacampa
Samuel Gonçalves-Ribeiro
Laia Paré
Carla Anjos Souza
Vanesa Ortega
Stephen-John Sammut
Pol Cusco
Roberta Fasani
Suet-Feung Chin
Jose Perez-Garcia
Rodrigo Dienstmann
Paolo Nuciforo
Patricia Villagrasa
Isabel T. Rubio
Aleix Prat
Carlos Caldas
author_facet Leticia De Mattos-Arruda
Javier Cortes
Juan Blanco-Heredia
Daniel G. Tiezzi
Guillermo Villacampa
Samuel Gonçalves-Ribeiro
Laia Paré
Carla Anjos Souza
Vanesa Ortega
Stephen-John Sammut
Pol Cusco
Roberta Fasani
Suet-Feung Chin
Jose Perez-Garcia
Rodrigo Dienstmann
Paolo Nuciforo
Patricia Villagrasa
Isabel T. Rubio
Aleix Prat
Carlos Caldas
author_sort Leticia De Mattos-Arruda
title The temporal mutational and immune tumour microenvironment remodelling of HER2-negative primary breast cancers
title_short The temporal mutational and immune tumour microenvironment remodelling of HER2-negative primary breast cancers
title_full The temporal mutational and immune tumour microenvironment remodelling of HER2-negative primary breast cancers
title_fullStr The temporal mutational and immune tumour microenvironment remodelling of HER2-negative primary breast cancers
title_full_unstemmed The temporal mutational and immune tumour microenvironment remodelling of HER2-negative primary breast cancers
title_sort temporal mutational and immune tumour microenvironment remodelling of her2-negative primary breast cancers
publisher Nature Portfolio
publishDate 2021
url https://doaj.org/article/206a008b2ff14604b0c18a4e4d55bbec
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