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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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) |
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 |
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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. |
format |
article |
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 |
work_keys_str_mv |
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