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      Assessment of PD-L1 expression across breast cancer molecular subtypes, in relation to mutation rate, BRCA1-like status, tumor-infiltrating immune cells and survival

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          ABSTRACT

          To better understand the expression pattern of programmed death-ligand 1 (PD-L1) expression in different breast cancer types, we characterized PD-L1 expression in tumor and tumor-infiltrating immune cells, in relation to mutation rate, BRCA1-like status and survival. We analyzed 410 primary treatment-naive breast tumors comprising 162 estrogen receptor-positive (ER+) and HER2−, 101 HER2+ and 147 triple-negative (TN) cancers. Pathologists quantified tumor-infiltrating lymphocytes (TILs) and PD-L1 expression in tumor cells and TILs using whole slides and tissue microarray. Mutation rate was assessed by DNA sequencing, BRCA1-like status using multiplex ligation-dependent probe amplification, and immune landscape by multiplex image analyses of CD4, CD68, CD8, FOXP3, cytokeratin, and PD-L1. Half of PD-L1 scores evaluated by tissue microarray were false negatives compared to whole slide evaluations. We observed at least 1% of PD-L1-positive (PD-L1+) cells in 53.1% of ER+HER2−, 73.3% of HER2+, and 84.4% of TN tumors. PD-L1 expression was higher in ductal compared to lobular carcinomas, also within ER+HER2− tumors (p = 0.04). High PD-L1+ TILs score (> 50%) was independently associated with better outcome in TN tumors (HR = 0.27; 95%CI = 0.10–0.69). Within TN tumors, PD-L1 and TIL scores showed a modest but significant positive association with the number of silent mutations, but no association with BRCA1-like status. Multiplex image analyses indicated that PD-L1 is expressed on multiple immune cells (CD68+ macrophages, CD4+, FOXP3+, and CD8+ T cells) in the breast tumor microenvironment, independent of the PD-L1 status of the tumor cells. We found no evidence that levels of PD-L1+ TILs in TN breast cancer are driven by high mutation rate or BRCA1-like status.

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          Author and article information

          Journal
          Oncoimmunology
          Oncoimmunology
          KONI
          koni20
          Oncoimmunology
          Taylor & Francis
          2162-4011
          2162-402X
          2018
          11 September 2018
          : 7
          : 12
          : e1509820
          Affiliations
          [a ] Division of Molecular Pathology, Netherlands Cancer Institute , Amsterdam, The Netherlands
          [b ] Coordenação de Pesquisa, Instituto Nacional de Câncer , Rio de Janeiro, RJ, Brasil
          [c ] Department of Pathology, Netherlands Cancer Institute , Amsterdam, The Netherlands
          [d ] Division of Molecular Carcinogenesis, Oncode Institute, Netherlands Cancer Institute , Amsterdam, The Netherlands
          [e ] Department of Pathology, Academic Medical Center , Amsterdam, The Netherlands
          [f ] Laboratory Medicine Program, University Health Network , Toronto, ON, Canada
          [g ] Department of Laboratory Medicine and Pathobiology, University of Toronto , Toronto, ON, Canada
          [h ] University Health Network , Toronto, ON, Canada
          [i ] Agendia NV, Science Park , Amsterdam, The Netherlands
          [j ] Division of Tumor Biology and Immunology, Oncode Institute, Netherlands Cancer Institute , Amsterdam, The Netherlands
          [k ] Departments of Pathology and Oncology, The Johns Hopkins Hospital , Baltimore, USA
          [l ] Core Facility Molecular Pathology and Biobanking, Division of Molecular Pathology, Netherlands Cancer Institute , Amsterdam, The Netherlands
          [m ] Lunenfeld-Tanenbaum Research Institute, Sinai Health System , Toronto, Canada
          [n ] Department of Molecular Genetics, University of Toronto , Toronto, ON, Canada
          [o ] Division of Molecular Oncology and Immunology, Netherlands Cancer Institute , Amsterdam, The Netherlands
          [p ] Division of Medical Oncology, Netherlands Cancer Institute , Amsterdam, The Netherlands
          Author notes
          CONTACT Marjanka K. Schmidt mk.schmidt@ 123456nki.nl Division of Molecular Pathology, Netherlands Cancer Institute , Plesmanlaan 121 - 1066CX Amsterdam, The Netherlands

          Present address of Koen Van de Vijver is Ghent University Hospital, Ghent, Belgium.

          Present address of Magali Michaut is Biotech Research & Innovation Centre, Københavns Universitet, Copenhagen, Denmark.

          Present address of Kelly Kersten is Department of Pathology, University of California, San Francisco, USA.

          [#]

          Department of Pathology, University of California, San Francisco, USA

          Author information
          http://orcid.org/0000-0002-4275-8050
          http://orcid.org/0000-0002-2026-9790
          http://orcid.org/0000-0003-2002-2277
          http://orcid.org/0000-0003-4782-8828
          http://orcid.org/0000-0002-7568-4705
          http://orcid.org/0000-0003-2907-4380
          http://orcid.org/0000-0002-0551-7813
          http://orcid.org/0000-0002-0775-138X
          http://orcid.org/0000-0002-4482-2191
          http://orcid.org/0000-0001-8677-3423
          http://orcid.org/0000-0001-9043-9815
          http://orcid.org/0000-0002-0293-868X
          http://orcid.org/0000-0002-2228-429X
          Article
          PMC6279322 PMC6279322 6279322 1509820
          10.1080/2162402X.2018.1509820
          6279322
          30524905
          3fc760e1-fa3d-4f13-8121-b50af919fa64
          © 2018 Taylor & Francis Group, LLC
          History
          : 30 April 2018
          : 3 August 2018
          : 4 August 2018
          Page count
          Figures: 6, Tables: 1, References: 57, Pages: 15
          Funding
          Funded by: European Commission (EC)
          Award ID: FP7/2007-2013
          Funded by: Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)
          Award ID: 1321-13-7
          Funded by: HHS | National Institutes of Health (NIH)
          Award ID: #CA-95-003
          ONCOPOOL was supported by a European Commission Framework 5 Project Grant. RATHER was supported by European Commission Framework 7 Project Grant. MSL received a scholarship from Science without Borders - CAPES. Funding of group Schmidt at the Netherlands Cancer Institute provided a partial grant and covered the IHC staining and image analysis. This work was also supported by grant UM1 CA164920 from the USA National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the USA Government or the BCFR. I.L. Andrulis holds the Anne and Max Tanenbaum Chair in Molecular Medicine at Mount Sinai Hospital of the Sinai Health System and the University of Toronto.
          Categories
          Original Research

          PD-L1,TILs,mutations,Breast cancer, BRCA1-like
          PD-L1, TILs, mutations, Breast cancer, BRCA1-like

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