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      Immune Infiltration in Invasive Lobular Breast Cancer

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          Abstract

          Background

          Invasive lobular breast cancer (ILC) is the second most common histological subtype of breast cancer after invasive ductal cancer (IDC). Here, we aimed at evaluating the prevalence, levels, and composition of tumor-infiltrating lymphocytes (TILs) and their association with clinico-pathological and outcome variables in ILC, and to compare them with IDC.

          Methods

          We considered two patient series with TIL data: a multicentric retrospective series (n = 614) and the BIG 02-98 study (n = 149 ILC and 807 IDC). We compared immune subsets identified by immuno-histochemistry in the ILC (n = 159) and IDC (n = 468) patients from the Nottingham series, as well as the CIBERSORT immune profiling of the ILC (n = 98) and IDC (n = 388) METABRIC and The Cancer Genome Atlas patients. All ILC/IDC comparisons were done in estrogen receptor (ER)–positive/human epidermal growth factor receptor 2 (HER2)–negative tumors. All statistical tests were two-sided.

          Results

          TIL levels were statistically significantly lower in ILC compared with IDC (fold-change = 0.79, 95% confidence interval = 0.70 to 0.88, P < .001). In ILC, high TIL levels were associated with young age, lymph node involvement, and high proliferative tumors. In the univariate analysis, high TIL levels were associated with worse prognosis in the retrospective and BIG 02-98 lobular series, although they did not reach statistical significance in the latter. The Nottingham series revealed that the levels of intratumoral but not total CD8 + were statistically significantly lower in ILC compared with IDC. Comparison of the CIBERSORT profiles highlighted statistically significant differences in terms of immune composition.

          Conclusions

          This study shows differences between the immune infiltrates of ER-positive/HER2-negative ILC and IDC in terms of prevalence, levels, localization, composition, and clinical associations.

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          Most cited references47

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          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

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            Robust enumeration of cell subsets from tissue expression profiles

            We introduce CIBERSORT, a method for characterizing cell composition of complex tissues from their gene expression profiles. When applied to enumeration of hematopoietic subsets in RNA mixtures from fresh, frozen, and fixed tissues, including solid tumors, CIBERSORT outperformed other methods with respect to noise, unknown mixture content, and closely related cell types. CIBERSORT should enable large-scale analysis of RNA mixtures for cellular biomarkers and therapeutic targets (http://cibersort.stanford.edu).
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              The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups

              The elucidation of breast cancer subgroups and their molecular drivers requires integrated views of the genome and transcriptome from representative numbers of patients. We present an integrated analysis of copy number and gene expression in a discovery and validation set of 997 and 995 primary breast tumours, respectively, with long-term clinical follow-up. Inherited variants (copy number variants and single nucleotide polymorphisms) and acquired somatic copy number aberrations (CNAs) were associated with expression in ~40% of genes, with the landscape dominated by cis- and trans-acting CNAs. By delineating expression outlier genes driven in cis by CNAs, we identified putative cancer genes, including deletions in PPP2R2A, MTAP and MAP2K4. Unsupervised analysis of paired DNA–RNA profiles revealed novel subgroups with distinct clinical outcomes, which reproduced in the validation cohort. These include a high-risk, oestrogen-receptor-positive 11q13/14 cis-acting subgroup and a favourable prognosis subgroup devoid of CNAs. Trans-acting aberration hotspots were found to modulate subgroup-specific gene networks, including a TCR deletion-mediated adaptive immune response in the ‘CNA-devoid’ subgroup and a basal-specific chromosome 5 deletion-associated mitotic network. Our results provide a novel molecular stratification of the breast cancer population, derived from the impact of somatic CNAs on the transcriptome.
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                Author and article information

                Journal
                J Natl Cancer Inst
                J. Natl. Cancer Inst
                jnci
                JNCI Journal of the National Cancer Institute
                Oxford University Press
                0027-8874
                1460-2105
                July 2018
                20 February 2018
                20 February 2018
                : 110
                : 7
                : 768-776
                Affiliations
                [1 ]J.C. Heuson Breast Cancer Translational Research Laboratory, Université Libre de Bruxelles, Institut Jules Bordet, Brussels, Belgium
                [2 ]Department of Pathology, Université Libre de Bruxelles, Institut Jules Bordet, Brussels, Belgium
                [3 ]Department of Pathology, GZA Ziekenhuizen, Campus Sint Augustinus, Wilrijk, Belgium
                [4 ]Unit of Medical Statistics, Biometry and Bioinformatics “Giulio A. Maccacaro,” Department of Clinical Sciences and Community Health, University of Milan Campus, Cascina Rosa, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
                [5 ]Division of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
                [6 ]Department of Pathology, European Institute of Oncology, University of Milan, Milan, Italy
                [7 ]Molecular Immunology Unit, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
                [8 ]Department of Internal Medicine (DiMI), University of Genoa and IRCCS San Martino-National Cancer Institute, Genoa, Italy
                [9 ]Department of Pathology, Cliniques Universitaires Saint Luc, Brussels, Belgium
                [10 ]Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France
                [11 ]Division of Research and Clinical Medicine, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
                [12 ]Sandro Pitigliani Medical Oncology Unit, Hospital of Prato, Instituto Toscano Tumori, Prato, Italy
                [13 ]Academic Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham City Hospital, Nottingham, UK
                [14 ]Histopathology, Nottingham University Hospitals NHS Trust, Nottingham, UK
                Author notes

                Elia Biganzoli and Christos Sotiriou contributed equally to this work.

                Correspondence to: Christine Desmedt, PhD, Breast Cancer Translational Research Laboratory (BCTL), Institut Jules Bordet, 125 Boulevard de Waterloo, 1000 Brussels, Belgium (e-mail: christine.desmedt@ 123456bordet.be )
                Article
                djx268
                10.1093/jnci/djx268
                6037125
                29471435
                1231c3ee-4dab-42ca-b5d2-6d717156b0c9
                © The Author(s) 2018. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 22 August 2017
                : 10 October 2017
                : 20 November 2017
                Page count
                Pages: 9
                Funding
                Funded by: Susan Komen for the Cure, Fondation MEDIC, Les Amis de Bordet
                Funded by: Fonds National de Recherche Scientifique
                Categories
                Articles

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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