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      HER2 expression, copy number variation and survival outcomes in HER2-low non-metastatic breast cancer: an international multicentre cohort study and TCGA-METABRIC analysis

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          Abstract

          Background

          HER2-low breast cancer (BC) is currently an area of active interest. This study evaluated the impact of low expression of HER2 on survival outcomes in HER2-negative non-metastatic breast cancer (BC).

          Methods

          Patients with HER2-negative non-metastatic BC from 6 centres within the Asian Breast Cancer Cooperative Group (ABCCG) ( n = 28,280) were analysed. HER2-low was defined as immunohistochemistry (IHC) 1+ or 2+ and in situ hybridization non-amplified (ISH−) and HER2-zero as IHC 0. Relapse-free survival (RFS) and overall survival (OS) by hormone receptor status and HER2 IHC 0, 1+ and 2+ ISH− status were the main outcomes. A combined TCGA-BRCA and METABRIC cohort ( n = 1967) was also analysed to explore the association between HER2 expression, ERBB2 copy number variation (CNV) status and RFS.

          Results

          ABCCG cohort median follow-up was 6.6 years; there were 12,260 (43.4%) HER2-low BC and 16,020 (56.6%) HER2-zero BC. The outcomes were better in HER2-low BC than in HER2-zero BC (RFS: centre-adjusted hazard ratio (HR) 0.88, 95% CI 0.82–0.93, P < 0.001; OS: centre-adjusted HR 0.82, 95% CI 0.76–0.89, P < 0.001). On multivariable analysis, HER2-low status was prognostic (RFS: HR 0.90, 95% CI 0.85–0.96, P = 0.002; OS: HR 0.86, 95% CI 0.79–0.93, P < 0.001). These differences remained significant in hormone receptor-positive tumours and for OS in hormone receptor-negative tumours. Superior outcomes were observed for HER2 IHC1+ BC versus HER2-zero BC (RFS: HR 0.89, 95% CI 0.83–0.96, P = 0.001; OS: HR 0.85, 95% CI 0.78–0.93, P = 0.001). No significant differences were seen between HER2 IHC2+ ISH− and HER2-zero BCs. In the TCGA-BRCA and METABRIC cohorts, ERBB2 CNV status was an independent RFS prognostic factor (neutral versus non-neutral HR 0.71, 95% CI 0.59–0.86, P < 0.001); no differences in RFS by ERBB2 mRNA expression levels were found.

          Conclusions

          HER2-low BC had a superior prognosis compared to HER2-zero BC in the non-metastatic setting, though absolute differences were modest and driven by HER2 IHC 1+ BC. ERBB2 CNV merits further investigation in HER2-negative BC.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s12916-022-02284-6.

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          Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.

          J. Gao, B. A. Aksoy, U Dogrusoz … (2015)
          The cBioPortal for Cancer Genomics (http://cbioportal.org) provides a Web resource for exploring, visualizing, and analyzing multidimensional cancer genomics data. The portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression, and proteomic events. The query interface combined with customized data storage enables researchers to interactively explore genetic alterations across samples, genes, and pathways and, when available in the underlying data, to link these to clinical outcomes. The portal provides graphical summaries of gene-level data from multiple platforms, network visualization and analysis, survival analysis, patient-centric queries, and software programmatic access. The intuitive Web interface of the portal makes complex cancer genomics profiles accessible to researchers and clinicians without requiring bioinformatics expertise, thus facilitating biological discoveries. Here, we provide a practical guide to the analysis and visualization features of the cBioPortal for Cancer Genomics.
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            The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data.

            Ethan Cerami, Jianjiong Gao, Ugur Dogrusoz … (2012)
            The cBio Cancer Genomics Portal (http://cbioportal.org) is an open-access resource for interactive exploration of multidimensional cancer genomics data sets, currently providing access to data from more than 5,000 tumor samples from 20 cancer studies. The cBio Cancer Genomics Portal significantly lowers the barriers between complex genomic data and cancer researchers who want rapid, intuitive, and high-quality access to molecular profiles and clinical attributes from large-scale cancer genomics projects and empowers researchers to translate these rich data sets into biologic insights and clinical applications. © 2012 AACR.
            Article 0 comments Cited 4308 times – based on 0 reviews     Review now
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              The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups

              Christina Curtis, Sohrab Shah, Suet-Feung Chin … (2012)
              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.
              Article 0 comments Cited 1125 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Yoon-Sim Yap:
                ORCID: http://orcid.org/0000-0002-0347-5066
                Yap.Y.S@nccs.com.sg
                Journal
                Journal ID (nlm-ta): BMC Med
                Journal ID (iso-abbrev): BMC Med
                Title: BMC Medicine
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1741-7015
                Publication date (Electronic): 17 March 2022
                Publication date PMC-release: 17 March 2022
                Publication date Collection: 2022
                Volume: 20
                Electronic Location Identifier: 105
                Affiliations
                [1 ]GRID grid.410724.4, ISNI 0000 0004 0620 9745, Division of Medical Oncology, , National Cancer Centre Singapore, ; 11 Hospital Crescent, Singapore, 169610 Singapore
                [2 ]GRID grid.410724.4, ISNI 0000 0004 0620 9745, Division of Clinical Trials and Epidemiological Sciences, , National Cancer Centre Singapore, ; Singapore, Singapore
                [3 ]GRID grid.31501.36, ISNI 0000 0004 0470 5905, Department of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, , Seoul National University College of Medicine, ; Seoul, Republic of Korea
                [4 ]GRID grid.410724.4, ISNI 0000 0004 0620 9745, Cancer Discovery Hub, , National Cancer Centre Singapore, ; Singapore, Singapore
                [5 ]GRID grid.264381.a, ISNI 0000 0001 2181 989X, Department of Health Sciences and Technology, SAIHST, , Sungkyunkwan University, ; Seoul, Republic of South Korea
                [6 ]GRID grid.264381.a, ISNI 0000 0001 2181 989X, Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, , Sungkyunkwan University School of Medicine, ; Seoul, Republic of South Korea
                [7 ]GRID grid.412094.a, ISNI 0000 0004 0572 7815, Department of Oncology, , National Taiwan University Hospital, ; Taipei, Taiwan
                [8 ]GRID grid.410807.a, ISNI 0000 0001 0037 4131, Department of Medical Oncology, Cancer Institute Hospital, , Japanese Foundation for Cancer Research, ; Tokyo, Japan
                [9 ]GRID grid.410807.a, ISNI 0000 0001 0037 4131, Breast Surgical Oncology, Breast Oncology Center, Cancer Institute Hospital, , Japanese Foundation for Cancer Research, ; Tokyo, Japan
                [10 ]GRID grid.497282.2, Department of Medical Oncology, , National Cancer Center Hospital East, ; Kashiwa, Chiba Japan
                [11 ]GRID grid.497282.2, Department of Breast Surgery, , National Cancer Center Hospital East, ; Kashiwa, Chiba Japan
                [12 ]GRID grid.414963.d, ISNI 0000 0000 8958 3388, Breast Department, , KK Women’s and Children’s Hospital, ; Singapore, Singapore
                [13 ]GRID grid.4280.e, ISNI 0000 0001 2180 6431, Sing Health Duke-NUS Breast Centre, ; Singapore, Singapore
                [14 ]GRID grid.413815.a, ISNI 0000 0004 0469 9373, Division of Breast Surgery, Department of General Surgery, , Changi General Hospital, ; Singapore, Singapore
                [15 ]GRID grid.31501.36, ISNI 0000 0004 0470 5905, Department of Surgery, Seoul National University Hospital, Cancer Research Institute, , Seoul National University College of Medicine, ; Seoul, Republic of Korea
                [16 ]GRID grid.31501.36, ISNI 0000 0004 0470 5905, Department of Pathology, Seoul National University Hospital, Cancer Research Institute, , Seoul National University College of Medicine, ; Seoul, Republic of Korea
                [17 ]GRID grid.410724.4, ISNI 0000 0004 0620 9745, Division of Surgery and Surgical Oncology, , National Cancer Centre Singapore, ; Singapore, Singapore
                [18 ]GRID grid.163555.1, ISNI 0000 0000 9486 5048, Department of Breast Surgery, , Singapore General Hospital, ; Singapore, Singapore
                [19 ]GRID grid.410724.4, ISNI 0000 0004 0620 9745, Division of Radiation Oncology, , National Cancer Centre Singapore, ; Singapore, Singapore
                [20 ]GRID grid.163555.1, ISNI 0000 0000 9486 5048, Division of Pathology, , Singapore General Hospital, ; Singapore, Singapore
                [21 ]GRID grid.428397.3, ISNI 0000 0004 0385 0924, Duke-NUS Medical School, ; Singapore, Singapore
                Author information
                http://orcid.org/0000-0002-0347-5066
                Article
                Publisher ID: 2284
                DOI: 10.1186/s12916-022-02284-6
                PMC ID: 8928638
                PubMed ID: 35296300
                SO-VID: d3ca4490-3575-4dc9-aceb-4b2af60ff074
                Copyright © © The Author(s) 2022
                License:

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                Date received : 18 December 2021
                Date accepted : 4 February 2022
                Categories
                Subject: Research Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2022

                ScienceOpen disciplines: Medicine
                Keywords: her2-low breast cancer,erbb2 neutral,prognosis,tcga,metabric
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: her2-low breast cancer, erbb2 neutral, prognosis, tcga, metabric

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