Journal Article
. 2017 Oct; 10:4423-4433.
doi: 10.2147/OTT.S144015.

Prognostic immune-related gene models for breast cancer: a pooled analysis

Jianli Zhao 1 Ying Wang 1 Zengding Lao 2 Siting Liang 2 Jingyi Hou 3 Yunfang Yu 1 Herui Yao 1 Na You 2 Kai Chen 1 
Affiliations
  • PMID: 28979134
  •     50 References
  •     4 citations

Abstract

Breast cancer, the most common cancer among women, is a clinically and biologically heterogeneous disease. Numerous prognostic tools have been proposed, including gene signatures. Unlike proliferation-related prognostic gene signatures, many immune-related gene signatures have emerged as principal biology-driven predictors of breast cancer. Diverse statistical methods and data sets were used for building these immune-related prognostic models, making it difficult to compare or use them in clinically meaningful ways. This study evaluated successfully published immune-related prognostic gene signatures through systematic validations of publicly available data sets. Eight prognostic models that were built upon immune-related gene signatures were evaluated. The performances of these models were compared and ranked in ten publicly available data sets, comprising a total of 2,449 breast cancer cases. Predictive accuracies were measured as concordance indices (C-indices). All tests of statistical significance were two-sided. Immune-related gene models performed better in estrogen receptor-negative (ER-) and lymph node-positive (LN+) breast cancer subtypes. The three top-ranked ER- breast cancer models achieved overall C-indices of 0.62-0.63. Two models predicted better than chance for ER+ breast cancer, with C-indices of 0.53 and 0.59, respectively. For LN+ breast cancer, four models showed predictive advantage, with C-indices between 0.56 and 0.61. Predicted prognostic values were positively correlated with ER status when evaluated using univariate analyses in most of the models under investigation. Multivariate analyses indicated that prognostic values of the three models were independent of known clinical prognostic factors. Collectively, these analyses provided a comprehensive evaluation of immune-related prognostic gene signatures. By synthesizing C-indices in multiple independent data sets, immune-related gene signatures were ranked for ER+, ER-, LN+, and LN- breast cancer subtypes. Taken together, these data showed that immune-related gene signatures have good prognostic values in breast cancer, especially for ER- and LN+ tumors.

Keywords: breast cancer; immune-related gene; prognostic models.

PAM50 proliferation score as a predictor of weekly paclitaxel benefit in breast cancer.
Miguel Martín, Aleix Prat, +24 authors, Philip S Bernard.
Breast Cancer Res Treat, 2013 Feb 21; 138(2). PMID: 23423445    Free PMC article.
Receptor tyrosine kinase signaling favors a protumorigenic state in breast cancer cells by inhibiting the adaptive immune response.
Josie Ursini-Siegel, Sean Cory, +15 authors, William J Muller.
Cancer Res, 2010 Oct 07; 70(20). PMID: 20924104    Free PMC article.
Tailoring therapies--improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015.
A S Coates, E P Winer, +6 authors, Panel Members.
Ann Oncol, 2015 May 06; 26(8). PMID: 25939896    Free PMC article.
Highly Cited.
Prognostic significance of progesterone receptor-positive tumor cells within immunohistochemically defined luminal A breast cancer.
Aleix Prat, Maggie Chon U Cheang, +8 authors, Charles M Perou.
J Clin Oncol, 2012 Dec 13; 31(2). PMID: 23233704    Free PMC article.
Highly Cited.
The PAM50 risk-of-recurrence score predicts risk for late distant recurrence after endocrine therapy in postmenopausal women with endocrine-responsive early breast cancer.
Martin Filipits, Torsten O Nielsen, +22 authors, Austrian Breast and Colorectal Cancer Study Group.
Clin Cancer Res, 2014 Feb 13; 20(5). PMID: 24520097
Macrophage-tumour cell interactions: identification of MUC1 on breast cancer cells as a potential counter-receptor for the macrophage-restricted receptor, sialoadhesin.
D Nath, A Hartnell, +4 authors, P R Crocker.
Immunology, 1999 Dec 28; 98(2). PMID: 10610356    Free PMC article.
Cross-Stratification and Differential Risk by Breast Cancer Index and Recurrence Score in Women with Hormone Receptor-Positive Lymph Node-Negative Early-Stage Breast Cancer.
Ivana Sestak, Yi Zhang, +4 authors, Dennis Sgroi.
Clin Cancer Res, 2016 Jun 03; 22(20). PMID: 27252417
Supervised risk predictor of breast cancer based on intrinsic subtypes.
Joel S Parker, Michael Mullins, +17 authors, Philip S Bernard.
J Clin Oncol, 2009 Feb 11; 27(8). PMID: 19204204    Free PMC article.
Highly Cited.
Development of a prognostic model for breast cancer survival in an open challenge environment.
Wei-Yi Cheng, Tai-Hsien Ou Yang, Dimitris Anastassiou.
Sci Transl Med, 2013 Apr 19; 5(181). PMID: 23596202
The humoral immune system has a key prognostic impact in node-negative breast cancer.
Marcus Schmidt, Daniel Böhm, +7 authors, Mathias Gehrmann.
Cancer Res, 2008 Jul 03; 68(13). PMID: 18593943
Highly Cited.
An association study of established breast cancer reproductive and lifestyle risk factors with tumour subtype defined by the prognostic 70-gene expression signature (MammaPrint®).
M Makama, C A Drukker, +6 authors, M K Schmidt.
Eur J Cancer, 2017 Feb 20; 75. PMID: 28214658
Molecular portraits of human breast tumours.
C M Perou, T Sørlie, +15 authors, D Botstein.
Nature, 2000 Aug 30; 406(6797). PMID: 10963602
Highly Cited.
Improved prognostic classification of breast cancer defined by antagonistic activation patterns of immune response pathway modules.
Andrew E Teschendorff, Sergio Gomez, +4 authors, Carlos Caldas.
BMC Cancer, 2010 Nov 06; 10. PMID: 21050467    Free PMC article.
Gene modules and response to neoadjuvant chemotherapy in breast cancer subtypes: a pooled analysis.
Michail Ignatiadis, Sandeep K Singhal, +7 authors, Christos Sotiriou.
J Clin Oncol, 2012 Apr 18; 30(16). PMID: 22508827
Highly Cited.
The Clinical Significance of CD169-Positive Lymph Node Macrophage in Patients with Breast Cancer.
Takuya Shiota, Yuko Miyasato, +5 authors, Yoshihiro Komohara.
PLoS One, 2016 Nov 20; 11(11). PMID: 27861544    Free PMC article.
PADGE: analysis of heterogeneous patterns of differential gene expression.
Li Li, Amitabha Chaudhuri, John Chant, Zhijun Tang.
Physiol Genomics, 2007 Oct 11; 32(1). PMID: 17925482
High expression of lymphocyte-associated genes in node-negative HER2+ breast cancers correlates with lower recurrence rates.
Gabriela Alexe, Gul S Dalgin, +9 authors, Gyan Bhanot.
Cancer Res, 2007 Nov 17; 67(22). PMID: 18006808
Diagnosis of multiple cancer types by shrunken centroids of gene expression.
Robert Tibshirani, Trevor Hastie, Balasubramanian Narasimhan, Gilbert Chu.
Proc Natl Acad Sci U S A, 2002 May 16; 99(10). PMID: 12011421    Free PMC article.
Highly Cited.
The pattern of clinical breast cancer metastasis correlates with a single nucleotide polymorphism in the C1qA component of complement.
Emilian Racila, Doina M Racila, +3 authors, George J Weiner.
Immunogenetics, 2006 Feb 09; 58(1). PMID: 16465510
Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013.
A Goldhirsch, E P Winer, +5 authors, Panel members.
Ann Oncol, 2013 Aug 07; 24(9). PMID: 23917950    Free PMC article.
Highly Cited.
An immune response gene expression module identifies a good prognosis subtype in estrogen receptor negative breast cancer.
Andrew E Teschendorff, Ahmad Miremadi, +2 authors, Carlos Caldas.
Genome Biol, 2007 Aug 09; 8(8). PMID: 17683518    Free PMC article.
Highly Cited.
Meta-analysis of gene expression profiles in breast cancer: toward a unified understanding of breast cancer subtyping and prognosis signatures.
Pratyaksha Wirapati, Christos Sotiriou, +10 authors, Mauro Delorenzi.
Breast Cancer Res, 2008 Jul 30; 10(4). PMID: 18662380    Free PMC article.
Highly Cited.
Characterisation of multifocal breast cancer using the 70-gene signature in clinical low-risk patients enrolled in the EORTC 10041/BIG 03-04 MINDACT trial.
K C Aalders, A Kuijer, +12 authors, TRANSBIG Consortium and the MINDACT Investigators.
Eur J Cancer, 2017 May 10; 79. PMID: 28477490
70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer.
Fatima Cardoso, Laura J van't Veer, +32 authors, MINDACT Investigators.
N Engl J Med, 2016 Aug 25; 375(8). PMID: 27557300
Highly Cited.
PD-L1 protein expression in breast cancer is rare, enriched in basal-like tumours and associated with infiltrating lymphocytes.
H R Ali, S-E Glont, +10 authors, C Caldas.
Ann Oncol, 2015 Apr 22; 26(7). PMID: 25897014
Highly Cited.
Interactions between immunity, proliferation and molecular subtype in breast cancer prognosis.
Srikanth Nagalla, Jeff W Chou, +9 authors, Lance D Miller.
Genome Biol, 2013 Apr 27; 14(4). PMID: 23618380    Free PMC article.
Highly Cited.
Breast cancer classification and prognosis based on gene expression profiles from a population-based study.
Christos Sotiriou, Soek-Ying Neo, +7 authors, Edison T Liu.
Proc Natl Acad Sci U S A, 2003 Aug 15; 100(18). PMID: 12917485    Free PMC article.
Highly Cited.
Association of S100A4 and osteopontin with specific prognostic factors and survival of patients with minimally invasive breast cancer.
Suzete de Silva Rudland, Lee Martin, +7 authors, Philip Rudland.
Clin Cancer Res, 2006 Feb 21; 12(4). PMID: 16489073
Prognostic and therapeutic implications of distinct kinase expression patterns in different subtypes of breast cancer.
Giampaolo Bianchini, Takayuki Iwamoto, +9 authors, Lajos Pusztai.
Cancer Res, 2010 Oct 21; 70(21). PMID: 20959472
Prognostic significance of CD169-positive lymph node sinus macrophages in patients with endometrial carcinoma.
Koji Ohnishi, Munekage Yamaguchi, +5 authors, Yoshihiro Komohara.
Cancer Sci, 2016 Mar 19; 107(6). PMID: 26991548    Free PMC article.
Genomic analysis reveals that immune function genes are strongly linked to clinical outcome in the North Central Cancer Treatment Group n9831 Adjuvant Trastuzumab Trial.
Edith A Perez, E Aubrey Thompson, +16 authors, Monica M Reinholz.
J Clin Oncol, 2015 Jan 22; 33(7). PMID: 25605861    Free PMC article.
Highly Cited.
A prognostic model for lymph node-negative breast cancer patients based on the integration of proliferation and immunity.
Ensel Oh, Yoon-La Choi, +3 authors, Young Kee Shin.
Breast Cancer Res Treat, 2011 Jun 15; 132(2). PMID: 21667120
Role of the integrin-binding protein osteopontin in lymphatic metastasis of breast cancer.
Alison L Allan, Rosamma George, +12 authors, Alan B Tuck.
Am J Pathol, 2006 Jul 04; 169(1). PMID: 16816376    Free PMC article.
Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer.
Soonmyung Paik, Gong Tang, +11 authors, Norman Wolmark.
J Clin Oncol, 2006 May 25; 24(23). PMID: 16720680
Highly Cited.
Prediction of late distant recurrence in patients with oestrogen-receptor-positive breast cancer: a prospective comparison of the breast-cancer index (BCI) assay, 21-gene recurrence score, and IHC4 in the TransATAC study population.
Dennis C Sgroi, Ivana Sestak, +9 authors, Mitch Dowsett.
Lancet Oncol, 2013 Sep 17; 14(11). PMID: 24035531    Free PMC article.
Highly Cited.
A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer.
Soonmyung Paik, Steven Shak, +12 authors, Norman Wolmark.
N Engl J Med, 2004 Dec 14; 351(27). PMID: 15591335
Highly Cited.
Generalized singular value decomposition for comparative analysis of genome-scale expression data sets of two different organisms.
Orly Alter, Patrick O Brown, David Botstein.
Proc Natl Acad Sci U S A, 2003 Mar 13; 100(6). PMID: 12631705    Free PMC article.
A multigene predictor of metastatic outcome in early stage hormone receptor-negative and triple-negative breast cancer.
Christina Yau, Laura Esserman, +3 authors, Christopher C Benz.
Breast Cancer Res, 2010 Oct 16; 12(5). PMID: 20946665    Free PMC article.
Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer.
Maggie C U Cheang, Stephen K Chia, +10 authors, Torsten O Nielsen.
J Natl Cancer Inst, 2009 May 14; 101(10). PMID: 19436038    Free PMC article.
Highly Cited.
Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial.
S Loi, S Michiels, +13 authors, C Sotiriou.
Ann Oncol, 2014 Mar 13; 25(8). PMID: 24608200
Highly Cited.
Breast Cancer Index predicts pathological complete response and eligibility for breast conserving surgery in breast cancer patients treated with neoadjuvant chemotherapy.
M C Mathieu, C Mazouni, +8 authors, F André.
Ann Oncol, 2011 Nov 25; 23(8). PMID: 22112967
Assessment of the prognostic and predictive utility of the Breast Cancer Index (BCI): an NCIC CTG MA.14 study.
Dennis C Sgroi, Judy-Anne W Chapman, +10 authors, Michael Pollak.
Breast Cancer Res, 2016 Jan 06; 18(1). PMID: 26728744    Free PMC article.
Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial.
Kathy S Albain, William E Barlow, +20 authors, Breast Cancer Intergroup of North America.
Lancet Oncol, 2009 Dec 17; 11(1). PMID: 20005174    Free PMC article.
Highly Cited.
CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3.
Jingqi Chen, Yandan Yao, +14 authors, Erwei Song.
Cancer Cell, 2011 Apr 13; 19(4). PMID: 21481794    Free PMC article.
Highly Cited.
Biological processes associated with breast cancer clinical outcome depend on the molecular subtypes.
Christine Desmedt, Benjamin Haibe-Kains, +6 authors, Christos Sotiriou.
Clin Cancer Res, 2008 Aug 14; 14(16). PMID: 18698033
Highly Cited.
Factors predicting late recurrence for estrogen receptor-positive breast cancer.
Ivana Sestak, Mitch Dowsett, +4 authors, Jack Cuzick.
J Natl Cancer Inst, 2013 Sep 14; 105(19). PMID: 24029245    Free PMC article.
Highly Cited.
CD169-positive macrophages in regional lymph nodes are associated with a favorable prognosis in patients with colorectal carcinoma.
Koji Ohnishi, Yoshihiro Komohara, +4 authors, Motohiro Takeya.
Cancer Sci, 2013 Jun 06; 104(9). PMID: 23734742    Free PMC article.
Gene expression profiling of breast cancer.
Lajos Pusztai.
Breast Cancer Res, 2010 Jan 20; 11 Suppl 3. PMID: 20030862    Free PMC article.
Intermediate and longer-term outcomes from a prospective active-surveillance program for favorable-risk prostate cancer. Tosoian JJ, Mamawala M, Epstein JI, Landis P, Wolf S, Trock BJ, Carter HB.J Clin Oncol. 2015 Oct 20;33(30):3379-85. [Epub 2015 Aug 31]. doi: 10.1200/JCO.2015.62.5764.
Eggener Scott, M Mamawala, +4 authors, H B Carter.
Urol Oncol, 2017 Feb 06; 35(3). PMID: 28159497
Molecular anatomy of breast cancer stroma and its prognostic value in estrogen receptor-positive and -negative cancers.
Giampaolo Bianchini, Yuan Qi, +13 authors, Lajos Pusztai.
J Clin Oncol, 2010 Sep 02; 28(28). PMID: 20805453
Bioinformatic profiling of prognosis-related genes in the breast cancer immune microenvironment.
Fang Bai, Yuchun Jin, +5 authors, Kejin Wu.
Aging (Albany NY), 2019 Nov 13; 11(21). PMID: 31715586    Free PMC article.
Identification of FPR3 as a Unique Biomarker for Targeted Therapy in the Immune Microenvironment of Breast Cancer.
Jian Qi, Yu Liu, +5 authors, Wulin Yang.
Front Pharmacol, 2021 Mar 09; 11. PMID: 33679387    Free PMC article.
Development and verification of an immune-related gene pairs prognostic signature in ovarian cancer.
Bao Zhang, Xiaocui Nie, +3 authors, Shengke Wang.
J Cell Mol Med, 2021 Feb 06; 25(6). PMID: 33543590    Free PMC article.
Construction and Validation of an Immune Infiltration-Related Gene Signature for the Prediction of Prognosis and Therapeutic Response in Breast Cancer.
Yang Peng, Haochen Yu, +7 authors, Shengchun Liu.
Front Immunol, 2021 May 15; 12. PMID: 33986754    Free PMC article.