A clinically relevant gene signature in triple negative and basal-like breast cancer

IntroductionCurrent prognostic gene expression profiles for breast cancer mainly reflect proliferation status and are most useful in ER-positive cancers. Triple negative breast cancers (TNBC) are clinically heterogeneous and prognostic markers and biology-based therapies are needed to better treat this disease.MethodsWe assembled Affymetrix gene expression data for 579 TNBC and performed unsupervised analysis to define metagenes that distinguish molecular subsets within TNBC. We used n = 394 cases for discovery and n = 185 cases for validation. Sixteen metagenes emerged that identified basal-like, apocrine and claudin-low molecular subtypes, or reflected various non-neoplastic cell populations, including immune cells, blood, adipocytes, stroma, angiogenesis and inflammation within the cancer. The expressions of these metagenes were correlated with survival and multivariate analysis was performed, including routine clinical and pathological variables.ResultsSeventy-three percent of TNBC displayed basal-like molecular subtype that correlated with high histological grade and younger age. Survival of basal-like TNBC was not different from non basal-like TNBC. High expression of immune cell metagenes was associated with good and high expression of inflammation and angiogenesis-related metagenes were associated with poor prognosis. A ratio of high B-cell and low IL-8 metagenes identified 32% of TNBC with good prognosis (hazard ratio (HR) 0.37, 95% CI 0.22 to 0.61; P < 0.001) and was the only significant predictor in multivariate analysis including routine clinicopathological variables.ConclusionsWe describe a ratio of high B-cell presence and low IL-8 activity as a powerful new prognostic marker for TNBC. Inhibition of the IL-8 pathway also represents an attractive novel therapeutic target for this disease.

[1]  Soonmyung Paik,et al.  Use of archived specimens in evaluation of prognostic and predictive biomarkers. , 2009, Journal of the National Cancer Institute.

[2]  Achim Rody,et al.  T cell marker metagene predicts a favourable prognosis in estrogen receptor negative and Her2 positive breast cancers. , 2009 .

[3]  K. Hess,et al.  Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  Ash A. Alizadeh,et al.  Individuality and variation in gene expression patterns in human blood , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[5]  M. Cronin,et al.  A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. , 2004, The New England journal of medicine.

[6]  C. Perou,et al.  The Triple Negative Paradox: Primary Tumor Chemosensitivity of Breast Cancer Subtypes , 2007, Clinical Cancer Research.

[7]  Christian A. Rees,et al.  Distinctive gene expression patterns in human mammary epithelial cells and breast cancers. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Howard Y. Chang,et al.  Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[9]  Carlos Caldas,et al.  A comprehensive analysis of prognostic signatures reveals the high predictive capacity of the Proliferation, Immune response and RNA splicing modules in breast cancer , 2008, Breast Cancer Research.

[10]  D. Grier,et al.  The pathophysiology of HOX genes and their role in cancer , 2005, The Journal of pathology.

[11]  I. Ellis,et al.  An immune response gene expression module identifies a good prognosis subtype in estrogen receptor negative breast cancer , 2007, Genome Biology.

[12]  D. Waugh,et al.  The Interleukin-8 Pathway in Cancer , 2008, Clinical Cancer Research.

[13]  A. Testori,et al.  Anti-CTLA-4 antibody adjuvant therapy in melanoma. , 2010, Seminars in oncology.

[14]  Daniel Birnbaum,et al.  How basal are triple‐negative breast cancers? , 2008, International journal of cancer.

[15]  J. Haerting,et al.  Gene-expression signatures in breast cancer. , 2003, The New England journal of medicine.

[16]  Kevin R Coombes,et al.  Melanoma antigen family A identified by the bimodality index defines a subset of triple negative breast cancers as candidates for immune response augmentation. , 2012, European journal of cancer.

[17]  M. West,et al.  Gene expression predictors of breast cancer outcomes , 2003, The Lancet.

[18]  Zhiyuan Hu,et al.  A compact VEGF signature associated with distant metastases and poor outcomes , 2009, BMC medicine.

[19]  Axel Benner,et al.  Effects of infiltrating lymphocytes and estrogen receptor on gene expression and prognosis in breast cancer , 2009, Breast Cancer Research and Treatment.

[20]  C. Sotiriou,et al.  Meta-analysis of gene expression profiles in breast cancer: toward a unified understanding of breast cancer subtyping and prognosis signatures , 2007, Breast Cancer Research.

[21]  Ian O Ellis,et al.  Basal-like breast cancer: a critical review. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  Van,et al.  A gene-expression signature as a predictor of survival in breast cancer. , 2002, The New England journal of medicine.

[23]  I. Ellis,et al.  Triple-Negative Breast Cancer: Distinguishing between Basal and Nonbasal Subtypes , 2009, Clinical Cancer Research.

[24]  D. Birnbaum,et al.  CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. , 2010, The Journal of clinical investigation.

[25]  M. Maio,et al.  Clinical studies with anti-CTLA-4 antibodies in non-melanoma indications. , 2010, Seminars in oncology.

[26]  M. J. van de Vijver,et al.  Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis. , 2006, Journal of the National Cancer Institute.

[27]  N Harbeck,et al.  Triple-negative breast cancer--current status and future directions. , 2009, Annals of oncology : official journal of the European Society for Medical Oncology.

[28]  T. Karn,et al.  Prognostic impact of thymidine phosphorylase expression in breast cancer--comparison of microarray and immunohistochemical data. , 2010, European journal of cancer.

[29]  S. Vacher,et al.  CXC chemokines located in the 4q21 region are up-regulated in breast cancer. , 2007, Endocrine-related cancer.

[30]  J. Reis-Filho,et al.  Histological and molecular types of breast cancer: is there a unifying taxonomy? , 2009, Nature Reviews Clinical Oncology.

[31]  Douglas G Altman,et al.  Reporting recommendations for tumor marker prognostic studies. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  J. Foekens,et al.  Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer , 2005, The Lancet.

[33]  Gianluca Bontempi,et al.  Biological Processes Associated with Breast Cancer Clinical Outcome Depend on the Molecular Subtypes , 2008, Clinical Cancer Research.

[34]  A. Dupuy,et al.  Critical review of published microarray studies for cancer outcome and guidelines on statistical analysis and reporting. , 2007, Journal of the National Cancer Institute.

[35]  Harry Bartelink,et al.  Gene expression profiling and histopathological characterization of triple-negative/basal-like breast carcinomas , 2007, Breast Cancer Research.

[36]  G. Azabdaftari.  Basal-Like Breast Cancer Defined by Five Biomarkers Has Superior Prognostic Value than Triple-Negative Phenotype , 2009 .

[37]  David Cameron,et al.  A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer , 2009, Nature Medicine.

[38]  F. Pépin,et al.  Stromal gene expression predicts clinical outcome in breast cancer , 2008, Nature Medicine.

[39]  A. Nobel,et al.  The molecular portraits of breast tumors are conserved across microarray platforms , 2006, BMC Genomics.

[40]  H. Kölbl,et al.  The humoral immune system has a key prognostic impact in node-negative breast cancer. , 2008, Cancer research.

[41]  T. Eberlein.  A Multigene Assay to Predict Recurrence of Tamoxifen-Treated, Node-Negative Breast Cancer , 2006 .

[42]  C. Sotiriou,et al.  Genomic grade index is associated with response to chemotherapy in patients with breast cancer. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[43]  Daniel Birnbaum,et al.  A gene expression signature identifies two prognostic subgroups of basal breast cancer , 2011, Breast Cancer Research and Treatment.

[44]  Federico Ambrogi,et al.  Challenges in projecting clustering results across gene expression-profiling datasets. , 2007, Journal of the National Cancer Institute.

[45]  Ash A. Alizadeh,et al.  Cell-type specific gene expression profiles of leukocytes in human peripheral blood , 2006, BMC Genomics.

[46]  B. Gusterson.  Do 'basal-like' breast cancers really exist? , 2009, Nature Reviews Cancer.

[47]  David Cameron,et al.  Identification of molecular apocrine breast tumours by microarray analysis , 2005, Oncogene.

[48]  Lajos Pusztai,et al.  Determination of oestrogen-receptor status and ERBB2 status of breast carcinoma: a gene-expression profiling study. , 2007, The Lancet. Oncology.

[49]  A. Ashworth,et al.  Breast cancer molecular profiling with single sample predictors: a retrospective analysis. , 2010, The Lancet. Oncology.

[50]  C. Perou,et al.  Mammary development meets cancer genomics , 2009, Nature Medicine.

[51]  G. Stein,et al.  Histone gene transcription: A model for responsiveness to an integrated series of regulatory signals mediating cell cycle control and proliferation/differentiation interrelationships , 1994, Journal of cellular biochemistry.

[52]  M. Wicha.  Targeting breast cancer stem cells. , 2009, Breast.

[53]  W. Gerald,et al.  An estrogen receptor-negative breast cancer subset characterized by a hormonally regulated transcriptional program and response to androgen , 2006, Oncogene.

[54]  Carsten Denkert,et al.  Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[55]  C. Pipper,et al.  [''R"--project for statistical computing]. , 2008, Ugeskrift for laeger.

[56]  Samuel Leung,et al.  Basal-Like Breast Cancer Defined by Five Biomarkers Has Superior Prognostic Value than Triple-Negative Phenotype , 2008, Clinical Cancer Research.

[57]  R. Kurzrock,et al.  Vascular Endothelial Growth Factor and Its Relationship to Inflammatory Mediators , 2007, Clinical Cancer Research.

[58]  Christian A. Rees,et al.  Molecular portraits of human breast tumours , 2000, Nature.

[59]  Are triple-negative tumours and basal-like breast cancer synonymous? Authors' response , 2007, Breast Cancer Research.

[60]  Nicholas J. Wang,et al.  Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. , 2009, Cancer research.

[61]  Jeffrey M. Rosen,et al.  Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features , 2009, Proceedings of the National Academy of Sciences.

[62]  Gabriela Alexe,et al.  High expression of lymphocyte-associated genes in node-negative HER2+ breast cancers correlates with lower recurrence rates. , 2007, Cancer research.

[63]  Achim Rody,et al.  T-cell metagene predicts a favorable prognosis in estrogen receptor-negative and HER2-positive breast cancers , 2009, Breast Cancer Research.

[64]  Gavin D. Grant,et al.  Common markers of proliferation , 2006, Nature Reviews Cancer.

[65]  A. Nobel,et al.  Concordance among Gene-Expression – Based Predictors for Breast Cancer , 2011 .

[66]  D. Metzler,et al.  Data driven derivation of cutoffs from a pool of 3,030 Affymetrix arrays to stratify distinct clinical types of breast cancer , 2010, Breast Cancer Research and Treatment.

[67]  Yuan Qi,et al.  Molecular anatomy of breast cancer stroma and its prognostic value in estrogen receptor-positive and -negative cancers. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.