Molecular Classification of Breast Carcinomas by Immunohistochemical Analysis: Are We Ready?

Gene expression profiling with breast carcinomas has allowed further classification of these tumors into 5 distinct subtypes (luminal A, luminal B, HER2-overexpression, basal-like, and normal-like) with unique clinical outcomes. Subsequent studies have shown that breast carcinomas can also be divided into 5 similar subgroups using immunohistochemical (IHC) analysis with a limited panel of molecular markers (including estrogen receptor, progesterone receptor, HER2, CK5/6, and epidermal growth factor receptor). These subgroups have distinguishing features closely associated with subtypes defined by gene expression profiling, including distinct clinical outcomes. This review aims to present the current data on molecular classification for breast carcinoma, and its clinical significance, with an emphasis on IHC-based studies and the pros and cons of these molecular classifications. We also propose a standardized IHC-based molecular classification, in the hope that it will promote more uniform large multicenter studies, and facilitate its clinical application.

[1]  Ping Tang,et al.  Molecular classifications of breast carcinoma with similar terminology and different definitions: are they the same? , 2008, Human pathology.

[2]  C. Perou,et al.  Molecular Subtypes in Breast Cancer Evaluation and Management: Divide and Conquer , 2008, Cancer investigation.

[3]  L. Crinò,et al.  ERCC1 expression in triple negative breast carcinoma: the paradox revisited , 2008, Breast Cancer Research and Treatment.

[4]  Robin L. Jones,et al.  Triple negative breast cancer: molecular profiling and prognostic impact in adjuvant anthracycline-treated patients , 2008, Breast Cancer Research and Treatment.

[5]  C. Perou,et al.  Epidemiology of basal-like breast cancer , 2008, Breast Cancer Research and Treatment.

[6]  F. Vicini,et al.  Molecular classification system identifies invasive breast carcinoma patients who are most likely and those who are least likely to achieve a complete pathologic response after neoadjuvant chemotherapy , 2007, Cancer.

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

[8]  Charles M Perou,et al.  FOXA1 Expression in Breast Cancer—Correlation with Luminal Subtype A and Survival , 2007, Clinical Cancer Research.

[9]  S. Narod,et al.  Triple-Negative Breast Cancer: Clinical Features and Patterns of Recurrence , 2007, Clinical Cancer Research.

[10]  Ofra Barnett-Griness,et al.  Clinical outcomes of breast cancer in carriers of BRCA1 and BRCA2 mutations. , 2007, The New England journal of medicine.

[11]  R. Cress,et al.  Descriptive analysis of estrogen receptor (ER)‐negative, progesterone receptor (PR)‐negative, and HER2‐negative invasive breast cancer, the so‐called triple‐negative phenotype , 2007, Cancer.

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

[13]  P. Bourne,et al.  Expression of cytokeratin markers, ER-alpha, PR, HER-2/neu, and EGFR in pure ductal carcinoma in situ (DCIS) and DCIS with co-existing invasive ductal carcinoma (IDC) of the breast. , 2007, Annals of clinical and laboratory science.

[14]  Wolfgang Heller,et al.  Triple-negative breast cancer: therapeutic options. , 2007, The Lancet. Oncology.

[15]  M. García-Closas,et al.  Differences in Risk Factors for Breast Cancer Molecular Subtypes in a Population-Based Study , 2007, Cancer Epidemiology Biomarkers & Prevention.

[16]  K. Siziopikou,et al.  The basal subtype of breast carcinomas may represent the group of breast tumors that could benefit from EGFR-targeted therapies. , 2007, Breast.

[17]  C. Perou,et al.  Identification of a basal-like subtype of breast ductal carcinoma in situ. , 2007, Human pathology.

[18]  J. Benítez,et al.  Vimentin and laminin expression is associated with basal-like phenotype in both sporadic and BRCA1-associated breast carcinomas , 2006, Journal of Clinical Pathology.

[19]  Ian O Ellis,et al.  Prognostic markers in triple‐negative breast cancer , 2007, Cancer.

[20]  D. Easton,et al.  Basal-like grade III invasive ductal carcinoma of the breast: patterns of metastasis and long-term survival , 2007, Breast Cancer Research.

[21]  P. Bourne,et al.  Relationship between nuclear grade of ductal carcinoma in situ and cell origin markers. , 2006, Annals of clinical and laboratory science.

[22]  D. Dabbs,et al.  Basal phenotype of ductal carcinoma in situ: recognition and immunohistologic profile , 2006, Modern Pathology.

[23]  A. Nobel,et al.  Gene expression profiles do not consistently predict the clinical treatment response in locally advanced breast cancer , 2006, Molecular Cancer Therapeutics.

[24]  Raymond R Tubbs,et al.  Breast Cancers With Brain Metastases are More Likely to be Estrogen Receptor Negative, Express the Basal Cytokeratin CK5/6, and Overexpress HER2 or EGFR , 2006, The American journal of surgical pathology.

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

[26]  J. Bergh,et al.  Basoluminal Carcinoma: A New Biologically and Prognostically Distinct Entity Between Basal and Luminal Breast Cancer , 2006, Clinical Cancer Research.

[27]  A. Ashworth,et al.  Basal-like breast carcinomas: clinical outcome and response to chemotherapy , 2006, Journal of Clinical Pathology.

[28]  D. Easton,et al.  Specific morphological features predictive for the basal phenotype in grade 3 invasive ductal carcinoma of breast , 2006, Histopathology.

[29]  C. Perou,et al.  Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. , 2006, JAMA.

[30]  S. Schnitt,et al.  Ductal carcinoma in situ with basal-like phenotype: a possible precursor to invasive basal-like breast cancer , 2006, Modern Pathology.

[31]  F. Bertucci,et al.  Gene expression profiling of breast cell lines identifies potential new basal markers , 2006, Oncogene.

[32]  S. Zucoloto,et al.  Vascular endothelial growth factor expression in the basal subtype of breast carcinoma. , 2006, American journal of clinical pathology.

[33]  P. Bourne,et al.  Expression patterns of ER-alpha, PR, HER-2/neu, and EGFR in different cell origin subtypes of high grade and non-high grade ductal carcinoma in situ. , 2006, Annals of clinical and laboratory science.

[34]  J. Benítez,et al.  Prognostic Significance of Basal-Like Phenotype and Fascin Expression in Node-Negative Invasive Breast Carcinomas , 2006, Clinical Cancer Research.

[35]  G. Hortobagyi,et al.  Prognostic value of pathologic complete response after primary chemotherapy in relation to hormone receptor status and other factors. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[36]  J. Robertson,et al.  Morphological and immunophenotypic analysis of breast carcinomas with basal and myoepithelial differentiation , 2006, The Journal of pathology.

[37]  Yan Peng,et al.  Molecular alterations in columnar cell lesions of the breast , 2006, Modern Pathology.

[38]  J. Reis-Filho,et al.  The impact of expression profiling on prognostic and predictive testing in breast cancer , 2006, Journal of Clinical Pathology.

[39]  W. Willett,et al.  Diet quality is associated with the risk of estrogen receptor-negative breast cancer in postmenopausal women. , 2006, The Journal of nutrition.

[40]  Alan Ashworth,et al.  Distribution and significance of nerve growth factor receptor (NGFR/p75NTR) in normal, benign and malignant breast tissue , 2006, Modern Pathology.

[41]  C. Perou,et al.  Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma , 2006, Modern Pathology.

[42]  P. Dam,et al.  Identification of cell-of-origin breast tumor subtypes in inflammatory breast cancer by gene expression profiling , 2006, Breast Cancer Research and Treatment.

[43]  Manuela Gariboldi,et al.  Limits of predictive models using microarray data for breast cancer clinical treatment outcome. , 2005, Journal of the National Cancer Institute.

[44]  L. Ford,et al.  Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. , 2005, Journal of the National Cancer Institute.

[45]  Zhao Chen,et al.  Ethnicity and breast cancer: factors influencing differences in incidence and outcome. , 2005, Journal of the National Cancer Institute.

[46]  Graham A Colditz,et al.  Alcohol and postmenopausal breast cancer risk defined by estrogen and progesterone receptor status: a prospective cohort study. , 2005, Journal of the National Cancer Institute.

[47]  D. Birnbaum,et al.  Typical medullary breast carcinomas have a basal/myoepithelial phenotype , 2005, The Journal of pathology.

[48]  C. Perou,et al.  Molecular portraits and 70-gene prognosis signature are preserved throughout the metastatic process of breast cancer. , 2005, Cancer research.

[49]  Å. Borg,et al.  Cytokeratin 5/14-positive breast cancer: true basal phenotype confined to BRCA1 tumors , 2005, Modern Pathology.

[50]  G. Ball,et al.  High‐throughput protein expression analysis using tissue microarray technology of a large well‐characterised series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analyses , 2005, International journal of cancer.

[51]  Roman Rouzier,et al.  Breast Cancer Molecular Subtypes Respond Differently to Preoperative Chemotherapy , 2005, Clinical Cancer Research.

[52]  W. Willett,et al.  Folate Intake and Risk of Breast Cancer Characterized by Hormone Receptor Status , 2005, Cancer Epidemiology Biomarkers & Prevention.

[53]  Andy J. Minn,et al.  Genes that mediate breast cancer metastasis to lung , 2005, Nature.

[54]  Julian Peto,et al.  Prediction of BRCA1 Status in Patients with Breast Cancer Using Estrogen Receptor and Basal Phenotype , 2005, Clinical Cancer Research.

[55]  F. Schmitt,et al.  p63, cytokeratin 5, and P-cadherin: three molecular markers to distinguish basal phenotype in breast carcinomas , 2005, Virchows Archiv.

[56]  D. Stram,et al.  Nonsteroidal anti-inflammatory drug use and breast cancer risk by stage and hormone receptor status. , 2005, Journal of the National Cancer Institute.

[57]  Y Wang,et al.  Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials , 2005, The Lancet.

[58]  S. Lakhani,et al.  Molecular evolution of breast cancer , 2005, The Journal of pathology.

[59]  C. Hudis,et al.  A phase II trial of imatinib mesylate monotherapy in patients with metastatic breast cancer , 2005, Breast Cancer Research and Treatment.

[60]  G. Colditz,et al.  Association of hormone replacement therapy to estrogen and progesterone receptor status in invasive breast carcinoma , 2004, Cancer.

[61]  Jorge S. Reis-Filho,et al.  Molecular Cytogenetic Identification of Subgroups of Grade III Invasive Ductal Breast Carcinomas with Different Clinical Outcomes , 2004, Clinical Cancer Research.

[62]  A. Gown,et al.  Immunohistochemical and Clinical Characterization of the Basal-Like Subtype of Invasive Breast Carcinoma , 2004, Clinical Cancer Research.

[63]  Puay Hoon Tan,et al.  Conservation of Breast Cancer Molecular Subtypes and Transcriptional Patterns of Tumor Progression Across Distinct Ethnic Populations , 2004, Clinical Cancer Research.

[64]  C. Perou,et al.  Cell-Type-Specific Responses to Chemotherapeutics in Breast Cancer , 2004, Cancer Research.

[65]  I. Ellis,et al.  Expression of luminal and basal cytokeratins in human breast carcinoma , 2004, The Journal of pathology.

[66]  Graham A Colditz,et al.  Risk factors for breast cancer according to estrogen and progesterone receptor status. , 2004, Journal of the National Cancer Institute.

[67]  G. Sauter,et al.  KIT (CD117)-positive breast cancers are infrequent and lack KIT gene mutations. , 2004, Clinical cancer research : an official journal of the American Association for Cancer Research.

[68]  L. Bégin,et al.  Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. , 2004, Journal of the National Cancer Institute.

[69]  M. King,et al.  Breast and Ovarian Cancer Risks Due to Inherited Mutations in BRCA1 and BRCA2 , 2003, Science.

[70]  A. Griffin,et al.  Kin Discrimination and the Benefit of Helping in Cooperatively Breeding Vertebrates , 2003, Science.

[71]  R. Tibshirani,et al.  Repeated observation of breast tumor subtypes in independent gene expression data sets , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[72]  M. Radmacher,et al.  Pitfalls in the use of DNA microarray data for diagnostic and prognostic classification. , 2003, Journal of the National Cancer Institute.

[73]  Yudong D. He,et al.  A Gene-Expression Signature as a Predictor of Survival in Breast Cancer , 2002 .

[74]  Horst Buerger,et al.  Usual ductal hyperplasia of the breast is a committed stem (progenitor) cell lesion distinct from atypical ductal hyperplasia and ductal carcinoma in situ , 2002, The Journal of pathology.

[75]  R. Tibshirani,et al.  Copyright © American Society for Investigative Pathology Short Communication Expression of Cytokeratins 17 and 5 Identifies a Group of Breast Carcinomas with Poor Clinical Outcome , 2022 .

[76]  Martin Eisenacher,et al.  Cytogenetic Alterations and Cytokeratin Expression Patterns in Breast Cancer: Integrating a New Model of Breast Differentiation into Cytogenetic Pathways of Breast Carcinogenesis , 2002, Laboratory Investigation.

[77]  G. Cevenini,et al.  p53 mutation in breast cancer. Correlation with cell kinetics and cell of origin. , 2002, Journal of clinical pathology.

[78]  Hermann Herbst,et al.  Common Adult Stem Cells in the Human Breast Give Rise to Glandular and Myoepithelial Cell Lineages: A New Cell Biological Concept , 2002, Laboratory Investigation.

[79]  Yudong D. He,et al.  Gene expression profiling predicts clinical outcome of breast cancer , 2002, Nature.

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

[81]  J. Bergh,et al.  Who should not receive adjuvant chemotherapy? International databases. , 2001, Journal of the National Cancer Institute. Monographs.

[82]  R. Tibshirani,et al.  Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[83]  Robert J. Mayer,et al.  National Institutes of Health Consensus Development Conference Statement: adjuvant therapy for breast cancer, November 1-3, 2000. , 2001, Journal of the National Cancer Institute.

[84]  E. Dougherty,et al.  Gene-expression profiles in hereditary breast cancer. , 2001, The New England journal of medicine.

[85]  P. Ravdin,et al.  Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[86]  J. Sudbø,et al.  Gene-expression profiles in hereditary breast cancer. , 2001, The New England journal of medicine.

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

[88]  A. Goldhirsch,et al.  Response to primary chemotherapy in breast cancer patients with tumors not expressing estrogen and progesterone receptors. , 2000, Annals of oncology : official journal of the European Society for Medical Oncology.

[89]  P. Chappuis,et al.  Clinico-pathological characteristics of BRCA1- and BRCA2-related breast cancer. , 2000, Seminars in surgical oncology.

[90]  S. Gapstur,et al.  Hormone receptor status of breast tumors in black, Hispanic, and non‐Hispanic white women: An analysis of 13,239 cases , 1996, Cancer.

[91]  R. Blamey,et al.  A prognostic index in primary breast cancer. , 1982, British Journal of Cancer.