Ductal Carcinoma In situ and the Emergence of Diversity during Breast Cancer Evolution

Purpose: Human invasive breast cancers (IBC) show enormous histologic and biological diversity. This study comprehensively evaluated diversity in ductal carcinoma in situ (DCIS), the immediate precursors of IBCs. Experimental Design: The extent of diversity for conventional histologic grade and standard prognostic biomarkers assessed by immunohistochemistry was evaluated in a series of pure DCIS (n = 200) compared with a contemporaneous series of IBCs (n = 200). A subset of the DCIS (n = 25) was evaluated by DNA microarrays for the presence of luminal, basal, and erbB2 intrinsic subtypes. The extent of diversity within individual cases of DCIS (n = 120) was determined by assessing multiple regions independently for histologic (nuclear) grade and several biomarkers by immunohistochemistry, which approximate microarrays in determining intrinsic subtypes. Results: DCIS showed a broad distribution of conventional histologic grades and standard biomarkers ranging from well to poorly differentiated, nearly identical to IBCs. Microarrays showed the same intrinsic subtypes in DCIS as in IBCs. However, higher resolution analysis showed that multiple histologic grades, biomarker phenotypes, and intrinsic subtypes often coexist within the same DCIS, and these diverse regions probably compete for dominance. Diversity within cases of DCIS was highly correlated with mutated p53 (P = 0.0007). Conclusions: These results support the hypothesis that poorly differentiated DCIS gradually evolve from well-differentiated DCIS by randomly acquiring genetic defects resulting in increasingly abnormal cellular features. This diversity is amplified by defects resulting in genetic instability (e.g., p53 mutation), and the alterations are propagated to IBC in a manner independent of progression to invasion.

[1]  J. Gow,et al.  Amplification of mRNA Populations Using aRNA Generated from Immobilized Oligo ( dT )-T 7 Primed cDNA , 2009 .

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

[3]  G. Dontu,et al.  Stem cells in mammary development and carcinogenesis , 2007, Stem Cell Reviews.

[4]  C. Maley,et al.  Cancer is a disease of clonal evolution within the body1–3. This has profound clinical implications for neoplastic progression, cancer prevention and cancer therapy. Although the idea of cancer as an evolutionary problem , 2006 .

[5]  M. J. van de Vijver,et al.  Classification of ductal carcinoma in situ by gene expression profiling , 2006, Breast Cancer Research.

[6]  L. Liotta,et al.  Use of immuno-LCM to identify the in situ expression profile of cellular constituents of the tumor microenvironment , 2006, Cancer biology & therapy.

[7]  Carissa A. Sanchez,et al.  Genetic clonal diversity predicts progression to esophageal adenocarcinoma , 2006, Nature Genetics.

[8]  M. Clarke,et al.  Stem Cells and Cancer: Two Faces of Eve , 2006, Cell.

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

[10]  S. Hilsenbeck,et al.  Hormones, receptors, and growth in hyperplastic enlarged lobular units: early potential precursors of breast cancer , 2005, Breast Cancer Research.

[11]  A. Balmain,et al.  Control of genomic instability and epithelial tumor development by the p53-Fbxw7/Cdc4 pathway. , 2005, Cancer research.

[12]  I. Ellis,et al.  Columnar Cell Lesions of the Breast: The Missing Link in Breast Cancer Progression?: A Morphological and Molecular Analysis , 2005, The American journal of surgical pathology.

[13]  G. Dontu,et al.  Mammary stem cells, self-renewal pathways, and carcinogenesis , 2005, Breast Cancer Research.

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

[15]  Zang Ai-hua,et al.  Stem Cells,Cancer and Cancer Stem Cells , 2005 .

[16]  A. Ramaioli,et al.  Different clinical impact of estradiol receptor determination according to the analytical method: a study on 1940 breast cancer patients over a period of 16 consecutive years , 2005, Breast Cancer Research and Treatment.

[17]  D. Allred,et al.  Progesterone receptor by immunohistochemistry and clinical outcome in breast cancer: a validation study , 2004, Modern Pathology.

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

[19]  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.

[20]  K. Chin,et al.  In situ analyses of genome instability in breast cancer , 2004, Nature Genetics.

[21]  S. Devries,et al.  Patterns of Chromosomal Alterations in Breast Ductal Carcinoma In situ , 2004, Clinical Cancer Research.

[22]  R. Cardiff,et al.  Genetically Engineered Mouse Models of Mammary Intraepithelial Neoplasia , 2000, Journal of Mammary Gland Biology and Neoplasia.

[23]  D. Medina.  The Preneoplastic Phenotype in Murine Mammary Tumorigenesis , 2000, Journal of Mammary Gland Biology and Neoplasia.

[24]  F. Miller.  Xenograft Models of Premalignant Breast Disease , 2000, Journal of Mammary Gland Biology and Neoplasia.

[25]  I. Christensen,et al.  Carcinoma in situ of the breast: correlation of histopathology to immunohistochemical markers and DNA ploidy , 2000, Breast Cancer Research and Treatment.

[26]  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.

[27]  Stuart J. Schnitt,et al.  Benign Breast Disease and Breast Cancer Risk: Morphology and Beyond , 2003, The American journal of surgical pathology.

[28]  R. Salunga,et al.  Gene expression profiles of human breast cancer progression , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[29]  Kornelia Polyak,et al.  Molecular markers in ductal carcinoma in situ of the breast. , 2003, Molecular cancer research : MCR.

[30]  D. DeMets,et al.  Her-2/neu overexpression and response to oophorectomy plus tamoxifen adjuvant therapy in estrogen receptor-positive premenopausal women with operable breast cancer. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  J. Sloane,et al.  Histopathologic Types of Benign Breast Lesions and the Risk of Breast Cancer: Case–Control Study , 2002, The American journal of surgical pathology.

[32]  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.

[33]  A. Leong,et al.  Biologic markers in ductal carcinoma in situ and concurrent infiltrating carcinoma. A comparison of eight contemporary grading systems. , 2001, American journal of clinical pathology.

[34]  G. Colditz,et al.  Pathologic features of breast cancers in women with previous benign breast disease. , 2001, American journal of clinical pathology.

[35]  D. Page,et al.  Pathology of preinvasive and excellent prognosis breast cancer. , 2001, Current opinion in oncology.

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

[37]  G. Bratthauer,et al.  Genetic abnormalities in mammary ductal intraepithelial neoplasia‐flat type (“clinging ductal carcinoma in situ”) , 2000, Cancer.

[38]  J. Sloane,et al.  Estrogen receptor-positive proliferating cells in the normal and precancerous breast. , 1999, The American journal of pathology.

[39]  I. Ellis,et al.  Pathological prognostic factors in breast cancer. , 1999, Critical reviews in oncology/hematology.

[40]  C K Osborne,et al.  Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[41]  E. Gabrielson,et al.  Comparison of loss heterozygosity in primary and recurrent ductal carcinoma in situ of the breast. , 1998, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[42]  P. O’Connell,et al.  Analysis of loss of heterozygosity in 399 premalignant breast lesions at 15 genetic loci. , 1998, Journal of the National Cancer Institute.

[43]  D. Allred,et al.  Prognostic and predictive factors in breast cancer by immunohistochemical analysis. , 1998, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[44]  B. Lloveras,et al.  Ductal carcinoma in situ of the breast: correlation between histologic classifications and biologic markers. , 1997, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[45]  R. Mansel,et al.  The clinical behavior of breast carcinoma is Probably determined at the preinvasive stage (Ductal carcinoma in Situ) , 1997, Cancer.

[46]  F. O'Malley,et al.  Relationship of a new histological categorization of ductal carcinoma in situ of the breast with size and the immunohistochemical expression of p53, c-erb B2, bcl-2, and ki-67. , 1997, Human pathology.

[47]  M. Lagios,et al.  Ductal carcinoma in situ of the breast: reproducibility of histological subtype analysis. , 1997, Human pathology.

[48]  V. Ernster,et al.  Increases in ductal carcinoma in situ (DCIS) of the breast in relation to mammography: a dilemma. , 1997, Journal of the National Cancer Institute. Monographs.

[49]  Phillips,et al.  Antisense RNA Amplification: A Linear Amplification Method for Analyzing the mRNA Population from Single Living Cells , 1996, Methods.

[50]  J. Eberwine,et al.  Amplification of mRNA populations using aRNA generated from immobilized oligo(dT)-T7 primed cDNA. , 1996, BioTechniques.

[51]  D. Schultz,et al.  Fifteen-year results of breast-conserving surgery and definitive breast irradiation for the treatment of ductal carcinoma in situ of the breast. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[52]  D. Page,et al.  Pathology of preinvasive and excellent-prognosis breast cancer. , 1996, Current opinion in oncology.

[53]  R. Brown,et al.  Characterization of extensive genetic alterations in ductal carcinoma in situ by fluorescence in situ hybridization and molecular analysis. , 1995, Journal of the National Cancer Institute.

[54]  R. Gray,et al.  Accumulation of p53 protein as a possible predictor of response to adjuvant combination chemotherapy with cyclophosphamide, methotrexate, fluorouracil, and prednisone for breast cancer. , 1995, Journal of the National Cancer Institute.

[55]  B. Vogelstein,et al.  An evaluation of six antibodies for immunohistochemistry of mutant p53 gene product in archival colorectal neoplasms , 1994, The Journal of pathology.

[56]  D. Page,et al.  Ductal carcinoma in situ of the breast. Heterogeneity of individual lesions , 1994, Cancer.

[57]  K. Kinzler,et al.  The multistep nature of cancer. , 1993, Trends in genetics : TIG.

[58]  W. McGuire,et al.  Association of p53 protein expression with tumor cell proliferation rate and clinical outcome in node-negative breast cancer. , 1993, Journal of the National Cancer Institute.

[59]  I. Ellis,et al.  Method for grading breast cancer. , 1993, Journal of clinical pathology.

[60]  W. McGuire,et al.  Overexpression of HER-2/neu and its relationship with other prognostic factors change during the progression of in situ to invasive breast cancer. , 1992, Human pathology.

[61]  H. Thornton,et al.  Ductal carcinoma-in-situ of the breast , 1992, The Lancet.

[62]  M. Silverstein,et al.  Duct carcinoma in situ: 227 cases without microinvasion. , 1992, European journal of cancer.

[63]  I. Ellis,et al.  Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. , 2002, Histopathology.

[64]  M. J. van de Vijver,et al.  Neu-protein overexpression in breast cancer. Association with comedo-type ductal carcinoma in situ and limited prognostic value in stage II breast cancer. , 1988, The New England journal of medicine.

[65]  David L. Page,et al.  Atypical hyperplastic lesions of the female breast. A long‐term follow‐up study , 1985, Cancer.

[66]  T. Akiyama,et al.  :A long term follow-up study , 1982 .

[67]  P. Nowell.  The clonal evolution of tumor cell populations. , 1976, Science.

[68]  H M Jensen,et al.  An atlas of subgross pathology of the human breast with special reference to possible precancerous lesions. , 1975, Journal of the National Cancer Institute.

[69]  B. Fisher,et al.  The pathology of invasive breast cancer A Syllabus Derived from Findings of the National Surgical Adjuvant Breast Project (Protocol No. 4) , 1975, Cancer.

[70]  H M Jensen,et al.  On the origin and progression of ductal carcinoma in the human breast. , 1973, Journal of the National Cancer Institute.

[71]  C. D. HAAGENSEN,et al.  Diseases of the Breast , 1972 .