Identification of a basal-like subtype of breast ductal carcinoma in situ

doi:10.1016/j.humpath.2006.08.017

Human Pathology

Volume 38, Issue 2, February 2007, Pages 197-204

https://doi.org/10.1016/j.humpath.2006.08.017 Get rights and content

Summary

Microarray profiling of invasive breast carcinomas has identified subtypes including luminal A, luminal B, HER2-overexpressing, and basal-like. The poor-prognosis, basal-like tumors have been immunohistochemically characterized as estrogen receptor (ER)–negative, HER2/neu–negative, and cytokeratin 5/6–positive and/or epidermal growth factor receptor (EGFR)–positive. The aim of this study was to determine the prevalence of basal-like ductal carcinoma in situ in a population-based series of cases using immunohistochemical surrogates. A total of 245 pure ductal carcinoma in situ cases from a population-based, case-control study were evaluated for histologic characteristics and immunostained for ER, HER2/neu, EGFR, cytokeratin 5/6, p53, and Ki-67. The subtypes were defined as: luminal A (ER+, HER2−), luminal B (ER+, HER2+), HER2 positive (ER−, HER2+), and basal-like (ER−, HER2−, EGFR+, and/or cytokeratin 5/6+). The prevalence of breast cancer subtypes was basal-like (n = 19 [8%]); luminal A, n = 149 (61%); luminal B, n = 23 (9%); and HER2+/ER−, n = 38 (16%). Sixteen tumors (6%) were unclassified (negative for all 4 defining markers). The basal-like subtype was associated with unfavorable prognostic variables including high-grade nuclei (P < .0001), p53 overexpression (P < .0001), and elevated Ki-67 index (P < .0001). These studies demonstrate the presence of a basal-like in situ carcinoma, a potential precursor lesion to invasive basal-like carcinoma.

Introduction

DNA microarray profiling studies on invasive breast tumors show distinct and reproducible subtypes of breast carcinoma associated with different clinical outcomes [1], [2], [3], [4], [5], [6], [7], [8], [9], [10]. These subtypes include at least 2 types of estrogen receptor (ER)–negative tumors (basal-like and HER2+/ER−) and at least 2 types of ER+ tumors (luminal A and luminal B) [2], [3]. The basal-like subtype is typically HER2− (ie, not amplified) and shows some characteristics of breast myoepithelial cells [11]. The basal-like subtype has been shown to have the highest proliferation rates and poor clinical outcomes [2], [3] and has also been described as the prevalent subtype in BRCA1-related breast carcinomas [12].

Studies have used basal/myoepithelial cytokeratins and other markers to identify a subset of ER- and HER2− breast carcinomas that are associated with a poor prognosis, providing further evidence that basal-like breast cancer represents a distinct subtype of invasive carcinoma [13], [14], [15], [16], [17], [18]. An association between epidermal growth factor receptor (EGFR) expression and the basal-like phenotype has been demonstrated [16]. Breast cancers showing immunoreactivity for cytokeratin 5/6 were also frequently found to coexpress EGFR. Nielsen et al [11] proposed a panel of four antibodies (ER, EGFR, HER2, and cytokeratin 5/6) to identify basal-like tumors in which the basal-like tumors were identified as those being ER−, HER2 not amplified, and positive for expression of cytokeratin 5/6 and/or EGFR.

Little is known with regard to the development of basal-like breast tumors. The aim of this study was to evaluate pure ductal carcinoma in situ (DCIS) cases from a large population-based series of incident cases to determine if a basal-like DCIS subtype exists and, if so, to determine the prevalence of this subtype and its correlations with histologic features and other immunohistochemical markers.

Section snippets

Study participants

The Carolina Breast Cancer Study (CBCS) is a population-based, case-control study of invasive and in situ breast cancer conducted in 24 counties of central and eastern North Carolina [19]. Incident cases were identified using a Rapid Case Ascertainment System, in cooperation with the North Carolina Central Cancer Registry [20]. Controls were selected from Division of Motor Vehicles (women younger than 65 years) and United States Health Care Financing Administration lists (women 65 years or

Results

Characteristics of the 245 pure DCIS cases with sufficient tumor tissue were as follows: African American (n = 57, 23%), non–African American (n = 188, 77%); premenopausal (n = 71, 29%), and postmenopausal (n = 174, 71%). Approximately 30% of DCIS cases were negative for ER, and approximately 25% of DCIS cases were positive for HER2/neu overexpression.

The prevalence of the breast cancer subtypes in the 245 DCIS patients is presented in Table 2. A basal-like immunophenotype (ER−, HER2−, and

Discussion

The designation of a molecular subtype of invasive breast carcinomas as basal-like was based on the finding that the gene expression patterns between these tumors and normal breast basal (myoepithelial) cells showed some similarities that included the expression of keratins 5, 6, and 17 [1], [2], [3]. Numerous studies have since confirmed the presence of a group of ER− invasive breast tumors that express basal cytokeratins and are associated with poor prognosis [13], [14], [15], [16], [17], [18]

Acknowledgments

The authors thank Elaine McSherry for her critical review.

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^☆: This work was supported by an award to the University of North Carolina for a Breast Cancer Specialized Program of Research Excellence (SPORE) from the National Cancer Institute, Bethesda, MD (CA58223), by the NCI (RO1-CA-101227-01) to C.M.P., and by the Breast Cancer Research Foundation, New York, NY.

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Original contributionIdentification of a basal-like subtype of breast ductal carcinoma in situ☆

Summary

Introduction

Section snippets

Study participants

Results

Discussion

Acknowledgments

Cancer Cell

Lancet

Am J Pathol

Mod Pathol

Lab Invest

Hum Pathol

Mod Pathol

Mod Pathol

Molecular portraits of human breast tumours

Nature

Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications

Proc Natl Acad Sci U S A

Repeated observation of breast tumor subtypes in independent gene expression data sets

Proc Natl Acad Sci U S A

Gene expression profiles derived from fine needle aspiration correlate with response to systemic chemotherapy in breast cancer

Breast Cancer Res

Gene expression profiling predicts clinical outcome of breast cancer

Nature

A gene expression signature as a predictor of survival in breast cancer

N Engl J Med

Breast cancer classification and prognosis based on gene expression profiles from a population based study

Proc Natl Acad Sci U S A

Original contribution
Identification of a basal-like subtype of breast ductal carcinoma in situ☆