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      Molecular subtyping of DCIS: heterogeneity of breast cancer reflected in pre-invasive disease

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          Abstract

          Background:

          Molecular profiling has identified at least four subtypes of invasive breast carcinoma, which exhibit distinct clinical behaviour. There is good evidence now that DCIS represents the non-obligate precursor to invasive breast cancer and therefore it should be possible to identify similar molecular subtypes at this stage. In addition to a limited five-marker system to identify molecular subtypes in invasive breast cancer, it is evident that other biological molecules may identify distinct tumour subsets, though this has not been formally evaluated in DCIS.

          Methods:

          Tissue microarrays were constructed for 188 cases of DCIS. Immunohistochemistry was performed to examine the expression patterns of oestrogen receptor (ER), progesterone receptor (PR), Her2, EGFR, cytokeratin (CK) 5/6, CK14, CK17, CK18, β4-integrin, β6-integrin, p53, SMA, maspin, Bcl-2, topoisomerase II α and P-cadherin. Hierarchical clustering analysis was undertaken to identify any natural groupings, and the findings were validated in an independent sample series.

          Results:

          Each of the intrinsic molecular subtypes described for invasive breast cancer can be identified in DCIS, though there are differences in the relative frequency of subgroups, in particular, the triple negative and basal-like phenotype is very uncommon in DCIS. Hierarchical cluster analysis identified three main subtypes of DCIS determined largely by ER, PR, Her2 and Bcl-2, and this classification is related to conventional prognostic indicators. These subtypes were confirmed in an analysis on independent series of DCIS cases.

          Conclusion:

          This study indicates that DCIS may be classified in a similar manner to invasive breast cancer, and determining the relative frequency of different subtypes in DCIS and invasive disease may shed light on factors determining disease progression. It also demonstrates a role for Bcl-2 in classifying DCIS, which has recently been identified in invasive breast cancer.

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          Most cited references48

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          Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype.

          Basal-like breast cancer is associated with high grade, poor prognosis, and younger patient age. Clinically, a triple-negative phenotype definition [estrogen receptor, progesterone receptor, and human epidermal growth factor receptor (HER)-2, all negative] is commonly used to identify such cases. EGFR and cytokeratin 5/6 are readily available positive markers of basal-like breast cancer applicable to standard pathology specimens. This study directly compares the prognostic significance between three- and five-biomarker surrogate panels to define intrinsic breast cancer subtypes, using a large clinically annotated series of breast tumors. Four thousand forty-six invasive breast cancers were assembled into tissue microarrays. All had staging, pathology, treatment, and outcome information; median follow-up was 12.5 years. Cox regression analyses and likelihood ratio tests compared the prognostic significance for breast cancer death-specific survival (BCSS) of the two immunohistochemical panels. Among 3,744 interpretable cases, 17% were basal using the triple-negative definition (10-year BCSS, 6 7%) and 9% were basal using the five-marker method (10-year BCSS, 62%). Likelihood ratio tests of multivariable Cox models including standard clinical variables show that the five-marker panel is significantly more prognostic than the three-marker panel. The poor prognosis of triple-negative phenotype is conferred almost entirely by those tumors positive for basal markers. Among triple-negative patients treated with adjuvant anthracycline-based chemotherapy, the additional positive basal markers identified a cohort of patients with significantly worse outcome. The expanded surrogate immunopanel of estrogen receptor, progesterone receptor, human HER-2, EGFR, and cytokeratin 5/6 provides a more specific definition of basal-like breast cancer that better predicts breast cancer survival.
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            Prognostic markers in triple-negative breast cancer.

            Triple-negative breast cancer (estrogen receptor-negative, progesterone receptor-negative, and HER2-negative) is a high risk breast cancer that lacks the benefit of specific therapy that targets these proteins. In this study, the authors examined a large and well characterized series of invasive breast carcinoma (n = 1944) with a long-term clinical follow-up (median, 56 months) by using tissue microarray. The series were also stained with concurrent immunohistochemical prognostic panels (estrogen receptor, progesterone receptor, HER-2, androgen receptor, epidermal growth factor receptor (EGFR), P-cadherin, E-cadherin, and basal (CK5/6, CK14), and p53), to characterize this specific subgroup of breast cancer and to identify prognostic markers that can identify tumors with more aggressive behavior. Of informative cases, 16.3% were of the triple-negative phenotype. The majority of these tumors were grade 3, ductal/no-specific-type carcinomas. There were positive associations with larger size, pushing margins, poorer Nottingham Prognostic Index, development of recurrence and distant metastasis, and poorer outcome. In addition, associations were found with loss of expression of androgen receptor and E-cadherin, and positive expression of basal cytokeratins (basal phenotype), P-cadherin, p53, and EGFR. In all tumors, tumor size, lymph node stage, and androgen receptor were the most useful prognostic markers. In the lymph node-positive subgroup, both size and androgen receptor retained their prognostic significance. However, in the lymph node-negative tumors, basal phenotype was the sole prognostic marker identified in this subgroup. Other parameters including age, histological grade, tumor size, vascular invasion or other biomarkers included in the current study were not significant. The authors concluded that assessment of androgen receptor and basal phenotype, in addition to the established pathologic variables, mainly lymph node status and tumor size, can be used to select high-risk and low-risk patients at the time of primary surgery and can provide valuable information on treatment options in these triple-negative tumors. (c) 2006 American Cancer Society.
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              A Wilcoxon-type test for trend.

              J Cuzick (1985)
              An extension of the Wilcoxon rank-sum test is developed to handle the situation in which a variable is measured for individuals in three or more (ordered) groups and a non-parametric test for trend across these groups is desired. The uses of the test are illustrated by two examples from cancer research.
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                Author and article information

                Journal
                Br J Cancer
                British Journal of Cancer
                Nature Publishing Group
                0007-0920
                1532-1827
                04 January 2011
                07 December 2010
                : 104
                : 1
                : 120-127
                Affiliations
                [1 ]simpleCentre for Tumour Biology, Institute of Cancer and CR-UK Clinical Centre, Barts and the London School of Medicine and Dentistry, John Vane Science Centre , Charterhouse Square, London EC1M 6BQ, UK
                [2 ]simpleCancer Research UK Centre for Epidemiology, Mathematics, and Statistics, Wolfson Institute of Preventive Medicine, Barts & The London School of Medicine and Dentistry, Queen Mary University of London , Charterhouse Square, London EC1M 6BQ, UK
                [3 ]simpleBreast Unit, St Bartholomew's Hospital, West Smithfield , London EC1A 7BE, UK
                Author notes
                Article
                6606021
                10.1038/sj.bjc.6606021
                3039794
                21139586
                06d7b489-2591-47ff-b179-419b2a37905e
                Copyright © 2011 Cancer Research UK
                History
                : 02 June 2010
                : 26 October 2010
                : 04 November 2010
                Categories
                Molecular Diagnostics

                Oncology & Radiotherapy
                basal,dcis,triple negative,bcl-2.,intrinsic subtypes
                Oncology & Radiotherapy
                basal, dcis, triple negative, bcl-2., intrinsic subtypes

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