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      Intratumoral concentration of estrogens and clinicopathological changes in ductal carcinoma in situ following aromatase inhibitor letrozole treatment

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          Abstract

          Background:

          Estrogens have important roles in ductal carcinoma in situ (DCIS) of the breast. However, the significance of presurgical aromatase inhibitor treatment remains unclear. Therefore, we examined intratumoral concentration of estrogens and changes of clinicopathological factors in DCIS after letrozole treatment.

          Methods:

          Ten cases of postmenopausal oestrogen receptor (ER)-positive DCIS were examined. They received oral letrozole before the surgery, and the tumour size was evaluated by ultrasonography. Surgical specimens and corresponding biopsy samples were used for immunohistochemistry. Snap-frozen specimens were also available in a subset of cases, and used for hormone assays and microarray analysis.

          Results:

          Intratumoral oestrogen levels were significantly lower in DCIS treated with letrozole compared with that in those without the therapy. A great majority of oestrogen-induced genes showed low expression levels in DCIS treated with letrozole by microarray analysis. Moreover, letrozole treatment reduced the greatest dimension of DCIS, and significantly decreased Ki-67 and progesterone receptor immunoreactivity in DCIS tissues.

          Conclusion:

          These results suggest that estrogens are mainly produced by aromatase in DCIS tissues, and aromatase inhibitors potently inhibit oestrogen actions in postmenopausal ER-positive DCIS through rapid deprivation of intratumoral estrogens.

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          Most cited references 36

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          American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer.

          To develop a guideline to improve the accuracy of human epidermal growth factor receptor 2 (HER2) testing in invasive breast cancer and its utility as a predictive marker. The American Society of Clinical Oncology and the College of American Pathologists convened an expert panel, which conducted a systematic review of the literature and developed recommendations for optimal HER2 testing performance. The guideline was reviewed by selected experts and approved by the board of directors for both organizations. Approximately 20% of current HER2 testing may be inaccurate. When carefully validated testing is performed, available data do not clearly demonstrate the superiority of either immunohistochemistry (IHC) or in situ hybridization (ISH) as a predictor of benefit from anti-HER2 therapy. The panel recommends that HER2 status should be determined for all invasive breast cancer. A testing algorithm that relies on accurate, reproducible assay performance, including newly available types of brightfield ISH, is proposed. Elements to reliably reduce assay variation (for example, specimen handling, assay exclusion, and reporting criteria) are specified. An algorithm defining positive, equivocal, and negative values for both HER2 protein expression and gene amplification is recommended: a positive HER2 result is IHC staining of 3+ (uniform, intense membrane staining of > 30% of invasive tumor cells), a fluorescent in situ hybridization (FISH) result of more than six HER2 gene copies per nucleus or a FISH ratio (HER2 gene signals to chromosome 17 signals) of more than 2.2; a negative result is an IHC staining of 0 or 1+, a FISH result of less than 4.0 HER2 gene copies per nucleus, or FISH ratio of less than 1.8. Equivocal results require additional action for final determination. It is recommended that to perform HER2 testing, laboratories show 95% concordance with another validated test for positive and negative assay values. The panel strongly recommends validation of laboratory assay or modifications, use of standardized operating procedures, and compliance with new testing criteria to be monitored with the use of stringent laboratory accreditation standards, proficiency testing, and competency assessment. The panel recommends that HER2 testing be done in a CAP-accredited laboratory or in a laboratory that meets the accreditation and proficiency testing requirements set out by this document.
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            Profiling of estrogen up- and down-regulated gene expression in human breast cancer cells: insights into gene networks and pathways underlying estrogenic control of proliferation and cell phenotype.

            Estrogens are known to regulate the proliferation of breast cancer cells and to alter their cytoarchitectural and phenotypic properties, but the gene networks and pathways by which estrogenic hormones regulate these events are only partially understood. We used global gene expression profiling by Affymetrix GeneChip microarray analysis, with quantitative PCR verification in many cases, to identify patterns and time courses of genes that are either stimulated or inhibited by estradiol (E2) in estrogen receptor (ER)-positive MCF-7 human breast cancer cells. Of the >12,000 genes queried, over 400 showed a robust pattern of regulation, and, notably, the majority (70%) were down-regulated. We observed a general up-regulation of positive proliferation regulators, including survivin, multiple growth factors, genes involved in cell cycle progression, and regulatory factor-receptor loops, and the down-regulation of transcriptional repressors, such as Mad4 and JunB, and of antiproliferative and proapoptotic genes, including B cell translocation gene-1 and -2, cyclin G2, BCL-2 antagonist/killer 1, BCL 2-interacting killer, caspase 9, and TGFbeta family growth inhibitory factors. These together likely contribute to the stimulation of proliferation and the suppression of apoptosis by E2 in these cells. Of interest, E2 appeared to modulate its own activity through the enhanced expression of genes involved in prostaglandin E production and signaling, which could lead to an increase in aromatase expression and E2 production, as well as the decreased expression of several nuclear receptor coactivators that could impact ER activity. Our studies highlight the diverse gene networks and metabolic and cell regulatory pathways through which this hormone operates to achieve its widespread effects on breast cancer cells.
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              Prognostic value of Ki67 expression after short-term presurgical endocrine therapy for primary breast cancer.

              Tumor expression of the proliferation antigen Ki67 is widely used to assess the prognosis of cancer patients. A change in the expression of Ki67 after short-term exposure of patients to therapeutic agents is frequently used as a pharmacodynamic marker of efficacy, particularly among breast cancer patients before undergoing surgery. To determine the clinical significance of the level of tumor cell proliferation during endocrine therapy for breast cancer, we measured the expression of Ki67 in tumor biopsy samples taken before and after 2 weeks of presurgical treatment with anastrozole or tamoxifen or the combination of anastrozole plus tamoxifen in 158 patients with hormone receptor-positive primary disease. In a multivariable analysis, we found that higher Ki67 expression after 2 weeks of endocrine therapy was statistically significantly associated with lower recurrence-free survival (P = .004) whereas higher Ki67 expression at baseline was not. Larger baseline tumor size and lower estrogen receptor level after 2 weeks of treatment were also statistically significantly associated with poorer recurrence-free survival (P < .001 and P = .04, respectively). Our data indicate that measurements of tumor Ki67 level after short-term endocrine treatment may improve the prediction of recurrence-free survival by integrating the prognostic value of Ki67 level at baseline with changes in Ki67 level that are associated with treatment benefit.
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                Author and article information

                Journal
                Br J Cancer
                Br. J. Cancer
                British Journal of Cancer
                Nature Publishing Group
                0007-0920
                1532-1827
                09 July 2013
                11 June 2013
                : 109
                : 1
                : 100-108
                Affiliations
                [1 ]Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine , 2-1 Seiryo-machi, Aoba-ku, 980-8575 Sendai, Japan
                [2 ]Department of Surgical Oncology, Tohoku University Graduate School of Medicine , 2-1 Seiryo-machi, Aoba-ku, 980-8575 Sendai, Japan
                [3 ]Department of Anatomic Pathology, Tohoku University Graduate School of Medicine , 2-1 Seiryo-machi, Aoba-ku, 980-8575 Sendai, Japan
                [4 ]Department of Surgery, Tohoku Kosai Hospital , 2-3-11 Kokubun-cho, Aoba-ku, 980-0803 Sendai, Japan
                [5 ]Department of Breast Oncology, Miyagi Cancer Center Hospital , Medeshimashiote, 47-1 Nodayama, 981-1239 Natori, Japan
                [6 ]Department of Surgery, Nihonkai General Hospital , 30 Akiho, 998-8501 Sakata, Japan
                [7 ]Department of Diagnostic Radiology, Tohoku University Graduate School of Medicine , 2-1 Seiryo-machi, Aoba-ku, 980-8575 Sendai, Japan
                [8 ]Department of Pathology, Tohoku University Hospital , Aoba-ku, 1-1 Seiryo-machi, 980-9574 Sendai, Japan
                Author notes
                Article
                bjc2013284
                10.1038/bjc.2013.284
                3708565
                23756858
                Copyright © 2013 Cancer Research UK

                From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

                Categories
                Translational Therapeutics

                Oncology & Radiotherapy

                breast carcinoma, aromatase, dcis, oestrogen, induced gene, letrozole

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