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      Circulating Tumour Cells, Circulating Tumour DNA and Circulating MicroRNA in Metastatic Breast Carcinoma – What is the Role of Liquid Biopsy in Breast Cancer? Translated title: Zirkulierende Tumorzellen, zirkulierende Tumor-DNA und zirkulierende microRNA beim metastasierten Mammakarzinom – oder: Welche Rolle spielt die Liquid Biopsy beim Brustkrebs?

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          Abstract

          Dissemination of tumour cells and the development of solid metastases occurs via blood vessels and lymphatics. Circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA) can be detected in venous blood in patients with early and metastatic breast cancer, and their prognostic relevance has been demonstrated on numerous occasions. Repeated testing for CTCs and ctDNA, or regular so-called “liquid biopsy”, can be performed easily at any stage during the course of disease. Additional molecular analysis allows definition of tumour characteristics and heterogeneity that may be associated with treatment resistance. This in turn makes personalised, targeted treatments possible that may achieve both improved overall survival and quality of life.

          Zusammenfassung

          Die Streuung von Tumorzellen und Entstehung solider Metastasen findet sowohl über das Lymph- als auch das Blutsystem statt. Der Nachweis zirkulierender Tumorzellen (CTCs) und der zirkulierenden Tumor-DNA (ctDNA) im venösen Blut ist sowohl beim frühen als auch beim metastasierten Mammakarzinom möglich. Ihre prognostische Relevanz wurde bereits mehrfach bewiesen. Dabei ist die repetitive Untersuchung der CTCs bzw. ctDNA im Sinne einer regelmäßigen „liquid biopsy“ jederzeit und problemlos möglich. Durch die zusätzlichen molekularen Analysen ist es möglich, Tumorcharakteristika und ihre Heterogenität, die mit möglichen Resistenzen einhergehen, zu definieren. Dies ermöglicht den Einsatz einer personalisierten und zielgerichteten Therapie, um neben einem verlängerten Gesamtüberleben auch die Verbesserung der Lebensqualität zu erreichen.

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          Circulating tumor cells and response to chemotherapy in metastatic breast cancer: SWOG S0500.

          Increased circulating tumor cells (CTCs; five or more CTCs per 7.5 mL of whole blood) are associated with poor prognosis in metastatic breast cancer (MBC). A randomized trial of patients with persistent increase in CTCs tested whether changing chemotherapy after one cycle of first-line chemotherapy would improve the primary outcome of overall survival (OS). Patients with MBC who did not have increased CTCs at baseline remained on initial therapy until progression (arm A). Patients with initially increased CTCs that decreased after 21 days of therapy remained on initial therapy (arm B). Patients with persistently increased CTCs after 21 days of therapy were randomly assigned to continue initial therapy (arm C1) or change to an alternative chemotherapy (arm C2). Of 595 eligible and evaluable patients, 276 (46%) did not have increased CTCs (arm A). Of those with initially increased CTCs, 31 (10%) were not retested, 165 were assigned to arm B, and 123 were randomly assigned to arm C1 or C2. No difference in median OS was observed between arm C1 and C2 (10.7 and 12.5 months, respectively; P = .98). CTCs were strongly prognostic. Median OS for arms A, B, and C (C1 and C2 combined) were 35 months, 23 months, and 13 months, respectively (P < .001). This study confirms the prognostic significance of CTCs in patients with MBC receiving first-line chemotherapy. For patients with persistently increased CTCs after 21 days of first-line chemotherapy, early switching to an alternate cytotoxic therapy was not effective in prolonging OS. For this population, there is a need for more effective treatment than standard chemotherapy. © 2014 by American Society of Clinical Oncology.
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            Circulating microRNAs as blood-based markers for patients with primary and metastatic breast cancer

            Introduction MicroRNAs (miRs) are interesting new diagnostic targets that may provide important insights into the molecular pathogenesis of breast cancer. Here we evaluated, for the first time, the feasibility and clinical utility of circulating miRs as biomarkers for the detection and staging of breast cancer. Methods The relative concentrations of breast cancer-associated miR10b, miR34a, miR141 and miR155 were measured in the blood serum of 89 patients with primary breast cancer (M0, n = 59) and metastatic disease (M1, n = 30), and 29 healthy women by a TaqMan MicroRNA Assay. Results The relative concentrations of total RNA (P = 0.0001) and miR155 (P = 0.0001) in serum significantly discriminated M0-patients from healthy women, whereas miR10b (P = 0.005), miR34a (P = 0.001) and miR155 (P = 0.008) discriminated M1-patients from healthy controls. In breast cancer patients, the changes in the levels of total RNA (P = 0.0001), miR10b (P = 0.01), miR34a (P = 0.003) and miR155 (P = 0.002) correlated with the presence of overt metastases. Within the M0-cohort, patients at advanced tumor stages (pT3 to 4) had significantly more total RNA (P = 0.0001) and miR34a (P = 0.01) in their blood than patients at early tumor stages (pT1 to 2). Conclusions This pilot study provides first evidence that tumor-associated circulating miRs are elevated in the blood of breast cancer patients and associated with tumor progression.
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              D538G mutation in estrogen receptor-α: A novel mechanism for acquired endocrine resistance in breast cancer.

              Resistance to endocrine therapy occurs in virtually all patients with estrogen receptor α (ERα)-positive metastatic breast cancer, and is attributed to various mechanisms including loss of ERα expression, altered activity of coregulators, and cross-talk between the ERα and growth factor signaling pathways. To our knowledge, acquired mutations of the ERα have not been described as mediating endocrine resistance. Samples of 13 patients with metastatic breast cancer were analyzed for mutations in cancer-related genes. In five patients who developed resistance to hormonal therapy, a mutation of A to G at position 1,613 of ERα, resulting in a substitution of aspartic acid at position 538 to glycine (D538G), was identified in liver metastases. Importantly, the mutation was not detected in the primary tumors obtained prior to endocrine treatment. Structural modeling indicated that D538G substitution leads to a conformational change in the ligand-binding domain, which mimics the conformation of activated ligand-bound receptor and alters binding of tamoxifen. Indeed, experiments in breast cancer cells indicated constitutive, ligand-independent transcriptional activity of the D538G receptor, and overexpression of it enhanced proliferation and conferred resistance to tamoxifen. These data indicate a novel mechanism of acquired endocrine resistance in breast cancer. Further studies are needed to assess the frequency of D538G-ERα among patients with breast cancer and explore ways to inhibit its activity and restore endocrine sensitivity.
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                Author and article information

                Journal
                Geburtshilfe Frauenheilkd
                Geburtshilfe Frauenheilkd
                10.1055/s-00000020
                Geburtshilfe und Frauenheilkunde
                Georg Thieme Verlag KG (Stuttgart · New York )
                0016-5751
                1438-8804
                December 2017
                18 December 2017
                : 77
                : 12
                : 1291-1298
                Affiliations
                [1 ]Klinik für Gynäkologie und Geburtshilfe, Universitätsklinikum Ulm, Ulm, Germany
                [2 ]Klinik für Gynäkologie und Geburtshilfe, Universitätsklinikum Tübingen, Tübingen, Germany
                [3 ]Klinik für Gynäkologie und Geburtshilfe, Universitätsklinikum Erlangen, Erlangen, Germany
                [4 ]Nationales Centrum für Tumorerkrankungen, Universitätsklinikum Heidelberg, Heidelberg, Germany
                [5 ]Klinik für Gynäkologie und Geburtshilfe, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
                [6 ]Klinik für Gynäkologie und Geburtshilfe, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
                Author notes
                Correspondence/Korrespondenzadresse Arkadius Polasik, Medical resident Ulm University Hospital Dpt. Gynecol. and Obstetrics Prittwitzstraße 4389074 UlmGermany arkadius.polasik@ 123456uniklinik-ulm.de
                Article
                5099260
                10.1055/s-0043-122884
                5734937
                d36074e0-8f6b-49bd-8099-1a3697e729c6

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License, which permits unrestricted reproduction and distribution, for non-commercial purposes only; and use and reproduction, but not distribution, of adapted material for non-commercial purposes only, provided the original work is properly cited.

                History
                : 16 July 2017
                : 09 November 2017
                : 12 November 2017
                Categories
                GebFra Science
                Review/Übersicht

                breast,her-2/neu (human epidermal growth factor recptor),hormonal receptor,mammary gland tumor,metastasis,brust,her-2/neu (humaner epidermaler wachstumsfaktor-rezeptor),hormonrezeptor,tumor der brustdrüse,metastase

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