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Molecular Cancer Therapeutics

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Molecular Medicine in Practice

Epithelial–Mesenchymal Transition and Stem Cell Markers in Patients with HER2-Positive Metastatic Breast Cancer

Antonio Giordano, Hui Gao, Simone Anfossi, Evan Cohen, Michal Mego, Bang-Ning Lee, Sanda Tin, Michele De Laurentiis, Charla A. Parker, Ricardo H. Alvarez, Vicente Valero, Naoto T. Ueno, Sabino De Placido, Sendurai A. Mani, Francisco J. Esteva, Massimo Cristofanilli and James M. Reuben
Antonio Giordano
Authors' Affiliations: Departments of Hematopathology and Breast Medical Oncology, The Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Molecular Pathology and Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Endocrinology and Molecular and Clinical Oncology, University of Naples Federico II; Department of Breast Oncology, National Cancer Institute “Fondazione Pascale”, Naples, Italy; Department of Medical Oncology, National Cancer Institute, Bratislava, Slovakia; and Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PennsylvaniaAuthors' Affiliations: Departments of Hematopathology and Breast Medical Oncology, The Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Molecular Pathology and Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Endocrinology and Molecular and Clinical Oncology, University of Naples Federico II; Department of Breast Oncology, National Cancer Institute “Fondazione Pascale”, Naples, Italy; Department of Medical Oncology, National Cancer Institute, Bratislava, Slovakia; and Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
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Hui Gao
Authors' Affiliations: Departments of Hematopathology and Breast Medical Oncology, The Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Molecular Pathology and Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Endocrinology and Molecular and Clinical Oncology, University of Naples Federico II; Department of Breast Oncology, National Cancer Institute “Fondazione Pascale”, Naples, Italy; Department of Medical Oncology, National Cancer Institute, Bratislava, Slovakia; and Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
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Simone Anfossi
Authors' Affiliations: Departments of Hematopathology and Breast Medical Oncology, The Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Molecular Pathology and Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Endocrinology and Molecular and Clinical Oncology, University of Naples Federico II; Department of Breast Oncology, National Cancer Institute “Fondazione Pascale”, Naples, Italy; Department of Medical Oncology, National Cancer Institute, Bratislava, Slovakia; and Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
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Evan Cohen
Authors' Affiliations: Departments of Hematopathology and Breast Medical Oncology, The Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Molecular Pathology and Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Endocrinology and Molecular and Clinical Oncology, University of Naples Federico II; Department of Breast Oncology, National Cancer Institute “Fondazione Pascale”, Naples, Italy; Department of Medical Oncology, National Cancer Institute, Bratislava, Slovakia; and Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
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Michal Mego
Authors' Affiliations: Departments of Hematopathology and Breast Medical Oncology, The Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Molecular Pathology and Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Endocrinology and Molecular and Clinical Oncology, University of Naples Federico II; Department of Breast Oncology, National Cancer Institute “Fondazione Pascale”, Naples, Italy; Department of Medical Oncology, National Cancer Institute, Bratislava, Slovakia; and Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
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Bang-Ning Lee
Authors' Affiliations: Departments of Hematopathology and Breast Medical Oncology, The Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Molecular Pathology and Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Endocrinology and Molecular and Clinical Oncology, University of Naples Federico II; Department of Breast Oncology, National Cancer Institute “Fondazione Pascale”, Naples, Italy; Department of Medical Oncology, National Cancer Institute, Bratislava, Slovakia; and Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
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Sanda Tin
Authors' Affiliations: Departments of Hematopathology and Breast Medical Oncology, The Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Molecular Pathology and Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Endocrinology and Molecular and Clinical Oncology, University of Naples Federico II; Department of Breast Oncology, National Cancer Institute “Fondazione Pascale”, Naples, Italy; Department of Medical Oncology, National Cancer Institute, Bratislava, Slovakia; and Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
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Michele De Laurentiis
Authors' Affiliations: Departments of Hematopathology and Breast Medical Oncology, The Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Molecular Pathology and Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Endocrinology and Molecular and Clinical Oncology, University of Naples Federico II; Department of Breast Oncology, National Cancer Institute “Fondazione Pascale”, Naples, Italy; Department of Medical Oncology, National Cancer Institute, Bratislava, Slovakia; and Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
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Charla A. Parker
Authors' Affiliations: Departments of Hematopathology and Breast Medical Oncology, The Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Molecular Pathology and Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Endocrinology and Molecular and Clinical Oncology, University of Naples Federico II; Department of Breast Oncology, National Cancer Institute “Fondazione Pascale”, Naples, Italy; Department of Medical Oncology, National Cancer Institute, Bratislava, Slovakia; and Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
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Ricardo H. Alvarez
Authors' Affiliations: Departments of Hematopathology and Breast Medical Oncology, The Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Molecular Pathology and Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Endocrinology and Molecular and Clinical Oncology, University of Naples Federico II; Department of Breast Oncology, National Cancer Institute “Fondazione Pascale”, Naples, Italy; Department of Medical Oncology, National Cancer Institute, Bratislava, Slovakia; and Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
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Vicente Valero
Authors' Affiliations: Departments of Hematopathology and Breast Medical Oncology, The Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Molecular Pathology and Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Endocrinology and Molecular and Clinical Oncology, University of Naples Federico II; Department of Breast Oncology, National Cancer Institute “Fondazione Pascale”, Naples, Italy; Department of Medical Oncology, National Cancer Institute, Bratislava, Slovakia; and Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
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Naoto T. Ueno
Authors' Affiliations: Departments of Hematopathology and Breast Medical Oncology, The Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Molecular Pathology and Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Endocrinology and Molecular and Clinical Oncology, University of Naples Federico II; Department of Breast Oncology, National Cancer Institute “Fondazione Pascale”, Naples, Italy; Department of Medical Oncology, National Cancer Institute, Bratislava, Slovakia; and Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
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Sabino De Placido
Authors' Affiliations: Departments of Hematopathology and Breast Medical Oncology, The Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Molecular Pathology and Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Endocrinology and Molecular and Clinical Oncology, University of Naples Federico II; Department of Breast Oncology, National Cancer Institute “Fondazione Pascale”, Naples, Italy; Department of Medical Oncology, National Cancer Institute, Bratislava, Slovakia; and Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
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Sendurai A. Mani
Authors' Affiliations: Departments of Hematopathology and Breast Medical Oncology, The Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Molecular Pathology and Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Endocrinology and Molecular and Clinical Oncology, University of Naples Federico II; Department of Breast Oncology, National Cancer Institute “Fondazione Pascale”, Naples, Italy; Department of Medical Oncology, National Cancer Institute, Bratislava, Slovakia; and Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
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Francisco J. Esteva
Authors' Affiliations: Departments of Hematopathology and Breast Medical Oncology, The Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Molecular Pathology and Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Endocrinology and Molecular and Clinical Oncology, University of Naples Federico II; Department of Breast Oncology, National Cancer Institute “Fondazione Pascale”, Naples, Italy; Department of Medical Oncology, National Cancer Institute, Bratislava, Slovakia; and Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
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Massimo Cristofanilli
Authors' Affiliations: Departments of Hematopathology and Breast Medical Oncology, The Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Molecular Pathology and Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Endocrinology and Molecular and Clinical Oncology, University of Naples Federico II; Department of Breast Oncology, National Cancer Institute “Fondazione Pascale”, Naples, Italy; Department of Medical Oncology, National Cancer Institute, Bratislava, Slovakia; and Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
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James M. Reuben
Authors' Affiliations: Departments of Hematopathology and Breast Medical Oncology, The Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Molecular Pathology and Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Endocrinology and Molecular and Clinical Oncology, University of Naples Federico II; Department of Breast Oncology, National Cancer Institute “Fondazione Pascale”, Naples, Italy; Department of Medical Oncology, National Cancer Institute, Bratislava, Slovakia; and Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PennsylvaniaAuthors' Affiliations: Departments of Hematopathology and Breast Medical Oncology, The Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Department of Molecular Pathology and Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Endocrinology and Molecular and Clinical Oncology, University of Naples Federico II; Department of Breast Oncology, National Cancer Institute “Fondazione Pascale”, Naples, Italy; Department of Medical Oncology, National Cancer Institute, Bratislava, Slovakia; and Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
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DOI: 10.1158/1535-7163.MCT-12-0460 Published November 2012
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    Figure 1.

    Gene expression levels of EMT-TFs (TWIST1, SNAIL1, ZEB1, and TG2) and HER2 in the CD45+ and CD326+ cell fractions. The GAPDH gene was used to normalize gene expression levels, and the relative expression of each gene was calculated using the equation Embedded Image, where Embedded Image Embedded Image. Samples were considered positive if the gene expression of Embedded Image was higher than the mean of that in the CD45+ cell fraction Embedded Image + 3 SD (cut-off line). The Embedded Image medians among fractions were compared using the Mann–Whitney test.

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    Figure 2.

    Gene expression levels of EMT-TFs (TWIST1, SNAIL1, ZEB1, and TG2) and HER2 in the CD45+ and CD45− cell fractions. The GAPDH gene was used to normalize gene expression levels, and the relative expression of each gene was calculated using the equation Embedded Image, where Embedded Image Embedded Image. Samples were considered positive if the gene expression of Embedded Image was equal to or higher than 2 (cut-off line).

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    Figure 3.

    A, flow cytometric gating strategy to identify the CSC populations (ALDEFLUOR+ CD44+CD24lo/CD45− and ALDEFLUOR+ CD133+/CD45−). SSC, side scatter. B, we compared the percentage of stem cell marker–positive cells, ALDEFLUOR+ CD44+CD24lo/CD45− on the left and ALDEFLUOR+ CD133+/CD45− on the right, in the CD45− cell fractions with and without amplified EMT-TFs. The groups were compared using the Mann–Whitney test as follows: at least one amplified EMT-TF versus none, trastuzumab-naïve (group 1) versus trastuzumab-treated (group 2).

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    Figure 4.

    PFS (A) and OS (B) Kaplan–Meier curves for all 17 patients according to EpCAM transcript expression in the CD326+ cell fraction. EpCAM high expression (solid line; n = 8); EpCAM low expression (dashed line; n = 9); time was measured from the basal blood draw to the death for OS and to radiological evidence of disease progression (PFS).

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  • Table 1.

    Patient characteristics

    Characteristicn (%)
    Overall28 (100)
    Age [median (range)], y52 (35–72)
    ER/PR+15 (53.6)
    ER/PR−13 (46.4)
    First-line10 (35.7)
    ≥Second-line18 (64.3)
    CTC = 012 (42.9)
    CTC = 1–47 (25)
    CTCs ≥ 53 (10.7)
    CellSearch not conducted6 (21.4)

    Abbreviations: ER, estrogen receptor; PR, progesterone receptor.

    • Table 2.

      EMT-TFs expression according to CTC count and treatment

      SubgroupsData available (no. of patients)EMT-TF+ CD326+, n/N (%)EMT-TF+ CD45−, n/N (%)
      No. of CTCs
       0124/6 (66.7)6/12 (50)
       1–473/3 (100)3/7 (42.9)
       ≥531/1 (100)3/3 (100)
      Trastuzumab-naïve (group 1)95/6 (83.3)8/9 (88.9)
      Trastuzumab-treated (group 2)1810/11 (90.9)8/18 (44.4)

    Additional Files

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      Files in this Data Supplement:

      • Supplementary Figure Legend - PDF file - 86K
      • Supplementary Figure 1 - PDF file - 64K, Gene expression levels of EMT-TFs in the tested cell lines (HMLE, HMLE-TWIST, MCF-7, BT-474, SKBR-3, MDA-MB-231)
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    Molecular Cancer Therapeutics: 11 (11)
    November 2012
    Volume 11, Issue 11
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    Epithelial–Mesenchymal Transition and Stem Cell Markers in Patients with HER2-Positive Metastatic Breast Cancer
    Antonio Giordano, Hui Gao, Simone Anfossi, Evan Cohen, Michal Mego, Bang-Ning Lee, Sanda Tin, Michele De Laurentiis, Charla A. Parker, Ricardo H. Alvarez, Vicente Valero, Naoto T. Ueno, Sabino De Placido, Sendurai A. Mani, Francisco J. Esteva, Massimo Cristofanilli and James M. Reuben
    Mol Cancer Ther November 1 2012 (11) (11) 2526-2534; DOI: 10.1158/1535-7163.MCT-12-0460

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    Epithelial–Mesenchymal Transition and Stem Cell Markers in Patients with HER2-Positive Metastatic Breast Cancer
    Antonio Giordano, Hui Gao, Simone Anfossi, Evan Cohen, Michal Mego, Bang-Ning Lee, Sanda Tin, Michele De Laurentiis, Charla A. Parker, Ricardo H. Alvarez, Vicente Valero, Naoto T. Ueno, Sabino De Placido, Sendurai A. Mani, Francisco J. Esteva, Massimo Cristofanilli and James M. Reuben
    Mol Cancer Ther November 1 2012 (11) (11) 2526-2534; DOI: 10.1158/1535-7163.MCT-12-0460
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