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T-DM1, a novel antibody-drug conjugate, is highly effective against uterine and ovarian carcinosarcomas overexpressing HER2

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Abstract

Ovarian and uterine carcinosarcoma (CS) are characterized by their aggressive clinical behavior and poor prognosis. We evaluated the efficacy of trastuzumab-emtansine (T-DM1), against primary HER2 positive and HER2 negative CS cell lines in vitro and in vivo. Eight primary CS cell lines were evaluated for HER2 amplification and protein expression by fluorescence in situ hybridization, immunohistochemistry, flow cytometry and qRT-PCR. Sensitivity to T-DM1-induced antibody-dependent-cell-mediated-cytotoxicity (ADCC) was evaluated in 4-h-chromium-release-assays. T-DM1 cytostatic and apoptotic activities were evaluated using flow cytometry based proliferation assays. In vivo activity of T-DM1 was also evaluated. HER2 protein overexpression and gene amplification were detected in 25 % (2/8) of the primary CS cell lines. T-DM1 and T were similarly effective in inducing strong ADCC against CS overexpressing HER2 at 3+ levels. In contrast, T-DM1 was dramatically more effective than T in inhibiting cell proliferation (P < 0.0001) and in inducing G2/M phase cell cycle arrest in the HER2 expressing cell lines (shift of G2/M: mean ± SEM from 14.87 ± 1.23 to 66.57 ± 4.56 %, P < 0.0001). Importantly, T-DM1 was highly active at reducing tumor formation in vivo in CS xenografts overexpressing HER2 (P = 0.0001 and P < 0.0001 compared to T and vehicle respectively) with a significantly longer survival when compared to T and vehicle mice (P = 0.008 and P = 0.0001 respectively). T-DM1 may represent a novel treatment option for the subset of HER2 positive CS patients with disease refractory to chemotherapy.

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Abbreviations

CS:

Carcinosarcoma

HER2/ErbB2:

Epidermal growth factor type 2 receptor

T-DM1:

Trastuzumab-emtansine

T:

Trastuzumab

FISH:

Fluorescence in situ hybridization

IHC:

Immunohistochemistry

qRT-PCR:

Quantitative real time polymerase chain reaction

ADCC:

Antibody-dependent-cell-mediated-cytotoxicity

MMMT:

Malignant mixed Müllerian tumors

DM1:

Maytansinoid cytotoxin

ASCO/CAP:

American Society of Clinical Oncology and the College of American Pathologists

PBL:

Peripheral blood lymphocytes

IV:

Intravenous

IACUC:

Institutional animal care and use committee

MFI:

Mean fluorescence intensity

ADC:

Antibody-drug conjugate

NK:

Natural killer

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Acknowledgments

We wish to thank Genentech for providing T-DM1. This work was supported in part by R01 CA154460-01 and U01 CA176067-01A1 grants from NIH, the Deborah Bunn Alley Foundation, the Tina Brozman Foundation and the Guido Berlucchi Foundation to ADS. RN was supported by the Italian Ministry of Health (RF-2010-2313497). This investigation was also supported by NIH Research Grant CA-16359 from the NCI.

Conflict of interests

The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, 06520, USA

    Roberta Nicoletti, Salvatore Lopez, Stefania Bellone, Emiliano Cocco, Carlton L. Schwab, Jonathan D. Black, Floriana Centritto, Liancheng Zhu, Elena Bonazzoli, Peter E. Schwartz, Thomas J. Rutherford & Alessandro D. Santin

  2. Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133, Milan, Italy

    Roberta Nicoletti, Floriana Centritto, Delia Mezzanzanica & Silvana Canevari

  3. Department of Pathology, Yale University School of Medicine, New Haven, CT, 06520, USA

    Natalia Buza & Pei Hui

  4. Division of Gynecologic Oncology, University Campus Bio-Medico of Rome, Via Alvaro del Portillo 21, 00128, Rome, Italy

    Salvatore Lopez

  5. Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medial University, Shenyang, 110004, China

    Liancheng Zhu

  6. 333 Cedar Street, LSOG 305, PO Box 208063, New Haven, CT, 06520-8063, USA

    Alessandro D. Santin

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  1. Roberta Nicoletti
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  2. Salvatore Lopez
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  3. Stefania Bellone
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  4. Emiliano Cocco
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  5. Carlton L. Schwab
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  6. Jonathan D. Black
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  7. Floriana Centritto
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  9. Elena Bonazzoli
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  10. Natalia Buza
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  14. Peter E. Schwartz
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  16. Alessandro D. Santin
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Correspondence to Alessandro D. Santin.

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Nicoletti, R., Lopez, S., Bellone, S. et al. T-DM1, a novel antibody-drug conjugate, is highly effective against uterine and ovarian carcinosarcomas overexpressing HER2. Clin Exp Metastasis 32, 29–38 (2015). https://doi.org/10.1007/s10585-014-9688-8

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  • DOI: https://doi.org/10.1007/s10585-014-9688-8

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