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In Vivo and In Vitro Efficacy of Trastuzumab Deruxtecan in Uterine Serous Carcinoma.
Mutlu, Levent; Manavella, Diego D; Bellone, Stefania; McNamara, Blair; Harold, Justin A; Mauricio, Dennis; Siegel, Eric R; Buza, Natalia; Hui, Pei; Hartwich, Tobias Max Philipp; Yang-Hartwich, Yang; Demirkiran, Cem; Verzosa, Miguel Skyler Z; Altwerger, Gary; Ratner, Elena S; Huang, Gloria S; Clark, Mitchell; Andikyan, Vaagn; Azodi, Masoud; Dottino, Peter R; Schwartz, Peter E; Santin, Alessandro D.
Affiliation
  • Mutlu L; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
  • Manavella DD; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
  • Bellone S; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
  • McNamara B; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
  • Harold JA; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
  • Mauricio D; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
  • Siegel ER; Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
  • Buza N; Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
  • Hui P; Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
  • Hartwich TMP; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
  • Yang-Hartwich Y; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
  • Demirkiran C; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
  • Verzosa MSZ; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
  • Altwerger G; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
  • Ratner ES; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
  • Huang GS; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
  • Clark M; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
  • Andikyan V; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
  • Azodi M; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
  • Dottino PR; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
  • Schwartz PE; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
  • Santin AD; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Mol Cancer Ther ; 22(12): 1404-1412, 2023 Dec 01.
Article in En | MEDLINE | ID: mdl-37676984
ABSTRACT
Uterine serous carcinoma (USC) is a rare, biologically aggressive variant of endometrial cancer with a high recurrence rate and poor prognosis. HER2 overexpression (3+ positivity) by IHC and/or FISH ERBB2 gene amplification is detected in approximately one-third of patients with USC. Clinical trials incorporating trastuzumab with standard chemotherapy have recently demonstrated improved progression-free and overall survival in advanced-stage or recurrent USC that overexpresses HER2. However, a large number of patients with USC eventually developed resistance to trastuzumab. Trastuzumab deruxtecan (T-DXd) is a novel HER2-directed antibody-drug conjugate with a topoisomerase I inhibitor payload recently approved by the Food and Drug Administration (FDA) for multiple tumor indications. Here, we investigated the in vitro and in vivo efficacy of T-DXd in primary USC cell lines and xenografts with different HER2 expression. T-DXd-induced cell growth suppression in HER2-overexpressing cell lines in vitro, increased early and late apoptosis as assessed by annexin and propidium iodide staining, and, similarly to trastuzumab, T-DXd-induced significant antibody-dependent cellular cytotoxicity in the presence of peripheral blood lymphocytes. While negligible activity was detected against USC cell lines with low HER2 expression, T-DXd demonstrated significant bystander killing against USC tumors with low/negligible HER2 when such cells were admixed with HER2 3+ tumor cells in vitro. T-DXd showed tumor growth suppression in in vivo USC PDX models that overexpress HER2 at 3+ levels, prolonging survival when compared with controls, with minimal toxicity. Future clinical trials are warranted in patients with USC failing trastuzumab treatment.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Uterine Neoplasms / Carcinoma / Immunoconjugates Limits: Female / Humans Language: En Journal: Mol Cancer Ther Year: 2023 Document type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Uterine Neoplasms / Carcinoma / Immunoconjugates Limits: Female / Humans Language: En Journal: Mol Cancer Ther Year: 2023 Document type: Article