In Vivo and In Vitro Efficacy of Trastuzumab Deruxtecan in Uterine Serous Carcinoma

Levent Mutlu, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Diego D. Manavella, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Stefania Bellone, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Blair McNamara, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Justin A. Harold, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Dennis Mauricio, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Eric R. Siegel, Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Natalia Buza, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
Pei Hui, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
Tobias Max Hartwich, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Yang Yang-Hartwich, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Cem Demirkiran, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Miguel Skyler Verzosa, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Gary Altwerger, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Elena S. Ratner, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Gloria S. Huang, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Mitchell Clark, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Vaagn Andikyan, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Masoud Azodi, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.Follow
Peter R. Dottino, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Peter E. Schwartz, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Alessandro D. Santin, Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.

Document Type

Article

Publication Title

Molecular cancer therapeutics

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.

First Page

1404

Last Page

1412

DOI

10.1158/1535-7163.MCT-23-0126

Publication Date

12-1-2023

Identifier

37676984 (pubmed); 10.1158/1535-7163.MCT-23-0126 (doi); 728973 (pii)

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