PMID- 36610380 OWN - NLM STAT- MEDLINE DCOM- 20230314 LR - 20240302 IS - 1095-6859 (Electronic) IS - 0090-8258 (Print) IS - 0090-8258 (Linking) VI - 170 DP - 2023 Mar TI - Trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate with topoisomerase I inhibitor payload, shows antitumor activity in uterine and ovarian carcinosarcoma with HER2/neu expression. PG - 38-45 LID - S0090-8258(22)02018-2 [pii] LID - 10.1016/j.ygyno.2022.12.018 [doi] AB - OBJECTIVES: Carcinosarcomas are highly aggressive gynecologic malignancies containing both carcinomatous and sarcomatous elements with heterogeneous HER2/neu expression and limited therapeutic options. We compared the efficacy of trastuzumab deruxtecan (DS-8201a), a novel HER2/neu-targeting antibody-drug conjugate (ADC) to an ADC isotype control (MAAA-9199) against primary uterine and ovarian carcinosarcomas in vitro and in vivo. METHODS: Twelve primary carcinosarcoma (CS) cell lines were evaluated for HER2/neu surface expression by immunohistochemistry (IHC) and by flow cytometry, and gene amplification by fluorescence in situ hybridization (FISH) assays. The in vitro experiments included cytotoxicity and bystander killing effect assays on three cell lines of variable HER2/neu expression. In vivo activity was studied in a mouse CS xenograft model of 3+ HER2/neu uterine CS. RESULTS: In vitro studies showed that DS-8201a was highly effective against uterine and ovarian CS cell lines demonstrating 3+ HER2/neu expression compared to MAAA-9199 control; there was no significant improvement in the 0 HER2/neu CS cell line. However, DS-8201a induced efficient bystander killing of 0 HER2/neu tumor cells when admixed with 3+ HER2/neu cells. In vivo studies confirmed that DS-8201a was more effective than MAAA-9199 in 3+ HER2/neu-expressing CS xenografts. CONCLUSION: DS-8201a may represent a novel and highly effective ADC against HER2/neu-expressing CS. CI - Copyright (c) 2022 Elsevier Inc. All rights reserved. FAU - Mauricio, Dennis AU - Mauricio D AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America. FAU - Bellone, Stefania AU - Bellone S AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America. FAU - Mutlu, Levent AU - Mutlu L AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America. FAU - McNamara, Blair AU - McNamara B AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America. FAU - Manavella, Diego D AU - Manavella DD AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America. FAU - Demirkiran, Cem AU - Demirkiran C AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America. FAU - Verzosa, Miguel Skyler Z AU - Verzosa MSZ AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America. FAU - Buza, Natalia AU - Buza N AD - Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, United States of America. FAU - Hui, Pei AU - Hui P AD - Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, United States of America. FAU - Hartwich, Tobias Max Philipp AU - Hartwich TMP AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America. FAU - Harold, Justin AU - Harold J AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America. FAU - Yang-Hartwich, Yang AU - Yang-Hartwich Y AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America. FAU - Zipponi, Margherita AU - Zipponi M AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America. FAU - Altwerger, Gary AU - Altwerger G AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America. FAU - Ratner, Elena AU - Ratner E AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America. FAU - Huang, Gloria S AU - Huang GS AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America. FAU - Clark, Mitchell AU - Clark M AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America. FAU - Andikyan, Vaagn AU - Andikyan V AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America. FAU - Azodi, Masoud AU - Azodi M AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America. FAU - Schwartz, Peter E AU - Schwartz PE AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America. FAU - Santin, Alessandro D AU - Santin AD AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, United States of America. Electronic address: alessandro.santin@yale.edu. LA - eng GR - P30 CA016359/CA/NCI NIH HHS/United States GR - U01 CA176067/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20230105 PL - United States TA - Gynecol Oncol JT - Gynecologic oncology JID - 0365304 RN - 5384HK7574 (trastuzumab deruxtecan) RN - 0 (Topoisomerase I Inhibitors) RN - EC 2.7.10.1 (Receptor, ErbB-2) RN - 0 (Antibodies, Monoclonal, Humanized) RN - P188ANX8CK (Trastuzumab) RN - 0 (Immunoconjugates) SB - IM MH - Humans MH - Female MH - Mice MH - Animals MH - Topoisomerase I Inhibitors/pharmacology/therapeutic use MH - In Situ Hybridization, Fluorescence MH - Receptor, ErbB-2/genetics MH - Antibodies, Monoclonal, Humanized/therapeutic use MH - Cell Line, Tumor MH - Trastuzumab/therapeutic use MH - *Immunoconjugates/therapeutic use MH - *Ovarian Neoplasms/pathology MH - *Carcinosarcoma/pathology PMC - PMC10445234 MID - NIHMS1863149 OTO - NOTNLM OT - Antibody-drug conjugate OT - DS-8201a OT - HER2/neu OT - Ovarian Carcinosarcoma OT - Trastuzumab deruxtecan OT - Uterine Carcinosarcoma COIS- Declaration of Competing Interest A.D.S. reports grants from PUMA, grants from IMMUNOMEDICS, grants from GILEAD, grants from SYNTHON, grants and personal fees from MERCK, grants from BOEHINGER-INGELHEIM, grants from GENENTECH, grants and personal fees from TESARO and grants and personal fees from EISAI and R-Pharm USA. The other authors declare no conflict of interest. EDAT- 2023/01/08 06:00 MHDA- 2023/03/15 06:00 PMCR- 2024/03/01 CRDT- 2023/01/07 18:24 PHST- 2022/10/06 00:00 [received] PHST- 2022/12/05 00:00 [revised] PHST- 2022/12/26 00:00 [accepted] PHST- 2023/01/08 06:00 [pubmed] PHST- 2023/03/15 06:00 [medline] PHST- 2023/01/07 18:24 [entrez] PHST- 2024/03/01 00:00 [pmc-release] AID - S0090-8258(22)02018-2 [pii] AID - 10.1016/j.ygyno.2022.12.018 [doi] PST - ppublish SO - Gynecol Oncol. 2023 Mar;170:38-45. doi: 10.1016/j.ygyno.2022.12.018. Epub 2023 Jan 5.