PMID- 38013631 OWN - NLM STAT- MEDLINE DCOM- 20240111 LR - 20240423 IS - 1096-9896 (Electronic) IS - 0022-3417 (Print) IS - 0022-3417 (Linking) VI - 262 IP - 2 DP - 2024 Feb TI - Decreased HER2 expression in endometrial cancer following anti-HER2 therapy. PG - 129-136 LID - 10.1002/path.6230 [doi] AB - Trastuzumab has demonstrated clinical efficacy in the treatment of HER2-positive serous endometrial cancer (EC), which led to its incorporation into standard-of-care management of this aggressive disease. Acquired resistance remains an important challenge, however, and its underlying mechanisms in EC are unknown. To define the molecular changes that occur in response to anti-HER2 therapy in EC, targeted next-generation sequencing (NGS), HER2 immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH) were performed on pre- and post-treatment tumour samples from 14 patients with EC treated with trastuzumab or trastuzumab emtansine. Recurrent tumours after anti-HER2 therapy acquired additional genetic alterations compared with matched pre-treatment ECs and frequently showed decreased HER2 protein expression by IHC (7/14, 50%). Complete/near-complete absence of HER2 protein expression (score 0/1+) observed post-treatment (4/14, 29%) was associated with retained HER2 gene amplification (n = 3) or copy number neutral status (n = 1). Whole-exome sequencing performed on primary and recurrent tumours from the latter case, which exhibited genetic heterogeneity of HER2 amplification in the primary tumour, revealed selection of an early HER2-non-amplified clone following therapy. Our findings demonstrate that loss of target expression, by selection of HER2-non-amplified clones or, more commonly, by downregulation of expression, may constitute a mechanism of resistance to anti-HER2 therapy in HER2-positive EC. (c) 2023 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. CI - (c) 2023 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. FAU - Chui, M Herman AU - Chui MH AUID- ORCID: 0000-0002-7220-3996 AD - Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - Brown, David N AU - Brown DN AD - Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - Da Cruz Paula, Arnaud AU - Da Cruz Paula A AD - Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - da Silva, Edaise M AU - da Silva EM AD - Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - Momeni-Boroujeni, Amir AU - Momeni-Boroujeni A AD - Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - Reis-Filho, Jorge S AU - Reis-Filho JS AUID- ORCID: 0000-0003-2969-3173 AD - Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - Zhang, Yanming AU - Zhang Y AD - Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - Makker, Vicky AU - Makker V AD - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - Ellenson, Lora Hedrick AU - Ellenson LH AD - Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - Weigelt, Britta AU - Weigelt B AUID- ORCID: 0000-0001-9927-1270 AD - Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. LA - eng GR - NCI P50 CA247749 01/NH/NIH HHS/United States GR - P30CA008748/CA/NCI NIH HHS/United States GR - P30 CA008748/CA/NCI NIH HHS/United States GR - P50 CA247749/CA/NCI NIH HHS/United States GR - UL1 TR002384/TR/NCATS NIH HHS/United States GR - UL1 TR000457/TR/NCATS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20231127 PL - England TA - J Pathol JT - The Journal of pathology JID - 0204634 RN - EC 2.7.10.1 (Receptor, ErbB-2) RN - P188ANX8CK (Trastuzumab) SB - IM MH - Female MH - Humans MH - *Receptor, ErbB-2/genetics/metabolism MH - In Situ Hybridization, Fluorescence MH - Neoplasm Recurrence, Local/genetics MH - Trastuzumab/therapeutic use MH - *Endometrial Neoplasms/drug therapy/genetics/pathology MH - Gene Amplification PMC - PMC10842011 MID - NIHMS1937870 OTO - NOTNLM OT - HER2 OT - drug resistance OT - high-grade endometrial cancer OT - intratumour heterogeneity OT - targeted therapy OT - trastuzumab OT - uterine serous cancer COIS- Disclosures: M.H.C. reports receiving an honorarium from Roche. S.S. reports receiving honoraria from MJH Life Sciences, outside the submitted work. J.S.R.-F. reports receiving personal/consultancy fees from Goldman Sachs, Bain Capital, REPARE Therapeutics, Saga Diagnostics and Paige.AI, membership of the scientific advisory boards of VolitionRx, REPARE Therapeutics and Paige.AI, membership of the Board of Directors of Grupo Oncoclinicas, and ad hoc membership of the scientific advisory boards of AstraZeneca, Merck, Daiichi Sankyo, Roche Tissue Diagnostics and Personalis, outside the submitted work. V.M. reports receiving research support/grants from Clovis, Merck, Eisai, Karyopharm, Faeth, Duality, and AstraZeneca; and serving as an advisory board member for Eisai, Merck, Novartis, AstraZeneca, Clovis, Karyopharm, Faeth, Duality, and Morphosys, outside the submitted work. B.W. reports research support by REPARE Therapeutics, outside the submitted work. The remaining authors have no conflicts of interest to declare. EDAT- 2023/11/28 06:42 MHDA- 2024/01/11 07:43 PMCR- 2025/02/01 CRDT- 2023/11/28 03:48 PHST- 2023/09/19 00:00 [revised] PHST- 2023/05/18 00:00 [received] PHST- 2023/10/12 00:00 [accepted] PHST- 2025/02/01 00:00 [pmc-release] PHST- 2024/01/11 07:43 [medline] PHST- 2023/11/28 06:42 [pubmed] PHST- 2023/11/28 03:48 [entrez] AID - 10.1002/path.6230 [doi] PST - ppublish SO - J Pathol. 2024 Feb;262(2):129-136. doi: 10.1002/path.6230. Epub 2023 Nov 27.