PMID- 37558129 OWN - NLM STAT- MEDLINE DCOM- 20231127 LR - 20240425 IS - 1530-0285 (Electronic) IS - 0893-3952 (Print) IS - 0893-3952 (Linking) VI - 36 IP - 11 DP - 2023 Nov TI - HER2 Genetic Intratumor Heterogeneity Is Associated With Resistance to Trastuzumab and Trastuzumab Emtansine Therapy in Recurrent High-Grade Endometrial Cancer. PG - 100299 LID - S0893-3952(23)00204-1 [pii] LID - 10.1016/j.modpat.2023.100299 [doi] AB - Anti-HER2 targeted therapies have recently demonstrated clinical activity in the treatment of high-grade endometrial carcinomas (ECs), particularly serous carcinomas with HER2 amplification and/or overexpression. Intratumor heterogeneity of HER2 amplification or HER2 genetic intratumor heterogeneity (G-ITH) has been associated with resistance to anti-HER2 therapies in breast and gastroesophageal cancers; however, its clinical relevance in EC is unknown. To characterize HER2 G-ITH in EC, archival specimens from a clinically annotated cohort of 57 ECs treated with trastuzumab or trasutuzmab emtansine in the recurrent (n = 38) or adjuvant (n = 19) setting were subjected to central pathology review, HER2 assessment by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), and next-generation sequencing. HER2 G-ITH, defined as HER2 amplification in 5% to 50% of tumor cells examined by FISH, was identified in 36% (19/53) of ECs and was associated with lower HER2 copy number and levels of protein expression. HER2 IHC revealed spatially distinct areas of strong expression juxtaposed with areas of low/absent expression in tumors with the "cluster" pattern of G-ITH, whereas the "mosaic" pattern was typically associated with a diffuse admixture of cells with variable levels of HER2 expression. HER2 G-ITH was frequently observed in cases with IHC/FISH or FISH/next-generation sequencing discrepancies and/or with an equivocal/negative FISH result (9/13, 69%). Although the objective response rate to anti-HER2 therapy in recurrent ECs was 52% (13/25) for tumors lacking HER2 G-ITH, none (0%, 0/10) of the patients with HER2 G-ITH achieved a complete or partial response (P = .005). HER2 G-ITH was significantly associated with worse progression-free survival (hazard ratio, 2.88; 95% CI, 1.33-6.27; P = .005) but not overall survival. HER2 IHC score, HER2/CEP17 ratio, HER2 copy number, histologic subtype, and other genetic alterations, including PIK3CA hotspot mutations, were not significantly associated with therapeutic response or survival outcomes. Treatment responses were not restricted to serous carcinomas, supporting consideration of anti-HER2 therapy in patients with HER2-positive high-grade ECs of non-serous histology. Our results demonstrate that HER2 G-ITH is an important determinant of response to trastuzumab and trastuzumab emtansine in EC, providing a rationale for the development of novel therapeutic strategies to target HER2-nonamplified resistant tumor subpopulations, such as HER2 antibody-drug conjugates with bystander effects. CI - Copyright (c) 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved. FAU - Shen, Sherry AU - Shen S AD - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Ma, Weining AU - Ma W AD - Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Brown, David AU - Brown D AD - Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Da Cruz Paula, Arnaud AU - Da Cruz Paula A AD - Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Zhou, Qin AU - Zhou Q AD - Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Iaosonos, Alexia AU - Iaosonos A AD - Department of Biostatistics and Epidemiology, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Tessier-Cloutier, Basile AU - Tessier-Cloutier B AD - Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Ross, Dara S AU - Ross DS AD - Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Troso-Sandoval, Tiffany AU - Troso-Sandoval T AD - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Reis-Filho, Jorge S AU - Reis-Filho JS AD - Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Abu-Rustum, Nadeem AU - Abu-Rustum N AD - Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Zhang, Yanming AU - Zhang Y AD - Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Ellenson, Lora H AU - Ellenson LH AD - Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Weigelt, Britta AU - Weigelt B AD - Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Makker, Vicky AU - Makker V AD - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. FAU - Chui, M Herman AU - Chui MH AD - Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address: chuim1@mskcc.org. LA - eng GR - P30 CA008748/CA/NCI NIH HHS/United States GR - P50 CA247749/CA/NCI NIH HHS/United States GR - UL1 TR000457/TR/NCATS NIH HHS/United States GR - UL1 TR002384/TR/NCATS NIH HHS/United States PT - Journal Article DEP - 20230807 PL - United States TA - Mod Pathol JT - Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc JID - 8806605 RN - P188ANX8CK (Trastuzumab) RN - SE2KH7T06F (Ado-Trastuzumab Emtansine) RN - EC 2.7.10.1 (Receptor, ErbB-2) SB - IM MH - Female MH - Humans MH - Trastuzumab/therapeutic use MH - Ado-Trastuzumab Emtansine/therapeutic use MH - In Situ Hybridization, Fluorescence MH - Receptor, ErbB-2/metabolism MH - *Endometrial Neoplasms/drug therapy/genetics/pathology MH - *Carcinoma/drug therapy MH - *Breast Neoplasms/drug therapy PMC - PMC10841308 MID - NIHMS1929842 OTO - NOTNLM OT - HER2 OT - high-grade endometrial cancer OT - intratumor heterogeneity OT - targeted therapy OT - trastuzumab OT - uterine serous cancer EDAT- 2023/08/10 00:42 MHDA- 2023/11/27 12:43 PMCR- 2024/11/01 CRDT- 2023/08/09 19:26 PHST- 2023/05/17 00:00 [received] PHST- 2023/07/11 00:00 [revised] PHST- 2023/07/31 00:00 [accepted] PHST- 2024/11/01 00:00 [pmc-release] PHST- 2023/11/27 12:43 [medline] PHST- 2023/08/10 00:42 [pubmed] PHST- 2023/08/09 19:26 [entrez] AID - S0893-3952(23)00204-1 [pii] AID - 10.1016/j.modpat.2023.100299 [doi] PST - ppublish SO - Mod Pathol. 2023 Nov;36(11):100299. doi: 10.1016/j.modpat.2023.100299. Epub 2023 Aug 7.