Decreased HER2 expression in endometrial cancer following anti-HER2 therapy Journal Article

   


Authors: Chui, M. H.; Brown, D. N.; Da Cruz Paula, A.; da Silva, E. M.; Momeni-Boroujeni, A.; Reis-Filho, J. S.; Zhang, Y.; Makker, V.; Ellenson, L. H.; Weigelt, B.
Article Title: Decreased HER2 expression in endometrial cancer following anti-HER2 therapy
Abstract: 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. © 2023 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. © 2023 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Keywords: immunohistochemistry; adult; clinical article; controlled study; human tissue; protein expression; treatment response; cancer surgery; primary tumor; human cell; somatic mutation; clinical feature; cancer recurrence; cancer growth; drug withdrawal; paclitaxel; cancer adjuvant therapy; cancer patient; endometrium carcinoma; endometrium cancer; gene targeting; gene overexpression; cancer immunotherapy; multiple cycle treatment; gene amplification; gene expression profiling; epidermal growth factor receptor 2; cohort analysis; tumor biopsy; drug resistance; transcriptomics; protein p53; tissue section; fluorescence in situ hybridization; drug combination; tumor recurrence; cancer cell; targeted therapy; down regulation; gene dosage; drug therapy; trastuzumab; pik3ca gene; therapy; genetic heterogeneity; her2; aggression; phylogenetic tree; uterine papillary serous carcinoma; high grade endometrial carcinoma; trastuzumab emtansine; rb1 gene; nf1 gene; high throughput sequencing; human; female; article; ppp2r1a gene; whole exome sequencing; monoclonal antibody therapy; genetic profile; mrna expression level; f box/wd repeat containing protein 7; tumor-related gene; neoplastic cell transformation; high-grade endometrial cancer; uterine serous cancer; intratumour heterogeneity
Journal Title: Journal of Pathology
Volume: 262
Issue: 2
ISSN: 0022-3417
Publisher: Wiley Blackwell  
Date Published: 2024-02-01
Start Page: 129
End Page: 136
Language: English
DOI: 10.1002/path.6230
PUBMED: 38013631
PROVIDER: scopus
PMCID: PMC10842011
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85178047126&doi=10.1002%2fpath.6230&partnerID=40&md5=33dfd83f3318d960b4dcc8d4cef6f3df
Notes: The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record. Corresponding MSK authora are M Herman Chui and Britta Weigelt -- Source: Scopus
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MSK Authors
  1. Vicky Makker
    265 Makker
  2. Britta Weigelt
    633 Weigelt
  3. Jorge Sergio Reis-Filho
    639 Reis-Filho
  4. Arnaud Fabian Da Cruz Paula
    145 Da Cruz Paula
  5. Edaise Maria Da Silva
    95 Da Silva
  6. Yanming Zhang
    199 Zhang
  7. David Norman Brown
    91 Brown
  8. Amir Momeni Boroujeni
    88 Momeni Boroujeni
  9. Michael Herman Chui
    60 Chui
  10. Lora Hedrick Ellenson
    109 Ellenson
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