HER2 Overexpression and Amplification in Uterine Carcinosarcomas With Serous Morphology

Abstract

Uterine carcinosarcoma (UCS) is an aggressive malignancy with few treatment options. A recent clinical trial has shown an increase in progression-free survival in patients with human epidermal growth factor receptor 2 (HER2)-positive serous endometrial carcinomas treated with anti-HER2-targeted therapies. Few studies have evaluated HER2 expression/amplification in UCS. Similar to serous endometrial carcinoma, the majority of UCS have TP53 mutations and a serous epithelial component, suggesting that UCS may show similar rates of HER2 positivity and therapeutic response. Therefore, we evaluated HER2 expression/amplification in a cohort of UCS over a 5-year period. HER2 immunohistochemistry (IHC) and chromogenic in situ hybridization were performed on tissue microarray and whole tissue sections and scored according to the most recent clinical trial recommendations. Three of 48 UCS (6%) had strong (3+) HER2 IHC expression, and 3 cases (6%) were equivocal (2+). Seven cases (15%) had HER2 amplification by chromogenic in situ hybridization, including all 3 with overexpression and 2 that were equivocal by IHC. Mismatch repair (MMR) protein, p53, and programmed cell death-ligand 1 (PD-L1) expression status was obtained from prior whole section analyses. All HER2-positive cases had a serous morphology and aberrant p53 expression. Only minimal PD-L1 expression was seen in the HER2-positive cases, and none had MMR loss. A subset of UCS with serous morphology have overexpression and/ or amplification of HER2, which may predict response to HER2-targeted therapies. HER2-positive UCS may be less susceptible to immune checkpoint inhibition as they uncommonly show MMR deficiency and/or strong PD-L1 expression. Thus, HER2-targeted therapies could be of clinical utility in a subset of UCS without other adjuvant treatment options.

Uterine Neoplasms, Version 1.2023, NCCN Clinical Practice Guidelines in Oncology

“…Rottmann et al 52 recently showed that 16% of 80 gynecologic carcinosarcomas (including uterine carcinosarcoma) showed HER2 overexpression and amplification when using the 2013 ASCO/College of American Pathologists scoring system. Similar results were reported by several studies, 53,54 including by Yoshida et al 55 and Jenkins et al 56 The panel recommends HER2 IHC testing (with reflex to HER2 fluorescence in situ hybridization for equivocal IHC) for possible treatment of advanced-stage or recurrent serous endometrial carcinoma or carcinosarcoma. HER2 IHC testing should also be considered in TP53-mutated/p53 abnormal endometrial carcinoma regardless of histotype.…”

Management and Prognosis of Patients with Recurrent or Persistent/Progressive Uterine Carcinosarcoma

“…HER2 overexpression in UCS has also been studied recently, and ORRs were around 10–20% in UCS [ 6 , 49 , 50 ]. Although there is no clinical trial data using HER2-targeting agents in treating UCS, a phase II trial revealed that a trastuzumab add-on to carboplatin and paclitaxel prolonged PFS more than chemotherapy alone in stage III/IV HER2/neu over-expressed serous endometrial cancer [ 51 ].…”

“…Although there is no clinical trial data using HER2-targeting agents in treating UCS, a phase II trial revealed that a trastuzumab add-on to carboplatin and paclitaxel prolonged PFS more than chemotherapy alone in stage III/IV HER2/neu over-expressed serous endometrial cancer [ 51 ]. Since these HER2-overexpressed UCS usually had a serous histology [ 49 , 50 ], HER2-targeted therapy would be a reasonable option in UCS with a serous component. We also had some patients with a check of HER2 IHC stain ( n = 10/98).…”

Ado-tratuzumab emtansine beyond breast cancer: therapeutic role of targeting other HER2-positive cancers

“…HER2 overexpression is also seen in USCs. Several studies have shown that 6% of USCs express HER2 IHC3 + and 15% of USCs express FISH + ( Jenkins et al, 2022 ). A preclinical study has revealed that T-DM1 seems to have a therapeutic effect on primary HER2-overexpressing USCs.…”