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. 2020 Dec 25;13(1):44.
doi: 10.3390/cancers13010044.

HER2 Status in High-Risk Endometrial Cancers (PORTEC-3): Relationship with Histotype, Molecular Classification, and Clinical Outcomes

Lisa Vermij  1 , Nanda Horeweg  2 , Alicia Leon-Castillo  1 , Tessa A Rutten  1 , Linda R Mileshkin  3 , Helen J Mackay  4 , Alexandra Leary  5 , Melanie E Powell  6 , Naveena Singh  7 , Emma J Crosbie  8   9 , Vincent T H B M Smit  1 , Carien L Creutzberg  2 , Tjalling Bosse  1
Affiliations

HER2 Status in High-Risk Endometrial Cancers (PORTEC-3): Relationship with Histotype, Molecular Classification, and Clinical Outcomes

Lisa Vermij et al. Cancers (Basel). .

Abstract

HER2 status has not been investigated in the context of the molecular endometrial cancer (EC) classification. Here, we aimed to determine the clinicopathological features and prognostic significance of the HER2 status in the molecularly classified PORTEC-3 trial population of patients with high-risk EC (HREC). HER2 testing was performed on tumor tissues of 407 molecularly classified HREC. HER2 status was determined by HER2 immunohistochemistry (IHC; all cases) and subsequent HER2 dual in situ hybridization for cases with any (in) complete moderate to strong membranous HER2 IHC expression. The Χ2 test and Spearman's Rho correlation coefficient were used to compare clinicopathological and molecular features. The Kaplan-Meier method, log-rank test, and Cox proportional hazards models were used for survival analysis. We identified 24 (5.9%) HER2-positive EC of various histological subtypes including serous (n = 9, 37.5%), endometrioid (n = 6, 25.0%), and clear cell (n = 5, 20.8%). HER2 positivity was highly associated with the p53-abnormal subgroup (p53abn, 23/24 cases; p < 0.0001). The correlation between p53abn and the HER2 status (ρ = 0.438; p < 0.0001) was significantly stronger (p < 0.0001) than between serous histology and the HER2 status (ρ = 0.154; p = 0.002). HER2 status did not have independent prognostic value for survival after correction for the molecular classification. Our study strongly suggests that molecular subclass-directed HER2 testing is superior to histotype-directed testing. This insight will be relevant for future trials targeting HER2.

Keywords: ERBB2; HER2; endometrial cancer; high-risk; p53.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Flowchart of HER2 testing of molecularly classified PORTEC-3 trial participants. * SISH was performed on a random selection of cases with absent (n = 10) and faint (n = 10) membranous staining to confirm the absence of HER2 amplification. Abbreviations: IHC, immunohistochemistry; SISH, silver in situ hybridization; NGS, next-generation sequencing.
Figure 2
Figure 2
Three examples of HER2-positive endometrial cancers (EC) of non-serous histology. (A) H&E of an EC diagnosed as International Federation of Gynecology and Obstetrics (FIGO) grade 2 endometrioid EC (EEC) with (B) aberrant mutant-like p53 immunostaining, (C) strong (in)complete membranous HER2 immunostaining, and HER2 gene amplification by dual in situ hybridization (DISH). (D) H&E of an EC diagnosed as FIGO grade 3 EEC with (E) aberrant mutant-like p53 immunostaining, (F) strong complete membranous HER2 immunostaining, and HER2 gene amplification by DISH. (G) H&E of an EC diagnosed as endometrial clear cell carcinoma with (H) aberrant mutant-like p53 immunostaining, (I) strong complete membranous HER2 immunostaining, and HER2 gene amplification by DISH. All images ×20 objective magnification.
Figure 3
Figure 3
Kaplan–Meier survival curves for 5-year (A) recurrence-free survival (RFS) and (B) overall survival (OS) for PORTEC-3 patients with HER2-positive and HER2-negative high-risk endometrial cancer (HREC); 5-year (C) RFS and (D) OS for patients with HER2-positive and HER2-negative p53 abnormal HREC.
See this image and copyright information in PMC

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