Ovarian clear cell carcinoma (OCCC) is a subtype of ovarian carcinoma characterized by unique biological features and highly malignant characteristics including low chemosensitivity. Therefore, new therapeutic targets are needed. These could include the downstream pathways of receptor tyrosine kinases, especially the human epidermal growth factor receptor 2 (HER2). Our main objective was to characterize the HER2 status using immunohistochemistry (IHC) and FISH on 118 OCCCs, also considering the novel paradigm of HER2-zero and HER2-low status. Other aims included determination of the association between HER2 status and survival, HER2 gene DNA and RNA NGS analysis, HER2 gene expression analysis, and correlation between IHC and gene expression in HER2-zero and HER2-low cases. Cases with HER2 overexpression/amplification accounted for 5.1% (6/118), with additional 3% harbouring HER2 gene mutation. The remaining 112 (94.9%) cases were HER2-negative. Of these, 75% were classified as HER2-zero and 25% as HER2-low. This percentage of HER2 aberrations is significant concerning their possible therapeutic influence. Cases from the HER2-zero group showed significantly better survival. Although this relationship lost statistical significance in multivariate analysis, the results have potential therapeutic significance. HER2 gene expression analysis showed a significant correlation with HER2 IHC status in the entire cohort (HER2-positive vs. HER2-negative), while in the cohort of only HER2-negative cases, the results did not reach statistical significance, suggesting that gene expression analysis would not be suitable to confirm the subdivision into HER2-low and HER2-zero. Our results also emphasize the need for standardized HER2 testing in OCCC to determine the best predictor of clinical response.

Department of Obstetrics and Gynecology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Oncological Pathology Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Pathology 1st Faculty of Medicine Charles University and General University Hospital Prague Studničkova 2 12800 Prague 2 Prague Czech Republic

Department of Pathology 3rd Faculty of Medicine Charles University University Hospital Kralovske Vinohrady 10034 Prague Czech Republic

Department of Pathology and Molecular Medicine 2nd Faculty of Medicine Charles University Prague and Motol University Hospital Prague Czech Republic

Department of Pathology and Molecular Medicine 3rd Faculty of Medicine Charles University Thomayer University Hospital Prague Czech Republic

Department of Pathology Faculty of Medicine University of Debrecen 4032 Debrecen Hungary

Department of Pathology University Hospital Brno and Medical Faculty Masaryk University Brno Czech Republic

Institute of Medical Biochemistry and Laboratory Diagnostics 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Šikl's Department of Pathology The Faculty of Medicine and Faculty Hospital in Pilsen Charles University Pilsen Czech Republic

The Fingerland Department of Pathology Charles University Faculty of Medicine Hradec Králové and University Hospital Hradec Králové Hradec Králové Czech Republic

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