Assessing the Status of Cyclin E1 (CCNE1) From Gene to Protein Level in Ovarian and Endometrial Carcinomas: A...

Twenty percent and 45.4% of high-grade ovarian carcinomas (OC) and endometrial carcinomas (EC) exhibit CCNE1 amplification (CCNE1-amp), respectively, which is related to poor prognosis, but could serve as predictive biomarker for response to innovative targeted therapies. However, there is no consensus regarding how to evaluate the CCNE1 status (at the DNA, RNA, and/or protein level). Therefore, we conducted a systematic review of CCNE1 status testing in tubo-ovarian neoplasms and EC, comparing their performance for clinical purposes and highlighting the test's interpretation criteria (CRD420250651291). Among the 734 records initially found on PubMed and Google Scholar, 48 reports were finally included. Molecular analyses and immunohistochemistry (IHC) were reported on 9774 tubo-ovarian neoplasms and 750 EC, and 6966 tubo-ovarian neoplasms and 856 EC, respectively. The most frequently morphological used method to detect CCNE1-amp was fluorescent in situ hybridization (13/16 studies, 81.3%), with quite consensual criteria to defined amplification (ie, CCNE1/chromosome 19 ratio ≥2, and/or >8/≥8 copies of CCNE1 per nucleus, and/or ≥4 CCNE1 copies in ≥40% of cells). The proportion of tubo-ovarian neoplasms with CCNE1 immunohistochemical overexpression varied from 13.5% to 96%, and 14.6% to 86.1% in EC. The sensitivity and specificity of CCNE1 IHC to detect/exclude CCNE1-amp varied from 54.5% to 100% and 59.3% to 90.1%, respectively. Given the reported data, CCNE1 overexpression should be considered either when an H-score is ≥100 or when the staining is >60% with >5% of cells strongly stained. Both CCNE1-amp and CCNE1 overexpressions were associated with poor prognosis and with response to Wee1 and CDK2 inhibitors in high-grade serous OC (overall response rate up to 53%, objective response rate of 32%-40%). In contrast, CCNE1 messenger RNA overexpression had no prognostic value. Thus, both CCNE1-amp detection by fluorescent in situ hybridization and CCNE1 protein levels quantification using IHC represent today the most validated tools to determine the CCNE1 status in OC/EC.