Unveiling the unique identity of clear-cell endometrial cancer (CCEC): A comprehensive comparative analysis with ovarian counterpart and other endometrial subtypes.

person Felix Blanc-Durand Institut Gustave Roussy, Villejuif, France info_outline Felix Blanc-Durand, Natalie Ngoi, Etienne Rouleau, Patricia Pautier, Judith Michels, Kaïssa Ouali, Catherine Genestie, Yi Wan Lim, Diana Lim, Silvana Talisa Wijaya, Alexandra Leary, David Shao Peng Tan

Authors person Felix Blanc-Durand Institut Gustave Roussy, Villejuif, France info_outline Felix Blanc-Durand, Natalie Ngoi, Etienne Rouleau, Patricia Pautier, Judith Michels, Kaïssa Ouali, Catherine Genestie, Yi Wan Lim, Diana Lim, Silvana Talisa Wijaya, Alexandra Leary, David Shao Peng Tan Organizations Institut Gustave Roussy, Villejuif, France, Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore, Service de Génétique des Tumeurs, Gustave Roussy Cancer Campus, Villejuif, France, Gustave Roussy Cancer Centre, Villejuif, France, Gustave Roussy Cancer Center, Villejuif, France, Gustave Roussy, Drug Development Department (DITEP), Villejuif, France, Gustave Roussy Institute, INSERM U981, Villejuif, France, National University Hospital, Singapore, Singapore, Singapore, Department of Pathology, National University of Singapore, Singapore, Singapore, National University Cancer Institute Singapore, Singapore, Singapore Abstract Disclosures Research Funding Nuovo Soldati Foundation President Graduate Fellowship Singapore, Pangestu Family Foundation Gynaecological Cancer Research Fund, Singapore Ministry of Health’s National Medical Research Council Background: Clear cell endometrial cancer (CCEC) is a rare and poorly understood entity, comprising less than 10% of endometrial cancer cases. In contrast, clear-cell ovarian cancer (CCOC) ranks as the second most prevalent subtype among epithelial ovarian cancers. CCOC is distinguished by specific phenotypic and molecular features, coupled with an overall aggressive behavior. CCEC and CCEC both share clinical and pathologic characteristics, suggesting common pathogenesis. This study aims to elucidate the molecular landscape of CCEC, in comparison with CCOC and other EC subtypes (nEC). Methods: We conducted a multicenter, retrospective analysis of CCOC, CCEC and nEC patients from Institut Gustave Roussy in France and National University Cancer Institute in Singapore. All patients underwent comprehensive molecular profiling using the tumor-based FoundationOneCDX panel. Results: This study analyzed 19 patients with CCEC, 81 patients with CCOC and 91 patients with nEC. CCEC exhibited distinct clinical and molecular features compared to CCOC or nEC. CCEC patients were significantly older (mean age 64.6 years) compared to CCOC (53.0 years, p<0.001) and nEC (59.9 years, p<0.001) cohorts. They also presented more frequently with FIGO IV disease (63.2%) versus 16.7% in CCOC patients (p<0.001) and 28.9% in nEC patients (p=0.007). Compared to CCOC, CCEC harbored significantly fewer ARID1A mutations (15.8% vs 54.3%, p=0.004), fewer KRAS mutations (0% vs 19.8%, p=0.035), significantly more TP53 mutations (42.1% vs 13.6%, p=0.008), and higher loss-of-heterozygosity (LOH) scores (10.5% vs 4.5%, p=0.004). Compared to nEC, CCEC exhibited significantly fewer CTNNB1 mutations (0% vs 18.7%, p=0.04), fewer PTEN mutations (5.3% vs 57.1%, p<0.001) and fewer KRAS mutations (0% vs 22.0%, p=0.021). Additionally, CCEC had higher LOH scores (10.5% vs 3.7%, p=0.019), and tended be less frequently associated with microsatellite instability (0% vs 19.3%, p=0.07) compared to nEC. Conclusions: CCEC significantly differs from CCOC and nEC in both clinical and molecular aspects. These findings support the consideration of CCEC as a distinct entity, advocating for a personalized approach that takes into account both the clear-cell aspect and the endometrial cancer molecular stratification.