ESR1 Overexpression Is Associated With Recurrence On Stage I Endometrioid Endometrial Carcinoma

Claudia CHAVES, Brazilian National Camcer Institute, Brazil
SIMAO T. 5 , NICOLAU-NETO P. 2 , SANTOS P. 2 , LISBOA L. 5 , MOREIRA F. 4 , BIANCCHI B. 4 , MOREIRA M. 3 , PINTO L. 2 , BESSA C. 1

1 Gynecologic Oncology Department, Brazilian National Cancer Institute, Rio de Janeiro, Brazil
2 Molecular Carcinogenesis Program, Brazilian National Cancer Institute, Rio de Janeiro, Brazi
3 Department of Genetics, Brazilian National Cancer Institute, Rio de Janeiro, Brazi
4 Pathology Department, Brazilian National Cancer Institute, Rio de Janeiro, Brazi
5 Biochemistry Department, IBRAG, Rio de Janeiro State University, Rio de Janeiro, Brazi

Purposes: Endometrial cancer is classified into two subtypes of tumors with different clinicopathological features and prognosis. Endometriod endometrial carcinoma (EEC) is the most frequent subtype. Most of these tumors are diagnosed in early stages and have a favorable prognosis, but some may present an unexpected recurrence, with limited responsiveness to treatment. As prognosis is based solely on clinicopathological features, this study was designed to analyze the EEC global gene expression profile in stage I cases which presented relapse comparing to non-recurrent cases.
 
Methods: DNA microarray platform was applied in tumor samples of 10 stage I EEC cases, from which 5 presented relapse and 5 didn’t. An enrichment analysis of differentially expressed genes (DEG) and a transcriptional factor network assessment were performed in recurrent cases, where one overexpressed factor was identified. Therefore, a quantitative PCR (RT-qPCR) of its encoded gene was performed with a larger number of formalin-fixed paraffin-embedded (FFPE) samples of stage I EEC (n=64): 22 recurrent and 42 not recurrent (n=42) cases.
 
Results: The estrogen receptor, encoded by ESR1, presented overexpressed in recurrence. ESR1 expression was 4.3-fold higher in relapse cases compared to no recurrence cases in DNA microarray analysis (n=10). Assessment of ESR1 expression by RT-qPCR showed 4.29-fold higher expression in recurrent tumors. ROC curve demonstrated 81.4% of specificity and 65.9% of sensitivity, with 87% of accuracy.  Univariate analysis showed a significant association between high expression of ESR1 and worse prognosis in disease-free survival (p = 0.001) and overall survival rates (p = 0.013), increasing the risk of relapse in 5.48 fold and the risk of death in 4.188-fold. In multivariate analysis, high expression of ESR1 was reported as independent prognosis variable for both disease-free survival (p=0.003) and overall survival (p=0.023).
 
Conclusion: ESR1 overexpression is associated with worse prognosis in stage I EEC.

Funding: CNPq, FAPERJ, CAPES, MS