The prognostic significance of estrogen and progesterone receptors in grade I and II endometrioid endometrial adenocarcinoma: hormone receptors in risk stratification

Abstract

Objectives: Although patients with grade I and II endometrioid endometrial adenocarcinoma (EEA) are considered with good prognosis, among them 15%-25% died in 5 years. It is still unknown whether integrating estrogen receptor (ER) and progesterone receptor (PR) into clinical risk stratification can help select high-risk patients with grade I-II EEA. This study was to investigate the prognostic value of ER and PR double negativity (ER/PR loss) in grade I-II EEA, and the association between ER/PR loss and The Cancer Genome Atlas (TCGA) classification.

Methods: ER and PR were assessed by immunohistochemistry on hysterectomy specimens of 903 patients with grade I-II EEA. ER and PR negativity were determined when <1% tumor nuclei were stained. Gene expression data were obtained from the TCGA research network.

Results: Compared with ER or PR positive patients (n=868), patients with ER/PR loss (n=35) had deeper myometrial infiltration (p=0.012), severer FIGO stage (p=0.004), and higher rate of pelvic lymph node metastasis (p=0.020). In univariate analysis, ER/PR loss correlated with a shorter progression-free survival (PFS; hazard ratio [HR]=5.25; 95% confidence interval [CI]=2.21-12.52) and overall survival (OS; HR=7.59; 95% CI=2.55-22.60). In multivariate analysis, ER/PR loss independently predicted poor PFS (HR=3.77; 95% CI=1.60-10.14) and OS (HR=5.56; 95% CI=1.37-22.55) for all patients, and poor PFS for patients in stage IA (n=695; HR=5.54; 95% CI=1.28-23.89) and stage II-IV (n=129; HR=5.77; 95% CI=1.57-21.27). No association was found between ER/PR loss and TCGA classification.

Conclusion: Integrating ER/PR evaluation into clinical risk stratification may improve prognosis for grade I-II EEA patients.

Keywords: Biomarker; Endometrial Cancer; Endometrioid Carcinoma; Estrogen Receptor; Low-Grade; Progesterone Receptor.

Fig. 1. Representative photomicrographs of immunohistochemical staining for estimation of ER-α, PR, and p53: (A) ER loss, (B) ER positive, (C) PR loss, (D) PR positive, (E) p53 loss, (F) p53 normal, and (G) p53 over-expression (A-D: original magnification ×40; E,F: original magnification ×20).

ER, estrogen receptor; PR, progesterone receptor.

Fig. 2. Estimated PFS and OS for grade I–II EEA patients (A, B) according to ER/PR status and within risk subgroups based on FIGO stage: stage IA (C, D), stage IB (E, F) and stage II–IV (G, H) (Kaplan-Meier estimation).

PFS, progression-free survival; OS, overall survival; ER, estrogen receptor; PR, progesterone receptor; FIGO, International Federation of Gynecology and Obstetrics.

Fig. 3. Prognostic values of ER/PR status, ESR1/PGR status and TCGA genomic subgroups in grade I–II EEA patients (Kaplan-Meier estimation) and association between TCGA classification and ESR1/PGR expression(χ² test): (A) estimated PFS according to ER/PR status by immunohistochemistry in Shanghai cohort, (B) estimated PFS according to mRNA expression of ESR1/PGR status in TCGA cohort, (C) estimated PFS according to TCGA genomic subgroups in TCGA cohort, and (D) distribution of TCGA genomic subgroups in low- and high-ESR1/PGR groups and the association between TCGA classification and ESR1/PGR status.

ER, estrogen receptor; PR, progesterone receptor; TGCA, The Cancer Genome Atlas; EEA, endometrioid endometrial adenocarcinoma; PFS, progression-free survival.