IMMUNOHISTOCHEMICAL BIOMARKERS IN EC 111 5 INTRODUCTION Endometrial cancer (EC) is the most common gynecologic malignancy in industrialized countries and the incidence is rising due to advanced life expectancy and obesity1. In general, patients diagnosed at an early stage have a favorable prognosis. Yet, about 20% of patients with clinical early stage disease have a poor outcome2, 3. ECs are histologically classified into type 1, comprising endometrioid EC (EEC) with a favorable prognosis, and type 2, comprising of non-endometrioid EC (NEEC) most commonly with serous-, carcinosarcoma- or clear cell histology and unfavorable prognosis4. Currently used risk classifications systems are based on clinicopathological risk factors, and guide primary- and/or adjuvant treatment. Different EC risk classifications are used in clinical practice: the European Society for Medical Oncology - European Society of Gynaecological Oncology - European SocieTy for Radiotherapy & Oncology (ESMOESGO-ESTRO), Post-operative Radiation Therapy for Endometrial Carcinoma (PORTEC) and Gynecologic Oncology Group (GOG) criteria1, 5-7. All these risk classifications stratify into ‘low, low-intermediate, intermediate, high-intermediate, high or advanced/metastatic’ based on tumor grade, stage, histology, and age (GOG and PORTEC)5-8. The ESMO-ESGOESTRO risk classification can be used preoperatively to guide the need for lymph node (LN) directed surgery, and postoperatively to define adjuvant treatment. Recently, we published the ENDORISK model showing improved preoperative risk classification in EC with easy accessible biomarkers integrated in a Bayesian network9. This personalized network included immunohistochemical (IHC) expression of p53, L1 cell-adhesion molecule (L1CAM), estrogen receptor (ER), progesterone receptor (PR), and clinical preoperative biomarkers and was established to predict lymph node metastasis (LNM) and outcome preoperatively. The Cancer Genome Atlas (TCGA) identified four important prognostic molecular subgroups based on integrated genomic data10, in which patients with p53-abn had the poorest outcome11-13. Integration of molecular profiling according to the TCGA in the ESMO risk classification was evaluated by Talhouk et al. and showed high prevalence of p53-abn in the ESMO ‘high’ risk group. However, for the other ESMO risk groups molecular profiling was not discriminative11. The integration of molecular profiling appears promising in guiding adjuvant treatment14. However, routine molecular profiling in each patient is expensive, and as most patients have a good outcome with hysterectomy and bilateral salpingo-oophorectomy only, a costeffective stepwise approach might be a suitable alternative. It is hypothesized that the use of preoperative IHC biomarkers such as p53, L1CAM and ER/PR, is not only valuable in guiding primary surgical approach (e.g. ENDORISK), yet also adjuvant treatment in daily clinical
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