CHAPTER 5 122 To our knowledge the prognostic relevance of integrating IHC biomarkers in the ESMOESGO-ESTRO risk classification groups has not been studied so far. Yet, there are some limitations that need to be addressed. First, in addition to the IHC biomarkers, we did not include the well-established final histopathological markers related to the prognosis. However, as expected the preoperative abnormal biomarker expression of p53, L1CAM and ER/PR are significant associated with grade 3, NEEC, LVSI, MI and cervical stromal invasion (CSI) (data not shown). Abnormal preoperative biomarkers could therefore serve as surrogate biomarkers for these final histopathological risk factors. Second, as we used p53 IHC expression as indicator for p53-abn without information on POLE or mismatch repair deficient (MMR-D) status, we might have slightly overestimated the number of patients with p53-abn. However, as multiple classifiers are only present in 3% of the cases, it is unlikely that this has influenced our findings36. Finally, inherent to the retrospective character of the study, differences in outcome might be explained by the fact that adjuvant treatment was not uniformly applied. The majority (80-100%) of the patients with LNM and abnormal IHC expression received chemotherapy (CT) or chemo- and radiotherapy (CTRT) as adjuvant treatment, compared with 55% for patients with LNM and normal IHC expression (data not shown). This difference in percentage could be explained by patients being treated according final tumor stage and histology in different ENITEC centers in Europe, i.e. patients that received more often radiotherapy mainly had endometrioid histology, whereas those with adjuvant chemotherapy more often non-endometrioid histology. Thus, patients having worst outcome most frequently received CT or CTRT instead of RT alone, and this does therefore not explain the specifically worse outcome in these patients. The strength of this multicenter study is the large patient cohort, and well-documented and long-term follow-up. Although primary and adjuvant treatment was not uniformly applied, the current study reflects actual clinical practice facilitating implementation. For this study we focused on the IHC expression in the preoperative setting, as the risk of extended disease and LNM appears mainly associated with p53-abn and significantly less with the other TCGA groups12. We expect that molecular profiling will be incorporated in future treatment planning37-40. The study of Leslie et al. revealed that patients with TP53 mutation had significant better PFS with adjuvant chemotherapy + bevacizumab when compared to chemotherapy + temsirolimus, this significant difference was not shown in patients with TP53 wildtype41. This illustrated the relevance of TCGA with respect to the adjuvant treatment. However, routine molecular analysis is expensive and requires fully equipped laboratory, therefore a step-wise approach could bridge this gap, and contribute to selective molecular profiling in ‘high’ risk EC patients13. Cosgrove et al. showed that even selective molecular profiling in patients with only EEC histology could provide additional prognostic information. This step-wise approach could be used combined with the Lynch
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