MOLECULAR PROFILING IN LOW-GRADE EC 61 3 DISCUSSION A new era of incorporating molecular profiling in EC to guide adjuvant treatment has started. This study assessed whether molecular profiling is prognostically relevant specifically in patients with low-grade EC. Interestingly, low-grade EC patients had a very favorable 5-years DSS independent of the molecular subgroups, when compared to high-grade EC. Furthermore, high-grade EC as well as TP53-mutant and FIGO advanced-stage, were independently associated with a decreased DSS. Within patients with low-grade EC, none of the molecular subgroups seemed independently associated with reduced DSS. Our study confirmed the excellent prognosis for POLE-mutant, good/intermediate for MSI and NSMP, and poor for TP53-mutant when analyzing all histological subtypes.3, 14 Moreover, the present study illustrated that the molecular subgroups were mainly discriminative amongst high-grade EC.3, 8 So far, no previous studies have evaluated the outcome for the molecular subgroups within patients with low-grade EC. We analyzed the open access data of Kandoth et al.3 to validate our results. Molecular profiling has been proposed to perform routinely in all EC patients.2, 18 However, as the majority of EC patients are diagnosed with low-grade EC, it is questioned whether this strategy is beneficial and cost-effective. Our data on low-grade EC demonstrate that full molecular profiling seems not necessary (except for screening for Lynch syndrome).19 Multivariate analyses did not show any statistically significant effect of the molecular subgroups within patients with low-grade EC. However, the number of events was low in this subgroup analysis. Analyzing the HR’s, the high HR of TP53-mutant could possibly still be associated with a reduced DSS in low-grade EC patients. We question whether this is mainly attributed to grade 2 EC as shown in the DSS curve of TP53-mutant within grade 2 EC. Poor interobserver reproducibility is mainly observed within grade 2 and 3 EC, in these patients the use of immunohistochemical (IHC) or molecular markers could be recommended, e.g. TP53 mutation analyses in patients with doubtful low-grade (grade 2) EC.4, 8, 20, 21 In this way binary grading (low- vs. high-grade) including molecular profiling or immunohistochemistry could be optimized with respect to reproducibility.2 Molecular profiling is demanding for health care facilities and comes with high costs, especially challenging in low income countries. The primary clinical management of EC should therefore be guided based on morphological tumor characteristics, consideration of immunohistochemistry in doubtful cases, and selective molecular profiling in high-grade and/or advanced stage patients for guiding adjuvant treatment decisions.22
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