Molecular endometrial carcinoma classification: facing up to the challenges of clinical implementation

Abstract

A proportion of patients with endometrial carcinoma are currently over- or undertreated due to the lack of reproducibility of some of the traditional factors used to assess risk of recurrence and death due to the cancer, as

well as intrinsic differences in the biological background of tumours within the same risk category. This underlines

the need for additional biomarkers for the improvement of current risk classification systems and adjuvant treatment selection. In this context, the molecular endometrial carcinoma classification offers an opportunity to categorize tumours according to their molecular background, resulting in more biologically homogeneous groups of patients, with a more precise prognostic and, possibly, predictive value. However, before clinical implementation is possible, information regarding the interpretation of non-hotspot POLE exonuclease domain mutations, as

well as the molecular background and clinical outcome of EC with more than one molecular classifying feature (multiple classifier EC) is needed in order to obtain a reproducible and accurate classification system. Additionally, the integration of the molecular subgroups with clinicopathological features has proven to have a strong prognostic value in intermediate to high-risk and unselected cohorts, highlighting its potential to refine prognosis in high-risk patients and perhaps its predictive value. Finally, not all women in the molecularly profiled EC cohorts published were staged by lymphadenectomy and most patients had received adjuvant treatment. These features could have influenced the prognostic value of the molecular subgroups. The aims of this thesis were: 1) To refine the molecular profiling of endometrial carcinoma by addressing essential remaining questions on the interpretation of POLE variants and characterization of multiple classifier ECs. 2) To elucidate the prognostic role of the molecular subgroups in high-risk patients. 3) To evaluate the value of the molecular classification to guide adjuvant treatment decisions. 4) To investigate the natural behaviour of the molecular EC subgroups among patients staged with lymphadenectomy or not receiving adjuvant treatment.