p53abn Endometrial Cancer: understanding the most aggressive endometrial cancers in the era of molecular classification

Over the past decade, our understanding of endometrial cancer has changed dramatically from the two-tiered clinicopathologic classification system of type I and type II endometrial cancer through to the four distinct molecular subtypes identified by The Cancer Genome Atlas (TCGA) in 2013. In both systems there is a small subset of endometrial cancers (serous histotype/high numbers of somatic copy number abnormalities) that account for a disproportionately high percentage of endometrial cancer related deaths. This subset can be identified in routine clinical practice by first identifying the approximately one-third of endometrial cancers that are either ultramutated/POLEmut tumors, with pathogenic mutations in the exonuclease domain of POLE, or hypermutated/MMRd tumors, with loss of DNA mismatch repair. Immunostaining for p53 stratifies the remaining endometrial cancers into those with wild-type staining pattern and those with mutant pattern staining (p53abn endometrial cancer). This latter group of p53abn endometrial cancer is the subject of this review. Most p53abn endometrial cancers are serous type and high grade, but it also includes other histotypes and lower grade tumors, and has consistently been associated with the poorest clinical outcomes. Although it only accounts for 15% of all endometrial cancer cases, it is responsible for 50-70% of endometrial cancer mortality. A better understanding of the molecular alterations in the p53abn subgroup, beyond the ubiquitous and definitional TP53 mutations, is required so we can identify better treatments for these most aggressive endometrial cancers. Recent evidence has shown improved survival outcomes with the addition of chemotherapy compared with radiation alone in p53abn endometrial cancers. Opportunities for targeted therapy for p53abn endometrial cancers also exist with a proportion of p53abn endometrial cancers known to have homologous recombination deficiency (HRD) or human epidermal growth factor 2 (HER2) overexpression/amplification. This review will provide an overview of our current understanding of p53abn endometrial cancer.