The time is now to start molecular subtyping high-intermediate and high-risk endometrial cancers.

Nearly a decade ago the Cancer Genome Atlas (TCGA) 2013 analysis used sequencing data to cluster endometrial cancers into four distinct molecular subtypes with distinct survival patterns, rather than relying on traditional clinicopathologic criteria. Subsequent studies have validated these molecular subtypes in both single center and population-based analyses. The Proactive Molecular risk classifier for Endometrial cancer (ProMisE) study refined these subtypes using an alternative subtyping strategy that begins with immunohistochemistry-based (IHC) identification of the mismatch repair deficient (MMRD) subtype, followed by next-generation sequencing identification of polymerase ε exonuclease domain mutated (POLE EDM) tumors¹.

The US-based National Comprehensive Cancer Network 2021 guidelines recommend the consideration of molecular analysis in initial evaluation of endometrial cancers, with further indicated immunohistochemical staining for p53 abnormal tumors and a genetic evaluation for MMRD subtypes ². Further, the 2021 ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma recommend molecular subtyping of all clinicopathologic high-intermediate and high-risk tumors, and consideration in low risk tumors³. They then provide management guidelines for adjuvant therapy based on these molecular subtypes. Recent investigations have shown that molecular subtyping can identify low-risk cancers among clinicopathologically high-risk tumors, and vice versa⁴. Additionally, the testing of high- and high-intermediate risk cancers has been shown to be cost-effective compared to no testing or MMR testing only in a US-based cost-effectiveness analysis⁵. Finally, the PORTEC-4a (NCT03469674) and TAPER (NCT04705649) trials are investigating the effect of molecular subtype-based adjuvant therapy decisions on clinical outcomes.

Despite guidelines and a clear potential to change clinical outcomes, few centers have implemented the routine molecular subtyping of high-intermediate and high-risk endometrial cancers. Barriers exist including the time sensitive nature of beginning adjuvant therapy, as well as additional costs and coordination of multidisciplinary care. Few centers are ready to begin performing universal Sanger or next-generation sequencing to identify POLE EDM subtypes due to time and cost concerns for this common cancer. Yet, no commercially available, validated, and certified alternatives exist despite proposed multiplex qPCR or SNaPshot testing. It is clear that there is an imminent need for an alternative strategy that relies less on sequencing for POLE EDM subtypes or an alternative POLE testing method.

We won’t be ready to apply the molecular subtype informed adjuvant treatment strategies in PORTEC 4a, regardless of outcome, if we do not have the ability to subtype these tumors in clinical practice. The time to investigate and implement these strategies is now.