The emerging role of molecular pathology in directing the systemic treatment of endometrial cancer

Abstract

Following the discovery of the four molecular subtypes of endometrial cancer (EC) by The Cancer Genome Atlas (TCGA) in 2013, subsequent studies used surrogate markers to develop and validate a clinically relevant EC classification tool to recapitulate TCGA subtypes. Molecular classification combines focused sequencing ( POLE) and immunohistochemistry (mismatch repair and p53 proteins) to assign patients with EC to one of four molecular subtypes: POLEmut, MMRd, p53abn and NSMP (no specific molecular profile). Unlike histopathological evaluation, the molecular subtyping of EC offers an objective and reproducible classification system that has been shown to have prognostic value and therapeutic implications. It is an exciting time in EC care where we have moved beyond treatment based on histomorphology alone, and molecular classification will now finally allow assessment of treatment efficacy within biologically similar tumours. It is now recommended that molecular classification should be considered for all ECs, and should be performed routinely in all high grade tumours. It is also recommended to incorporate molecular classification into standard pathology reporting and treatment decision-making algorithms. In this review, we will discuss how the molecular classification of EC can be used to guide both conventional and targeted therapy in this new molecular era.

What Has Changed in the Management of Uterine Serous Carcinomas? Two Decades of Experience

“…Currently, the RAINBO umbrella trial attempts to redefine adjuvant therapy in endometrial carcinomas on the basis of molecular testing. More specifically, in patients with p53abn disease, the study will evaluate the role of PARPi maintenance treatment post chemotherapy and radiotherapy [ 44 ].…”

Endometrial Cancer: Transitioning from Histology to Genomics

“…The improved reproducibility of these classifications compared to historic histotyping make it an attractive strategy to incorporate in the everyday management of patients. The molecular classification was proven to have prognostic ramifications [ 3 , 4 ], however, there are limitations as to how this categorization affects subsequent treatment decision-making. The current review provides a summary of landmark trials defining traditional management in endometrial cancer, discusses the introduction of molecular classification, interprets trials in the context of the new molecular classification, and finally discusses current or proposed trials to define optimal treatment based on molecular classification.…”

“…Furthermore, the molecular classification provides an ability to sort tumors that is standardized, highly reproducible, and shows concordance between the initial biopsy and final hysterectomy specimen. These are all advantages compared to historical histological classification [ 3 , 23 , 24 ]. In particular, the concordance between the initial biopsy and the final hysterectomy specimen has important future implications for pre-operative planning, for example, leading to potentially omitting sentinel lymph node dissection in POLE-mutated biopsies, or perhaps completing full lymphadenectomy in p53 abn tumors on endometrial biopsy.…”

“…De-escalating care appears to be a safe step based on a recent meta-analysis, with recurrences in only 11 out of 294 patients (3.7%), along with a high salvage rate and good survival in eight out of the 11 patients (72.7%). Additionally, given the resulting immunity upregulation in POLE-mutated tumors, immune checkpoint inhibitors are a potential treatment to use [ 3 ].…”

Molecular Profiling of Endometrial Cancer: An Exploratory Study in Aotearoa, New Zealand

“…There has been increased interest driving the use of molecular classification in clinical practice [ 8 ] since the PORTEC-3 trial results showed that molecular classification has a strong prognostic value in high-risk EC [ 9 ]. Women with p53abn tumours had significantly improved survival rates when treated with adjuvant chemo-radiation therapy, whilst women with POLE- mutated EC had incredibly good prognoses regardless of treatment arm (chemotherapy or chemo-radiation therapy).…”