Pre-treatment risk assessment of women with endometrial cancer: differences in outcomes of molecular and clinical classifications in the Slovenian patient cohort

Endometrial cancer is the most common gynaecological malignancy, with an increasing incidence in the developed world.1 Most endometrial carcinoma occur in post-menopausal women, however in rare cases they can also affect young women.2 In most cases it is diagnosed in early disease stages. With current therapeutic approaches, patients achieve an overall survival (OS) from 74% to 91%.1 Recently published data3 on 5-year OS of women with endometrial cancer in Slovenia shows a modest increase in survival between the years 2012–2016 (80.6%) as compared to between the years 1997–2001 (79.8%).3 Endometrial carcinoma are divided, based on their histopathological characteristics, into Type I and Type II carcinoma. Type I carcinomas represent the majority of EC and are of endometrioid subtype. Type II carcinomas are a more hetereogenous group of histopathological subtypes and include clear-cell, serous, mixed histology tumours and carcinosarcomas.4

There is a constant need to improve the risk assessment for improved precision in endometrial cancer treatment. An important aim is to identify patients that experience disease reccurrence regardless of the primary early stage endometrial cancer diagnosis. In the last decade, the molecular classification of endometrial cancer has emerged as a feasible possibility to stratify risk in women with endometrial cancer.5 The evaluated molecular classification showed, that determining the status of endometrial carcinoma tumours for: i) pathogenic variants of the exonuclease domain of DNA polymerase-epsilon (POLE), ii) mismatch repair deficiency (MMRd) and iii) copy-number high TP53 mutations, enables the determination of specific molecular endometrial cancer subtypes6 that could be used in the risk of recurrence assessment.4 Clinical trials showed that patients with POLE ultramutated (POLEmut) tumours had a 100% 10-year recurrence free survival (RFS) versus 80.1% in POLE wild type (POLEwt) patients.7 The recent individual patient meta-analysis has shown that the outcome of POLEmut tumours is good regardless of traditional risk classifiers.8 The prognosis is intermediate in MMRd tumours and significantly worse in p53 aberrant tumours.9 This led to the incorporation of molecular classification to the recently updated European Society of Gynaecological Oncology, European SocieTy for Radiotherapy and Oncology, and European Society of Pathology (ESGO/ESTRO/ESP) guidelines for endometrial cancer. The current guidelines recommend the use of clinical risk assessment or an integrated clinico-molecular risk assessment, if available.4

The molecular risk assessment has been applied for interventions and assessments of adjuvant therapy management decisions.9 Based on the current ESGO-ESTRO-ESP guidelines, women with low-risk EC do not need additional adjuvant therapy. For intermediate risk, radiotherapy has been suggested as the optimal course of treatment. In high-intermediate or some cases of intermediate risk, chemotherapy can be considered in addition to radiotherapy. The guidelines recommend for women with high risk EC to undergo radiotherapy with concurrent chemotherapy.4 Abdulfatah et al., reported also the use of molecular classification on biopsy specimens which showed a high level of concordance to hysterectomy specimens and outperformed pre-treatment risk assessment based on histological specimen sample and grade.10

Based on the currently available guidelines we aimed to assess the changes that clinical and integrated molecular risk assessment represent in terms of primary patient management.

Molecular characterisation was performed in all 45 women enrolled. Among them, 39 women (86.7%) were classified according to the current recommendations in one of the four molecular classification groups. Their characteristics are presented in Table 1. Six women (13.3%) had multiple molecular classifiers. The characteristics of these women are presented in Table 2.

Following the ESGO/ESTRO/ESP guidelines on risk assessment, women were classified according to the clinical risk assessment and the integrated molecular risk (Table 3). Most remained classified as low-risk endometrial cancer, reclassification changed for 4 women.

The risk profiles of three women decreased after integrated molecular risk classification: one was reclassified from high risk to high-intermediate risk and two from intermediate to low-risk. The risk profile of women changed from: i) intermediate to low risk as one woman had a POLEmut tumour, ii) from intermediate to low risk since it was of NSMP and iii) from high to high-intermediate (HIR) risk due to the MMRd classification. In one case, the risk profile increased from low to intermediate risk due to the detected p53abn mutation.

The impact of molecular classification on treatment decisions

In the post-operative period two women (5.1%) died. Two women (5.1%) rejected the recommended adjuvant therapy. The final analysis was performed for 37 women as depicted in Figure 1.

Figure 1

Our study was observational and the molecular classification did not impact the MDT decision making. Two women which were re-classified from intermediate to low risk by the molecular classification received radiation therapy and one women that has been reclassified from high risk to HIR received radiotherapy and chemotherapy. One patient for whom the risk assesment increased from low to intermediate risk has been recommended no adjuvant treatment. In one patient of the intermediate risk group, the presence of co-morbidities led the MDT to suggest follow-up as the optimal strategy.

In this study we assessed the risk of endometrial cancer for women using the clinical classification and the integrated molecular classification as suggested by the recent ESGO/ESTRO/ESP guidelines. Out of 45 women enrolled in our study, the risk evaluation through integrated molecular risk groups was possible for 39 women. Six women had multiple molecular classifiers, which precluded further risk assessment using the current molecular classification. In the remaining group, assessment of molecular risk decreased in three and increased in one woman.

The classification of women with endometrial cancer into risk groups based on clinical and molecular data aims to improve individualised treatment according to the tumour biological potential. According to the currently valid guidelines4, histopathological characteristics, including lymphvascular space invasion (LVSI) are the cornerstone of risk stratification. This is one of the reasons that shifts in risk groups between clinical and integrated molecular groups were present, as LVSI has been identified as an important marker of prognosis in low-risk endometrial cancer and is associated with adverse outcomes.15 In comparison with a study of Oberndorfer et al.16 which compared molecular risk with the guidelines on clinical risk assessment in endometrial cancer published in 201617, there were less shifts in the clinical risk assessment in our study. Therefore, by using the newly implemented clinical or integrated molecular risk assessment, comparable risk assessment is achieved. Our study is the first to compare the clinical and molecular risk stratification in the cohort of Slovenian patients. The clinical value of this approach needs to be verified in further prospective studies.

The nature of our study was observational and the molecular subtype was not taken into consideration for decision-making in regards to surgical or adjuvant therapy. Table 4 represents the surgical approach taken for women based on the pre-treatment assessment and the final ESGO Risk Group classification. The body of knowledge on using the integrated molecular classification for decision making on surgical treatment is scarce. Histopathological pre-operative evaluation might not always be concordant with post-operative diagnosis18,19 and could potentially impact the MDT to suggest less invasive surgical procedures. This is especially true in recognizing serous EC. In these instances based on the molecular characteristics such as TP53 mutations20, integrated molecular evaluation could potentially enable individualized therapy already in the primary surgical setting.

Considering the changes in risk assessment for patients within our study, if using the integrated molecular assessment, two patients would most likely been recommended follow-up instead of radiotherapy, thus de-escalating their therapy based on their individual biological features. One patient would have been, based on her biological characteristics upgraded from low to intermediate risk. Especially in the low-intermediate and intermediate-high risk group, it is important to identify the patients correctly. Without appropriate adjuvant therapy, these patients were found to be at a approximately 30% higher risk than if adjuvant therapy was offered.21 One of our patients was downgraded from high risk to the HIR risk group. While this individual has received radiotherapy and chemotherapy, this is also a valid strategy of treatment in the HIR risk group4 and the decision process most likely would have not changed for her. Participants in our study have been mostly classified as NSMP (56.4%). NSMP tumours are currently classified in the low-risk or intermediate risk4 based on a combination with other histopathological characteristics. As NSMP represents the largest group of currently classified tumours this shows the need for further refinements of molecular risk stratification.22,23 A potential additional marker which has shown potential prognostic value, especially in the intermediate risk groups, is L1CAM expression23,24 and in low risk endometrial cancer also mutation of CTNNB1.25 Further evaluation of these and other novel markers could enable us to further individualise and stratify risk assessment in this large and clinically diverse group.26

An important consideration in our study is how to evaluate and incorporate risk assessment for women with multiple classifiers. There were six women with multiple classifiers in which four tumours were p53abn and POLEmut. Multiple classifiers MMRd and p53abn were present in two women. Recently, Leon-Castilo et al.27 published data on their cohort of patients with multiple-classifier endometrial cancer. They supported the bioinformatic clustering of TCGA data which stated that MMRd-p53abn tumours mostly clustered around MMRd tumours and p53-POLEmut tumours mostly clustered around POLEmut tumours. Clinical outcomes showed that patients with MMRd-p53abn had a 5-year recurrence free survival (RFS) of 92.2% and patients with POLEmut-p53abn endometrial cancer a 5-year RFS of 94.1%.27 This also supports the hypothesis that these tumours are biologically less aggressive than single classifier p53abn tumors, which had a 5-year RFS of 48%.28 Further research and biomarker development is therefore needed to evaluate the appropriate approaches for patient treatment in cases of non-specific mutational profiles and multiple-classifiers.

The strength of our study is that it is the first prospectively designed study to evaluate the implementation of molecular risk stratification to endometrial cancer patients in Slovenia. The limitation is the low number of patients included. The follow-up data is not yet available and the clinical implications of this approach are yet to be determined.

The introduction of molecular risk stratification in the management of women with endometrial cancer represents a significant shift from the established clinical practice. Several adjustments to the routine workflow and significant additional resources are necessary in order to implement this approach to the clinics. Our data shows that in comparison to the current clinical risk stratification based on clinical and histopathological data, this may lead to change in management in a small proportion of women. The clinical value of this remains to be proven in further prospective studies. It is also important to note that the molecular risk stratification is not applicable to all women and refinements of the current classification with additional biomarkers are likely to improve and further de-escalate treatment in certain subtypes of endometrial cancer in the future.