Impact of Molecular Pathological And Clinical Features for Adjuvant Treatment Selection in Endometrial Cancer: Asian Registry

Impact of Molecular Pathological And Clinical Features for Adjuvant Treatment Selection in Endometrial Cancer: Multicentric Asian Registry (IMPACT-Endo-Asia)

The treatment practices for endometrial cancer have significantly changed over the last two decades. Nowadays, in addition to standard pathology, additional tests are performed to understand the behaviour of tumour so that personalized treatment can be advised for every patient. This approach ensures that patients with good cancer cell features receive minimum essential radiotherapy or surgery treatment with fewer side effects, while those with poor cell features undergo more aggressive treatment to improve their chances of survival.

However, this approach is not widely adopted in Asian countries. To address this, investigators are launching a project to gather data from various hospitals across Asia. The project aims to understand how different cancer cell factors impact treatment decisions and identify better ways to select additional treatment plans based on a patient's cancer cell features.

The project will gather data from around 250-300 patients who were evaluated or treated between January 2021 and December 2023. It will run for two years to improve our understanding and gain insights into the best ways to treat endometrial cancer.

Endometrial cancer (EC) is the second most common gynecological malignancy affecting women worldwide. As per GLOBOCAN data, the incidence was 382,069 with a mortality of 89,929 in 2018, out of which Asia accounts for 40% of the new cases. By 2040 global incidence is predicted to increase by more than 50% as per the International Agency for Research on Cancer. Although the incidence is higher in the Western world, there is a persistent rising trend among low- and middle-income countries. EC is the fourth most common cause of cancer death among women of low socioeconomic status .3-5% of patients have inherited (Mismatch repair) mutation and are diagnosed to have Lynch syndrome also suggesting an overlapping genetic predisposition. Historically Bokhman's dualistic EC histopathological classification was based on tumor biological behavior and prognosis. Type I (60-70%) included endometrioid histology with a 5-year overall survival (OS) of 83-88%. The rest of the non-endometrioid histology was included in Type II (30%) which was associated with a higher risk of relapse and showed a 5-year OS of 54-64%. This classification had limited risk stratification, which led to inter-observer error of 60% and poor reproducibility of patient outcomes when references to pathological subtypes. Later two-tier tumor grading systems as per the International Federation of Gynecology and Obstetrics (FIGO) defined criteria had combined Grade 1 and 2 EC as low grade and Grade 3 EC as high grade. Several other high-risk features like myometrial invasion (MI) of more than 50%, substantial lymph vascular space invasion (LVSI), lymph node involvement, and tumor size of more than 2 cm were also considered in the classification. Prognostic classification based on morphological features alone leads to inaccuracies in tumor biology characterization, non-reproducibility due to the overlap of clinical-genetic characteristics causing heterogeneous molecular groups, heterogenous adjuvant treatment decisions (due to pathology variation).

More recently developments in genetics and molecular characterization have integrated classification methods, which include genomic profiling along with histopathological features. The Cancer Genome Atlas (TCGA)molecular classification first described four distinct subgroups based on molecular features which estimated the recurrence risk and predicted the survival in serous and endometrioid EC.

1. Pole ultra mutated (mutation in exonuclease domain of DNA polymerase epsilon)
2. Hypermutated with MSI/MMRd (loss of Mismatch Repair protein immunoreactivity)
3. Somatic copy number-low with frequent PI3K and WNT signaling abnormality (endometrioid-like)
4. Somatic copy number-high with frequent pathological variants in TP53(serous-like)

This molecular classification when integrated with standard pathology provided a relatively clearer distinction of outcomes.

Key observations from molecular classification studies also looking into clinical outcomes were as follows:

1. POLE mutation groups have shown consistently excellent outcomes and may benefit from the de-escalation of adjuvant therapy. However, no prospective results from randomized trials are yet available.
2. MMR/MSI status in metastatic EC can guide to select patients who can benefit from immunotherapy thus acts as a predictive biomarker for response to immunotherapy. The non-metastatic EC group has an intermediate prognosis but shows minimal benefit with adjuvant chemotherapy and radiotherapy. It is also used as a screening test for LS (hereditary nonpolyposis colorectal cancer).
3. Copy number low groups show a frequent mutation in the CTNNB1 gene. This group has over-expression of progesterone receptors (PR).
4. Copy number high (Serous EC and high-grade endometrioid EC) has frequent p53 mutations and poor outcomes are stage independent due to intrinsic aggressive biology. This group showed greater benefit with adjuvant chemotherapy. Improved outcomes have been observed when bevacizumab was added along with chemotherapy. This group also has low estrogen receptors (ER/PR) levels.

To simplify further and also to decrease the cost of diagnostic testing of molecular subgroups, the ProMisE study used surrogate markers to classify EC into four subgroups: POLEmut, MMR-d, p53wt and p53abn. The p53wt group does not harbor POLE/MMR-d/p53 mutation, so it is also termed as 'No Specific Molecular Profile (NSMP)'. The L1 neuronal Cell adhesion molecule(L1-CAM) is an independent prognostic marker as its upregulation is associated with the epithelial to mesenchymal transition (EMT), cell migration, cell invasion and thus its presence guides in patient selection for aggressive therapies due to their aggressive biology.

With the recent ESGO/ESTRO/ESP guideline update in 2021, there is a paradigm shift with integrated prognostic risk group stratification of EC patients which guides regarding the optimal management, that includes surgery, adjuvant therapy and surveillance recommendations. It also recommends treatment options when molecular classification is not available, as till today many centers have limited access to it. But there is a Heterogenous slow adaptation of molecular based classification in making adjuvant treatment decisions. Molecular profile-based classification has demonstrated prognostically valuable in Intermediate, High Intermediate and High-risk EC patients. The updated FIGO 2023 staging suggest for complete molecular classification in all endometrial cancers, which provide a better understanding of biological behaviors in EC.

While there are rapid transitions in recommendations based on Integrated molecular risk group stratification, most of the data on EC management originates from Europe and the USA. Asian region consists of different populations with different socio-economic statuses, variable access to medical infrastructure facilities, and availability of molecular profiling. This causes heterogeneous tissue reporting and impacts treatment decisions and future clinical trials.

The aim of registry is for better understanding the availability histopathological, Molecular subtyping and immunohistochemistry in Asian Institutes and its impact on adjuvant treatment decisions.

Patients evaluated or treated between January 2021 to December 2023 will be eligible for study participation and will be included in the study as per eligibility criteria.

Descriptive statistics (means, distributions) will be used for descriptive analysis. Log-rank test and cox-proportional hazard will be used for analysis of known prognostic factors.

Inclusion Criteria:

- Patients who were diagnosed to have EC and have access to standard histopathological reports and availability of treatment decisions.

Exclusion Criteria:

- Patients with final histopathological diagnosis of any other gynecological malignancy other than EC and its subtypes.