Impactul clasificării moleculare în managementul cancerului de endometru

Introduction

Endometrial cancer is one of the most frequent gynecological cancers in the developed countries and the fourth cancer in women worldwide⁽¹⁾. The most important tool for treatment is surgery, incipient cases being treated by surgery alone, while advanced stages are also treated with adjuvant therapy.

Traditionally, endometrial cancer was divided into two categories, according to Bockhman in 1983: a type I estrogen-driven cancer, mostly endometrioid, with a more favorable prognosis, and a type II non-estrogenic cancer, which comprised more aggressive histologies (serous, clear cell), with a poorer prognosis⁽²⁾. Although this classification was of great use initially, it became clear that endometrial cancer was characterized by more complexity. While for advanced stage disease, the therapeutic decision is pretty straightforward, the main problems were raised by the early stages, where it was difficult to decide which cases needed adjuvant therapy and which not. The situation was further complicated by the fact that histologic grade assignment was not as reliable on the biopsy specimen, being frequently upgraded on the hysterectomy specimen⁽³⁾.

As knowledge of molecular pathogenesis became more and more abundant, it became clear that it could be of use to better categorize and predict endometrial cancer. A turning point was the year 2013, when The Cancer Genome Atlas (TCGA) identified four molecular subtypes (Table 1) of endometrial cancer based on tumor cell genomic characteristics and established for each of them a prognostic outcome and a clinicopathologic feature⁽⁴⁾.
 

Materials and method

We performed a narrative literature review in order to compress the latest abundant information on endometrial cancer classification and the changes it has brought to its management. We used the PubMed database, with a defined timed interval from 2013 to 2023, using the following keywords: “endometrial cancer”, “molecular classification”, “endometrial cancer management”. We selected the articles which related most to our interest.

Results

After the TCGA publication of the molecular classification, a clinical algorithm was published that is designed to diagnose one of the four molecular subtypes, as a surrogate for molecular testing – the PROMISE algorithm (Proactive Molecular Risk Classifier for Endometrial Cancer; Figure 1). The algorithm can be applied to diagnostic biopsies and is highly reproductible⁽⁶⁾. Also, it established a consensus on nomenclature which was later adopted by the World Health Organization and characterized a group of rare mutations named “multiple classifier”, were tumors exhibit more than one key molecular characteristic.
 

First, the POLE mutated endometrial cancers are pulled out. Next, the mismatch repair deficiency (loss of MMR proteins) cancers are identified, finally diagnosing patients with aberrant versus wild type p53. There is a rare category of “multiple classifier” endometrial carcinomas represented by tumor cells that have more than one key classification feature, and these occur in approximately 3% of cases. The aforementioned method is the correct way to segregate these rare tumors⁽⁷⁾. In 2020, the World Health Organization (WHO) published the new terminology in the Classification of Female Genital Tumors.

1. POLE mutated subtype (POLEmut; TCGA “POLE ultramutated”)

These tumors are characterized by a very high number of somatic mutations. Most of them are endometrioid cancers, and patients with this mutation are often thin and young. They have a favorable outcome, even though the tumor has aggressive characteristics, such as high grading or lymphovascular space invasion (LVSI)^(8,9). POLE mutated cancer has no advantages after adjuvant therapy. The tendency is to de-escalate treatment in these cases, and there are studies ongoing which will decide the best management for these patients⁽¹⁰⁾.

2. Mismatch repair deficiency subtype (MMRd; TCCGA “MSI hypermutated”)

Tumors in this group have dysfunctional mismatch repair (MMR) proteins represented by MLH1, PMS2, MSH2 and MSH6. This group is also characterized by germline mutations, and 2% to 5% of endometrial cancers with MMR deficiency are associated with Lynch syndrome (hereditary non-polyposis colorectal cancer – HNPCC). Patients with this condition are predisposed to a variety of cancers, especially colorectal, endometrial and/or ovarian cancer. An important aspect when diagnosing a patient with this type of tumor is to establish strategies for cancer risk reduction. There has been no evident disease outcome characteristics found in this group. The treatment with immune checkpoint inhibitors is being used in metastatic disease in this group⁽¹¹⁾.

3. No specific molecular profile (NSMP; TCGA copy number-low; previously p53 wild type)

These tumors have a stable genome, and the disease outcome is usually intermediate to favorable. The majority of endometrioid cancers with hormonal receptors are included in this category⁽¹²⁾.

4. p53 abnormal (p53abn; TCCGA copy-number high [serous-like])

Tumors in this group are similar to high-grade serous ovarian carcinoma and basal-like breast carcinoma, all of them having TP 53 mutations.

The prognosis is poor for these patients. Most of the cancers included in this group are serous carcinoma, carcinosarcoma and clear cell carcinoma. Patients in this group might benefit from chemotherapy alongside radiation therapy⁽¹³⁾.

In 2021, the European Society of Gynecological Oncology (ESGO), the European Society for Radiotherapy and Oncology (ESTRO) and the European Society of Pathology (ESP) published guidelines which integrated the molecular features into assignment of the risk groups. Until then, endometrial cancers were classified into risk groups based on the traditional clinicopathologic system (tumor histology, stage of disease, grade and lymphovascular space invasion). From 2021, mainly all early-stage (I and II) POLE mutated cancers were assigned as “low risk”, with no adjuvant therapy recommended and staging p53abn stage IA endometrial cancer as “high risk”, with a recommendation for chemotherapy⁽¹⁴⁾.

Currently, histologic type, grade, myometrial invasion and LVSI should be recorded in all patients, and molecular classification is encouraged in all cases⁽¹⁴⁾. The ESGO/ESTRO/ESP guidelines mention that POLE mutation may be omitted in cases of low-risk and intermediate-risk endometrial carcinoma with low-grade histology⁽¹⁴⁾. Then, patients can be assigned to one of the following risk groups, as presented in Table 2.
 

Endometrial cancer is surgically staged using the International Federation of Gynecology and Obstetrics (FIGO) classification. In 2023, a new classification was published which included the molecular classification, various histological types and tumor patterns in addition to the previous one (Tables 3 and 4)⁽¹⁵⁾.
 

In the current FIGO classification, if the POLE mutation is present, the tumor is staged as IAmPOLEmut if it is confined to the uterus or has cervical extension, regardless of the degree of LVSI or of the histological type⁽¹⁵⁾. On the opposite, if p53abn is present, the tumor, regardless of LVSI, with any myometrial invasion, with or without cervical extension, is classified as IICm_p53abn⁽¹⁵⁾.

Discussion

Endometrial cancer management has changed in many ways since the introduction of molecular classification. Staging of tumors has changed, therefore the treatment has been downstaged for POLE mutated cancer, while cases considered priorly as low risk have been upgraded to high risk, even in the case of small tumors. Survival has been shown to be considerably different with this new staging for stages I and II, but not for advanced stages⁽¹⁵⁾.

The surgical management has also changed due to the different risk group classification. Surgical lymph node staging is recommended for high-intermediate risk and high-risk groups, while sentinel lymph node is an acceptable method for stages I and II⁽¹⁴⁾. In low-risk and intermediate-risk disease, sentinel lymph node biopsy can be considered, but systemic lymphadenectomy is discouraged⁽¹⁴⁾. Consequently, higher stages with POLE mutation can now skip systemic lymphadenectomy, which is known for its important complications associated with lymph node drainage issues⁽¹⁶⁾. On the contrary, some of the p53abn cancers which would have not had necessarily a sentinel lymph node biopsy are now more prone to have a biopsy, which leads to better staging⁽¹⁴⁾.

Nonsurgical treatment has also changed significantly, since personalized therapy is now possible when molecular characteristics are present. Elimination of adjuvant treatment for POLE mutations, addition of immune checkpoint inhibitors, the benefits of radiotherapy for MMRd tumors and the use of chemotherapy in p53abn tumors are all due to the new information regarding the molecular characteristics⁽¹⁷⁾. Studies are ongoing to determine the best approach in each of these groups⁽¹⁸⁾.

There is great interest nowadays towards fertility preserving treatment for endometrial cancer, due to a higher incidence in women of childbearing age⁽¹⁹⁾. This is mainly explained by the western lifestyle which includes an accumulation of risk factors such as excess weight gain, diabetes mellitus, hypertension and high serum triglycerides, combined with an increase in the age when women decide to conceive⁽²⁰⁾. At present, fertility preserving management in reserved only for cancers confined to the endometrium, grade I with endometrioid histology⁽¹⁴⁾. Molecular classification may have an important place in the future, because it may include more cases in the fertility preserving group.

A problem concerning the molecular classification is the ability to perform it. Resources for molecular testing are not widely available, even in developed countries. The ESGO/ESTRO/ESP guidelines mention that POLE mutation may be omitted in low-risk and intermediate-risk endometrial carcinoma with low-grade histology⁽¹⁴⁾. Also, it is mentioned that when resources are scarce, some cases should be prioritized such as high-risk cases, where adjuvant therapy is greatly influenced by the classification⁽¹⁴⁾. Nevertheless, if molecular classification tools are not available, endometrial carcinoma classification should be based on traditional pathologic characteristics⁽¹⁴⁾. The British Association of Gynecological Pathologists has published a guideline in 2022 which proposed testing for POLE mutation only in selected cases, in order to improve cost efficiency (Figure 2)⁽²¹⁾.
 

Conclusions

The management of endometrial cancer has changed greatly since the introduction of molecular classification. Surgical staging is different from the past, and tumors thought to be aggressive are now known to have an excellent prognosis, while some of them need multiple treatment methods. The decision to add or not adjuvant treatment is now based on molecular classification for specific cases. Also, personalized treatment is now possible and will be further adjusted according to ongoing studies.  





 

Conflict of interest: none declared  
Financial support: none declared
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