The cancer genome atlas - TCGA molecular classification: A changing paradigm in the management of endometrial cancers

Rahul Deepak Modi

doi:10.4103/cmrp.cmrp_125_22

REVIEW ARTICLE

Year : 2023 | Volume : 13 | Issue : 2 | Page : 69-73

The cancer genome atlas - TCGA molecular classification: A changing paradigm in the management of endometrial cancers

Rahul Deepak Modi
Gynaecological Oncology Division, Institute of Obstetrics and Gynaecology, Sir Gangaram Hospital, New Delhi, India

Date of Submission	02-Dec-2022
Date of Decision	02-Feb-2023
Date of Acceptance	06-Feb-2023
Date of Web Publication	28-Apr-2023

Correspondence Address:
Dr. Rahul Deepak Modi
Institute of Obstetrics and Gynaecology - Office, First Floor, OPD Block Building, Sir Gangaram Hospital, Rajinder Nagar, New Delhi - 11060
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/cmrp.cmrp_125_22

Abstract

Conventionally, endometrial cancers have been risk-stratified as per the clinco-pathological factors. The Cancer Genome Atlas project identified four distinct molecular subtypes within endometrial cancers which further lead to the clinical validation of molecular classification by various research groups. The molecular classification has influenced the risk stratification, thereby impacting adjuvant treatment decisions and prognostication. Molecular classification has paved the precision oncology in gynaecological cancers further strengthening the ongoing advances in targeted therapies and immunotherapy. This review elaborately presents the development of a new molecular classification of endometrial cancers; its evidence-based clinical utility with a brief overview of future perspectives.

Keywords: Endometrial cancer, micro-satellite instability, molecular classification, p53 mutation, POLE mutation

How to cite this article:
Modi RD. The cancer genome atlas - TCGA molecular classification: A changing paradigm in the management of endometrial cancers. Curr Med Res Pract 2023;13:69-73

How to cite this URL:
Modi RD. The cancer genome atlas - TCGA molecular classification: A changing paradigm in the management of endometrial cancers. Curr Med Res Pract [serial online] 2023 [cited 2023 May 30];13:69-73. Available from: http://www.cmrpjournal.org/text.asp?2023/13/2/69/375230

Introduction

Endometrial cancer is the sixth most common cancer in the world among females. As per the Global Cancer Observatory data - 417,367 cases of endometrial cancer were newly diagnosed and roughly 97,000 died of the disease in 2020 globally.^[1] In India, endometrial cancer is the fourth most common cancer among females with a cumulative risk of 1 in 190 as per the data published in 2020 from the National Cancer Registry Programme.^[2] Majority of women with endometrial cancer present at an early stage which usually has a favourable prognosis. Around 15%–20% cases have high-risk features with increased incidence of distant metastasis and mortality.^[3] High-risk features include high grade disease, presentation at an advanced stage or non-endometrioid histology. Data from Tata Memorial Hospital, Mumbai for early stage endometrial cancers suggest 5-year disease-free survival rate of 80% and 5-year overall survival (OS) rate of 95% in Indian patients.^[4] Surgery is the primary treatment of endometrial cancers. Adjuvant treatment strategies usually include radiotherapy, chemotherapy or both.

Historical Classification of Endometrial Cancers

In 1983, Bokhman presented a hypothesis, i.e., there are two types of endometrial cancers based on the clinical and epidemiological profile.^[5] Type I was a favourable type with low grade features, oestrogen dependency and mostly an endometrioid variety. Type II was an aggressive type which was usually non-endometrioid/serous variety, oestrogen independent and more common in the elderly. The advantage of this classification was the ease of applicability and simplicity. The major issues with Bokhman classification are the high inter-observer variability and varied consensus among pathologist on multiple parameters like histological type and grade. Adding to the problem is its application on a heterogeneous class of high grade lesions, which leads to imprecise estimation of recurrence risk and deciding adjuvant therapy.^[6] To overcome these shortcomings, the World Health Organisation proposed a revised classification consisting of 4 types, i.e., low grade endometrioid, high grade endometrioid, serous and clear cell variety.^[7] However, similar issues of inter-observer variability and varied consensus among pathologists persisted. To compensate on these fallacies, international society guidelines have recommended risk-based stratification groups based on clinico-pathological factors and recently the molecular profile to decide on the adjuvant treatment and prognostication.^[3],[8]

New Molecular Classification of Endometrial Cancers

Development

In 2013, The Cancer Genome Atlas (TCGA) published the results of genomic analysis of 373 endometrioid and serous endometrial cancers identifying four distinct molecular subgroups among endometrial cancers.^[9] Four groups identified were Polymerase Epsilon ultra-mutated (POLE mut), microsatellite instability hyper-mutated/MMR deficient (MMRd), copy number low/no specific molecular profile (NSMP) and copy number high/p53 abnormal (p53 abn). Based on this TCGA data, two research groups – Vancouver group and transPORTEC group validated respective molecular classification's in their cohorts using surrogate immunohistochemical markers (IHC) and mutational analysis.^[10],[11] The Vancouver group's – Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) classification has been accepted as a better classifier as it encompasses a more heterogeneous group in its validation and being more pragmatic.^[12] This uses a combination of IHC markers and focused mutational analysis of POLE.

Overview of molecular subtypes

TCGA in its multi-comic analysis identified four distinct groups based on somatic mutational burden and copy number alterations as mentioned above. Here, a brief overview of these subtypes is presented.

POLE mut subtype has mutations in the exonuclease domain of POLE which is a DNA proof-reading domain, leading to exceptionally high frequency mutations with low copy number alterations.^[13],[14] Approximately 4%–12% of endometrial cancers carry these mutations.^{[15],[16],[17]} Few pathogenic variants in POLE mut have been defined but is still a work in progress. POLE mut tumours are commonly found in younger population with early stage presentation but high grade histology.^[9],[15] Despite being high grade, this subtype has an excellent prognosis with very few relapses.^{[9],[15],[18]}
MMRd subtype results from microsatellite instability which is of relevance in many cancers with colorectal and endometrial cancers leading the front.^[19] Either germline mutations in either of MLH1, MSH2, MSH6 or PMS2 described as Lynch syndrome or acquired somatic mutations like MLH1 hypermethylation are responsible.^[20] Of all endometrial cancers, 25%–30% belong to MMRd group, germline mutations accounting for only 2% and acquired somatic mutations being the rest.^{[9],[10],[15]} This group has an intermediate prognosis. Both POLE mut and MMRd groups elicit a strong immunological response.^[18],[21]
The p53 abn group consists of tumours with high copy number alterations with low somatic mutation rate. There is mutation of Tp53 gene in almost 90% of cases.^[9] This subtype comprises mainly of high grade tumours, non-endometrioid varieties such as serous, clear cell carcinomas and carcinosarcomas. It has the poorest prognosis among all subtypes and usually has early spread of disease. This subgroup comprises of 8%–24% of all endometrial cancers.^[18],[22]
NSMP is the largest subgroup with copy number low alterations and NSMP. As the name suggests, there is the lack of pathogenic POLE mutation, MMR deficiency and p53 mutation. This subgroup accounts for more than 50% of all endometrial cancers. This subtype is too heterogeneous and has intermediate prognosis.^[9] Most are endometrioid type cancers with positive status for oestrogen (ER)/progesterone (PR). Being a heterogeneous group, there is a spectrum of cases with good prognosis to cases where aggressive treatment would be required. Till-date mutations in potential biomarkers like B-catenin (CTNNB1), L1-cell adhesion molecule (L1CAM) and ER status have shown promising results in risk stratification of NSMP group.^{[23],[24],[25]} Further refinement in the group is being carried out and is a hot topic for ongoing research.

Issue of 'multiple-classifier'

In a small population of endometrial cancers, i.e., 3%–6%, there is the presence of more than one markers rendering this group to be classified under more than more subtype. This makes the so called 'multiple-classifier' group difficult to stratify and decide on the adjuvant therapy. However, as described by León-Castillo et al. in their excellent work, there is evidence to categorize POLE mut–p53 abn as POLE mut, MMRd–p53 abn as MMRd and MMRd–POLE mut as POLE mut.^[26] Although rare (3%–6%), but clinically relevant, this work has helped guiding these 'multiple-classifier' endometrial cancers in a single subtype.

Clinical Impact of Molecular Classification

Change in risk stratification

With the new molecular classification on the table along with validation of survival analysis and prognosis based on these molecular subtypes by various groups,^{[12],[15],[16],[17],[18]} the European Society of Gynaecological Oncology (ESGO), European Society for Radiotherapy and Oncology (ESTRO) and European Society of Medical Oncology (ESMO) has published a new consensus in 2021 on risk stratification based on the molecular classification updating the previous stratification risk groups of 2016, which involved clinico-pathological factors.^[3],[8] The 2021 ESGO/ESTRO/ESMO risk stratification system is given in [Table 1].

Table 1: 2021 European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology prognostic risk-stratification groups-Concin et al.^[9]

Click here to view

Impact on adjuvant therapy

Present evidence

The randomised Adjuvant Chemoradiotherapy Versus Radiotherapy Alone in Women with High-Risk Endometrial Cancer (PORTEC-3) trial investigated the benefit of adjuvant chemoradiation (CTRT) versus radiation (RT) alone in patients with high risk endometrial cancers.^[27] The results showed a significant benefit for CTRT over RT. In the data of 660 eligible women, at follow-up of 72.6 months, 5-year OS with CTRT was 81.4% versus 76.5% with RT (hazard ratio [HR] = 0.70; P = 0.034) and 5-year failure-free survival was 76.5% with CTRT versus 69.1% with RT (HR = 0.70; P = 0.016). There were more adverse side-effects with CTRT as compared to RT. Stage III and serous tumours showed the maximum benefit of CTRT over RT in the subgroup analyses. The challenge as discussed earlier is the substantial inter-observer variability for designation of high-grade disease based on clinical and pathological factors. Molecular classification thereby may help in more objective classification of high grade disease and deciding appropriate adjuvant treatment. For 410 of these 660 patients, where tissue samples were available and molecular testing successfully conducted-León-Castillo et al. recently published the translational research outcomes on PORTEC-3 data.^[18] In these high risk groups, all molecular groups were spread across all histological types and stages. Patients with p53 abn subtype had the worst outcomes. The 5-year recurrence-free survival (RFS) with CTRT in p53 abn group was 59% versus 36% for RT (HR = 0.52; P = 0.019). MMRd group had intermediate outcomes with no significant benefit of CTRT over RT. The best performing group was POLE mut, with 5-year RFS of 100% with CTRT versus 97% in RT. In the NSMP group, there was a trend of benefit towards CTRT (HR = 0.68; P = 0.246). Alexa et al. in a published review has summarized data from till-date existing trial cohorts for adjuvant treatment received by molecular subgroup.^[28] Adjuvant treatment was received by 58.8% of p53 abn, 51.2% of POLE mut, 46.5% of MMRd and 44.6% of NSMP group. This data shows there is a scope for de-escalation of therapy in POLE mut group, while showing more aggressive intent for p53 abn group. Stello et al. in their analysis of PORTEC-1 and 2 trials^[15] found significantly worse outcomes in p53 abn group with HR-3.77 (95% confidence interval = 2.364–6.037) while Cosgrove et al. concurred the same poor outcomes with p53 abn group in the NRG Oncology/ Gynecologic oncologic group (GOG) 210 trial data.^[16]

Impact on Fertility Sparing Treatment

Endometrial cancer occurs after 50 years of age in 80% of cases, with approximately 20% of women in premenopausal age, of which 5% are under the age of 40 years.^[29] As per the GLOBOCAN data, there would have been around 16,000 new cases of endometrial cancers in women under 40 years of age across the globe in 2020.^[1] Fertility sparing treatment (FST) is a feasible and a safe treatment option in a selected few.^[30] The options under FST are hormonal therapy and hysteroscopic treatment. Stage IA, Grade I and endometrioid histology are a must pre-requisites for advising FST in a patient with endometrial cancer. In a review of impact of molecular markers on conservative treatment in early endometrial cancers by Travaglino et al., MMRd and involvement of Phosphatase and TENsin homolog gene (PTEN) were important factors for treatment failure.^[31] In another study by Makabe et al., CTNNB1 mutation was a marker for treatment failure and higher relapse rate.^[32] Kurnit et al. in their analysis found that existence of either p53 mutation or CTNNB1 mutation in low grade early endometrial cancers was a poor prognostic marker with high relapse rates.^[23] An important principle behind FST is balancing risk-benefit ratio with oncological safety and an acceptable pregnancy chance. It is mandatory to counsel patients that FST is not a standard of care with emphasis on definitive surgery after childbearing completion. Although at present due to the lack of enough literature, there is limited clinical applicability of molecular classification on FST-evidence available should be used for counselling for or against FST in specific set of patients.

Ongoing Trials

There are two interesting ongoing trials which can have a profound impact on the way adjuvant treatment is planned for endometrial cancers – PORTEC 4a^[33] and RAINBO clinical trial program.^[34] Both the trials are investigating giving adjuvant treatment as per molecular subtype versus conventional clinic-pathological factors. PORTEC 4a is enrolling for high-intermediate and high risk groups up to stage II as against high-risk and advanced stages for RAINBO. These data can pave the way for the application of molecular classification as a standard of care.

Future Perspectives and Conclusion

With more studies on CTNNB1, L1CAM, oestrogen/PR status (ER/PR), PTEN and many other prognostic markers, molecular classification will undergo more metamorphosis with addition of more subclasses, especially refining the NSMP group.^{[15],[23],[24],[25]} Till date, adjuvant treatment for endometrial cancers has been planned based on clinico-pathological factors. With the advent of molecular classification and its proven clinical validity, time is ripe for more precise application in real world scenarios. As seen in PORTEC-3 trial data, there are specific subtypes where addition of chemotherapy can drastically change the prognosis and recurrence-free interval.^[18] As with POLE mut, the recurrence-free interval remained almost 100% with or without RT, suggesting de-escalation of therapy to be considered in such cases. There is a gathering interest for the subtypes of MMRd and p53 abn in terms of recent trials in targeted therapies and immunotherapy.^[35] With MMRd, studies using immune check-point inhibitors have shown statistically significant benefit, leading to FDA approval of same in advanced and recurrent disease. In p53 abn, there are two classes of drugs which have shown benefit in early studies – PARP inhibitors and antibodies targeting Her-2 over-expression. There have been hypothesis supporting studies showing RT to be more effective in MMRd group as compared to others.^[36] In recent discussions among experts, debates have arisen regarding role of lymphadenectomy in endometrial cancer surgeries. As from data available from two landmark trials–ASTEC and Italian consortium trial, it is a well-known fact that there is no survival advantage to lymphadenectomy but has a prognostic with an adjuvant decision making relevance.^[37],[38] With chemotherapy required even for early stages in certain subtypes, questions do arise for extensive lymphadenectomies in endometrial cancers with normal looking or radiologically negative nodes. Instead, debates for the role of omentectomy as for ovarian cancer staging have taken precedence. Molecular classification seems to have made indications for fertility sparing approach more precise. With ongoing PORTEC 4a and RAINBO, results of these trials are likely to have a profound impact on the way the treatment of endometrial cancers would be planned in coming years.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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