The various adjuvant treatments to be proposed for endometrial cancers, alone or in combination are external beam radiotherapy (EBRT), vaginal brachytherapy (VBT), chemotherapy, targeted therapies and/or immunotherapy. In our systematic review, we will attempt to detail the various therapeutic indications, taking into account the latest technical advances and the inclusion of molecular factors in the new classification.

Endometrial cancer is very common gynecological tumor in developed countries, due to increasing life expectancy. Generally discovered at the localized stage (70%), the standard treatment remains surgery, including total hysterectomy with bilateral salpingo oophorectomy and lymph node dissection or sentinel biopsy of pelvic +/- para-aortic nodes. The choice of adjuvant treatment depends essentially on clinico-pathological risk factors. Recently, a new molecular classification has identified 4 subgroups with different prognoses to be taken into account when choosing adjuvant treatments.

Keywords: endometrial cancer, adjuvant treatment, chemotherapy, radiotherapy, molecular profile

Endometrial cancer (EC) is the most common gynecological cancer in countries with high life expectancy, notably North America. Global disparities were observed with a high frequency among white women but high mortality in black women. The American cancer society had reported an absolute difference rates of 21% at 5 years with 84% of White women surviving compared with 63% of Black women.¹ Over the last years, its incidence has increased in developed countries (130% in 30 years) with a parallel considerable mortality (1.9% per year on average).^2,3 Oncologically, there are three stages: localized; the most common (65-70%), locally advanced (15-20%) and metastatic (less than 10%).⁴ According to SEER data, overall 5- year survival is around 82% for all stages combined.⁴ Generally sporadic, but also hereditary in 5-10% of cases as part of Lynch syndrome in young women with usually microsatellite instability.⁵ The standard primary treatment is surgery combining total hysterectomy with bilateral spapingo ovariectomy and pelvic

+/- para-aortic lymph node dissection. Sentinel lymph node biopsy is currently more widely used than dissection because of its low postoperative morbidity, particularly lymphedema.⁶ In 2023, FIGO staging of endometrial cancer are up-date according to many advances in the understanding of the pathologic and molecular features (Table 1).⁷

The indication for adjuvant treatment is based on the ESMO-ESGO-ESTRO 2016 consensus, according to the presence of prognostic factors: histological subtype, FIGO stage, grade, lymph node involvement and the presence or absence of lympho vascular invasion (LVSI) (Table 2).⁸

Recently, molecular biology has individualized four subgroups according to The Cancer Genome Atlas Research Network (TCGA): POLE ultra-mutated, mismatch repair deficient (MMRd), p53 abnormal and non-specific molecular profile (NSMP).⁹ This brand-new molecular classification has proven to have predictive value and serves as the foundation for new trials.

Analysis of 373 cases (303 endometrioid carcinomas and 66 serous carcinomas) from The Cancer Genom Atlas (TCGA) comprehensive platform assessment identified 4 genomic sub-classes using a combination of whole genome or exone sequencing, microsatellite instability (MSI) assays, and copy number alterations. A novel ultramutated subtype (>100 mutations/megabase) with pathogenic variations in the exonuclease domain of DNA polymerase epsilon (POLE)-ultramutated (POLEmut), hypermutated (10-100 mut/Mb) microsatellite-unstable, somatic copy number-high with frequent pathogenic variants in TP53 and somatic copy number-low with frequently phosphoinositide 3-kinase (PI3K) abnormalities (Table 3).⁹

Approximately 5–15% of EC carry one of these pathogenic POLE mutations. These POLEmut EC are found in relatively early-stage but high-grade tumors with prominent lymphovascular infiltration.^10,11 POLEmut carcinomas are associated with an exceptionally favorable prognosis with very low relapse incidence regardless of adjuvant treatment.^9–12 The mismatch-repair deficient (dMMR) is more often referred to the group with microsatellite instable group (MSI) detected in immunohistochemistry. The dMMR sub-group comprises about 25–30% of all EC and is defined by the loss of nuclear expression of one or more mismatch repair proteins and caused by somatic events such as MLH1 or PMS2 promoter hypermethylation but also due a germline mutation in one of the mismatch repair genes (Lynch syndrome). The dMMR sub-group has an intermediate prognosis and a strong immunogenic response.¹³

The third molecular sub-group (5-15% of EC) consists of EC with frequent occurrence of TP53 mutations, but a high number of somatic copy number alterations and a relatively low somatic mutation rate.¹⁴ This group comprises mainly high-grade EC and non-endometrioid histologies (serous, carcinosarcoma and clear cell cancers). The p53-abn groupe occur a poor prognosis due to aggressive growth with early spread of disease. The fourth and most commun sub-group of EC (30-40%), with no specific molecular profile (NSMP), has both a low mutational burden and low number of somatic copy number alterations. Prognosis in these tumors is stage dependent, but can be considered as intermediate risk. This sub-group typically contains endometrioid carcinomas with positive staining for estrogen and progesterone receptors.⁹

In some cases, about 3–6% have more than one classifying alteration and are referred to as multiple- classifier endometrial cancers. Vermij et al. has established the diagnostic algorithm for the classification of the four molecular sub-groups (Figure 1).¹⁵

Figure 1 Diagnostic algorithm for the integrated molecular EC classification.

This group includes stage I endometrial cancers, grade 1-2, infiltrating < 50% of the myometrium and without lymphovascular invasion, according to the ESMO classification. In the Sasada trial, the 5-years overall survival (OS) was 97.9% and 5-years recurrence rates were 2.6%.¹⁶ No OS benefits have been shown and local recurrence can be treated with radiotherapy.¹⁷ The PORTEC 1/2 trials had identified a POLE mut subgroup (5-15% of EC) as a favourable prognostic factor independently of other clinico- pathological parameters.^18,19 Further, patients with stage I-II/POLE mut are considered low risk and do not require adjuvant treatment. For stage III, no data are available and observation may be proposed as an option.²⁰

The Post-Operative Radiation Therapy in Endometrial Cancer (PORTEC) 1 and Gynaecologic Oncology Group (GOG) 99 trials demonstrated that adjuvant pelvic radiotherapy significantly reduced the risk of locoregional recurrence, without improving distant recurrence-free survival (DRFS) or overall survival (OS).^21,22 Further, another randomized trial (ASTEC/EN.5) also demonstrated this benefit without impacting OS.²³ The majority of recurrences occur in the vaginal vault (75%) in case of post-operative observation. In the PORTEC-1 trial, radiotherapy and vaginal brachytherapy for localized vaginal recurrence achieved 3 and 5-year survival rates of 73% and 65% respectively, and complete remissions of almost 90%. However, locoregional pelvic recurrence or distant metastatic disease shown poor 3-year survival rates (8-14%).^17–24

In the PORTEC-2 trial, vault brachytherapy (VBT) had the same disease-free and overall survival rates as pelvic external beam radiotherapy, but a lower rate of local vaginal recurrence (1.6% vs 1.8%) and, above all, less gastrointestinal toxicity.²⁵ In the European Society of Medical Oncology (ESMO) recommendations, omitting the VBT can be proposed for patients >60 years, referring to the Danish trial (14% locoregional recurrence risk but the same OS).^26,27 This option should be discussed on a case-by-case basis after concertation with patients. Patients with stage IA non-endometrioid EC or p53 abnormal are considered in the intermediate group. This subgroup has never been evaluated in randomized trials, and the benefit of pelvic radiotherapy or VBT is unclear. Simple observation or adjuvant treatment should be discussed in tumor boards.

According to PORTEC 1 and GOG-99, it includes stage I endometrioid, grade 3 (<50% myometrial invasion, regardless of LVSI) or stage I endometrioid, grade 1-2, unequivocally positive LVSI (regardless of depth of myometrial invasion). Long-term results of the PORTEC-2 trial showed no difference in vaginal recurrence rate (3.4% EBRT vs 2.4% VBT, p=0.55) and OS (69.5% EBRT vs 67.6% VBT). However, the risk of pelvic recurrence was higher with VBT than EBRT (6.3% vs. 0.9%, p=0.004).²⁸ Unfavourable factors risk of pelvic recurrence defined by significant LVSI, TP53 abnormality, and L1 cell- adhesion molecule (L1CAM) expression may benefit from pelvic EBRT.²⁸ Subgroup analysis of the MMR status of 197 patients with high intermediate risk found that MMR deficient increased the risk of recurrence (14.1% vs. 3%, p=0.003) and significantly reduced 5-year recurrence-free survival (73.5% vs. 95%, p=0.004).²⁹ Based on the new TCGA molecular classification, the PORTEC-4a trial will identify patients who could benefit from either observation, VBT or escalation by EBRT.³⁰ In the phase III GOG-249 trial, substituting pelvic EBRT by VBT plus carboplatin/paclitaxel chemotherapy over four cycles in this group of patients and/or stage I-II serous (15%) or clear cell (5%) cancers was unsuccessful in achieving the primary endpoint of 5-RFS (76% vs 81%, p=0.31) as well as OS (87% vs 85%, p=0.57). Acute side effects grade ≥ 2 were higher in the VBT and chemotherapy combination arm (94% vs. 44%).³¹ Result analysis by stage of the PORTEC-3 trial, which evaluated concomitant and adjuvant chemotherapy with radiotherapy versus exclusive EBRT, showed small benefit in stage I-II non-serous (5-year OS 2% and FFS 4%).³² Therefore, pelvic EBRT is the standard treatment for high intermediate risk; adjunction of chemotherapy should discussed by case considering side effects.

Heterogeneous group according to clinical stage, histological type and, more recently, molecular subtype. It includes endometrioid carcinomas stage I grade 3 with myometrial infiltration and/or lymphovascular invasion; endometrioid stage II-III and non-endometrioid (serous or clear cell or undifferentiated carcinoma, or carcinosarcoma) cancers stage I-III. Currently, stage III-IVA endometrioid EC without residual disease or stage I-IVA p53-abnormal are all considered high-risk EC. The risk of recurrence is high, ranging from 21 to 23%. Three main trials have evaluated the benefits of combined chemotherapy and radiotherapy treatment in this high-risk group (PORTEC-3, GOG-249 and GOG-258). Updated results from the PORTEC-3 trial at 6 years, comparing the addition of chemotherapy concomitantly and then adjuvant to radiotherapy versus EBRT alone, showed a 5% benefit in OS and 7% in FFS. The benefit was clearly higher in the serous and stage III subgroups. Clear-cell cancers have a worse prognosis, (only 5% of patients in the PORTEC-3); the frequency of recurrence in this subtype (especially wild-type p53) was similar to patients with endometrioid tumors but significantly lower than serous cancers.³² In GOG-249, the evaluation of the superiority of VBT with chemotherapy compared with pelvis EBRT for high intermediate-risk (according to GOG-33 criteria) and high risk (endometrioid stage II or serous/clear cell stage I-II) was negative. No benefit in recurrence-free survival or OS whatever the histological type.³¹

Recently, the phase III open label trial GOG-258, tested whether association of EBRT at 45 Gy and 6 months of platinum chemotherapy (Cisplatin Days 1-29 and 4 cycles od adjuvant Paclitaxel/Carboplatine) is associated with longer relapse-free survival than chemotherapy alone (6 cycles of

Paclitaxel/Carboplatine) in 818 EC patients with stage III-IVA. After 47 months of follow-up, no difference in 5 years-RFS (59% in the chemoradiotherapy group and 58% in the chemotherapy-only group). Chemoradiotherapy was associated with a lower 5-year incidence of vaginal recurrence (2% vs. 7%) and pelvic and paraaortic lymph-node recurrence (11% vs. 20%). Distant recurrence was more common in association with chemoradiotherapy but no statisticly significative (27% vs. 21%; hazard ratio

= 1.36). Adverse events grade 3 or more were higher in in the chemotherapy-only group (63% vs 58%). Taking into consideration all of this trials, concomitant or sequential chemoraditherapy is the recommended treatment for high-risk EC.³³

Two new studies have demonstrated the benefits of immunotherapy in combination with chemotherapy in locally advanced EC. The first trial used an anti-PD1 drug in 494 patients with locally advanced stage III- IV or first reccurent EC; 23.9% of whom were mismatch-repair deficient (dMMR) and microsatellite instability-high (MSI-H). Dostarlimab was administered concomitantly with 6 cycles of paclitaxel and carboplatin, then as maintenance for 3 years. In the dMMR-MSI-H population, the 24-months PFS was higher in the dostarlimab arm than placebo (61.3% vs 15%, HR = 0.28, p<0.001). Same benefit in the globa population (24-months PFS : 36.1% vs 18.1%). OS at 2 years is clearly superior with dostarlimab (71.3%) than placebo (56%). Adverse events are increased with immunotherapy but remain manageable.³⁴

The second trial, NRG GY018/Keynote-868 using Pembrolizumab in 816 EC patients with measurable disease (stage III or IVA) with paclitaxel plus carboplatin. The patients were stratified into two cohorts according to whether they had mismatch repair-deficient (dMMR) or mismatch repair-proficient (pMMR) disease. the second trial, using Pembrolizumab in 816 EC patients with measurable disease (stage III or IVA) in combination with paclitaxel plus carboplatin. The patients were stratified into according to whether they had mismatch repair-deficient (dMMR) or mismatch repair-proficient (pMMR) disease. One-year Progression-free survival in the dMMR cohort were 74% in the pembrolizumab group and 38% in the placebo group. In the pMMR cohort, median progression-free survival was 13.1 months with pembrolizumab and 8.7 months with placebo. Acute adverse events of immutherapy and chemotherapy were also manageable.³⁵ Therefore, the addition of immunotherapy should be discussed on a case-by-case at the multidisciplinary committee.

It is necessary to show the value of adjuvant chemotherapy treatment for each subgroup in light of the new molecular classification and its strong prognostic value. Regardless of the histological subtype, EC patients with p53-abn have a worse prognosis, according to analysis of PORTEC-3 tissue samples. Patients with POLEmut, have a good prognosis. In treatment, patients with p53-abn benefited from adjuvant radio- chemotherapy regardless of clinical stage or histological type, while those with POLEmut had excellent survival and could benefit from de-escalation.

In conclusion, adjuvant therapy for endometrial cancer is based not only on clinico-pathological risk factors, but also on molecular profiles with precise prognostic values, enabling personalized precision medicine. Four molecular subgroups have been identified by TCGA, enabling postoperative treatment to be tailored to the prognostic risk of local and/or distant progression. Adjuvant chemotherapy combined with radiotherapy has been shown to be beneficial for the p53-abn subtype, while the POLEmut has better recurrence-free survival and OS, so therapeutic de-escalation may be the standard, with the same results and fewer toxicities. The dMMR subtype seem to benefit more from adding immunotherapy to chemotherapy, while NSMPs have a moderately higher disease-free survival rate with radio-chemotherapy. Therefore, it's very important to select adjuvant therapies carefully, incorporating the new molecular classification into our decisions to improve therapeutic and prognostic outcomes. A program of trials has already been left RAINBO in high-risk EC patients, which will compare different therapeutic protocols according to molecular subclasses: for p53-abn ECs, the comparison will be between radio-chemotherapy with or without the addition of PARP inhibitors; for patients with a non-specific molecular profile, bi- therapy with radio-chemotherapy will be compared with other modalities such as chemotherapy alone or hormonal therapy; for POLE-mut patients, observation will be compared to adjuvant treatment with EBRT or VBT; and finally for dMMR patients, the benefit of immunotherapy with radiotherapy has yet to be demonstrated. Certainly, the results of these series of studies will have a real impact on the decision- making process for adjuvant treatment in the years to come.

None.

The authors declare that there are no conflicts of interest.

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