Abstract

Although surgery total abdominal hysterectomy with bilateral salpingo-oophorerctomy remains the cornerstone for all types of endometrial cancers, but histological types, stage and histological grade along its molecular subtypes are decided from surgical specimen which provides not only the outcome of disease and its recurrence or relapse but further guide the oncologist nature kind of adjuvant treatment in form of external beam pelvic radiotherapy, vaginal stump brachytherapy, chemotherapy with or without immunotherapy/ targeted therapies.

Keywords:Radiotherapy; Chemotherapy; Immunotherapy; Endometrial cancer; Carcinosarcoma

Abbreviations: EC: Endometrial Cancer; TAH: Trans Abdominal Hysterectomy; MIS: Micro Satellite Instability; L1-CAM: L1 Cell Adhesion Molecule; PDL1: Programe Death Legend 1; LVSI: Lymphovascular Space Invasion; PROTEC: Post Operative Radiotherapy in Endometrial Cancer

Introduction

In India incidence of endometrial cancer is 4.3/lac per year reported by many studies, notable risk factors include older age, obesity (especially those BMI more than 30%), diabetes, hypertension, infertility associated poly cystic ovarian syndrome. More than 90% of Endometrial cancers are sporadic in nature but 5% to 10% cases are hereditary mostly a part of hereditary non polyposis colorectal cancer syndrome which having 10-fold greater risk of developing EC (Endometrial cancer) typically known as lynch syndrome this kind of cases usually occurs at younger age [1-5].

Overall, 5-year Survival Rate of Endometrial Cancer Reported

i.stage1- more than 90%
ii.stage 2- 70% to 75%
iii.stage 3 - 50%
iv.stage 4- 25%

Prognostic factors of EC are: histological types, histological grade, stage of tumor, depth of myometrial invasion, cervical invasion, serosal and parametrial extension of disease along kind of molecular markers mutation present. Patients those are suitable candidates for surgery trans abdominal hysterectomy bilateral hysterectomy (TAH & BSO) along peritoneal wash and lymph node sampling if given below histopathology reports comes, we consider the EC patients for adjuvant treatment.
i.Stage 1A - Grade 1 & 2 less than 50% myometrial invasion - No Adjuvant treatment/ No radiotherapy.
ii.Stage 1A - Grade 3 - Only vaginal brachytherapy.
iii.Stage 1B - Grade 1/2/3 - Only vaginal brachytherapy.
iv.Stage 2 & 3, Any grade - If post operative case adjuvant external beam radiotherapy to pelvis 50 Gy and Intra Vaginal brachytherapy, HDR 7Gy OF 3 Fractions given to upper half of vaginal vault.

Above mention treatment policy did not incorporate molecular markers as well as several risks factors which author will be discussing below.

What are the Molecular Markers for Endometrial Cancers

Nowadays molecular markers have become very much integral part in the management of endometrial cancer,these markers help in risk stratification (high risk or low risk ), prognosis of disease , response to the treatment of patients, Molecular test help in the diagnosis and therapeutic approach into clinical practice particularly in advance stage of disease or in recurrent / relapse along metastatic endometrial cancer by the help of chemotherapy and immunotherapy [6-8].

Evidence reported by Cancer genome atlas (T-CGA) ProMise classification have divided endometrial cancer into different subtypes

a. POLE (DNA POLMERASE) Ultra mutated.
b. Micro satellite Instability (MIS) Hypermutated, MMRd (Mis match repair defect).
c. Copy number high abnormal p53 (p53abn).
d. Copy number low wild type p53 / NSMP (Nonspecific molecular type).

Among four kind of mutations POLE mutant tumors having best prognosis and p53abn mutant tumors having worst prognosis , MIS, MMRd mutant tumors having intermediate prognosis. Ultra mutation defined when > 100 mutations/ megabase present, and Hyper mutation defined when 10-100 mutations/ Megabase (also called as micro satellite instability - MIS), Somatic copy number high is frequently pathogonomic of p53 mutations. Inference drawn from above that p53abn tumors should be offer adjuvant chemotherapy, other molecular markers for immune check point studies found L1 Cell adhesion molecule (L1-CAM) proven to be strong predictor for poor outcome of disease, poor disease-free survival and over all survival even in early stage (stage 1 and stage 2) endometrial cancer due to early recurrence and distant metastasis, we must remember L1-CAM mutation is frequently associated with p53abn gene [9-12].

Similarly, MIS/MMRd gene frequently asscociated with PDL1 ( Programe death legend 1) mutation, actually PDL1 gene is an inhibiting receptor protein of lymphocytes henceforth it causes inhibition of host immune response against tumor means over expression of PDL1 leads poor survival in view of that Anti PDL1 antibodies (pembrlizumab) monoclonal antibodies becomes an indication for those endometrial cancer showing MMRd/ MIS mutations on IHC Studies. HER-2 gene amplified in 17% to 33% cases of endometrial cancers mainly among uterine carcinosarcoma, serous adenocarcinoma histological types so among these cases adjuvant chemotherapy along Transstuzamab increases the survival in terms of progression free survival as well as overall survival both [13-15].

FIGO Defining Risk Factors / Pathology and Diagnosis

EC traditionally defined into two categories type-1 histologically endometriod variety of endometrial carcinoma and type -2 fall in rest all histological kind of endometrial cancer , type-2 variety associated with high risk of relapse and recurrence compare to type-1 variety.

Risk Factors Defined for Endometral Cancers

i. Grade of tumor GI/G2/G3.
ii. Depth of myometrial invasion > 50%.
iii. Lymphovascular space invasion (LVSI).
iv. Tumor diameter > 2cm.

LVSI further defined weather it a focal or Substantial LVSI, Focal defined when < 4 vessels showing tumor emboli, Substantial LVSI defined on histopathology of tumor specimen showing > 4 vessels showing tumor emboli, Substantial LVSI is considerd as major poor prognostic factor.

Percentage wise Prevalence of Molecular Markers Associated with Endometrial Cancer are

i. POLE - 5% -15%,
ii. MMRd - 25% -30%
iii. p53abn - 5% - 15 %

Endometrial cancer PROTEC4a (Post operative radiotherapy in endometrial cancer) trail recent data suggest that maximum benefit found when adding chemotherapy among p53abn group of patients, p53abn patients more commonly associated with serous / carcino sarcoma variety of endometrial cancers .hence we see molecular test of EC is very vital for adjuvant chemotherapy or targeted therapy decision. In view of above said it is well established that IHC marker for p53 and MIS/MMRd test must be done in all kind of endometrial cancers, we further observed the fact that prioritization of EC Molecular test must be done particularly those EC who classify in high grade G3, or high stage (3or 4) or histological variants (high risk) found serious / poorly differentiated/ clear cell / uterine carcino sarcoma kinds of endometrial cancers [16,17].

Recommendations made for Endometrial Cancers are that must be Clearly Defined are

i. Histological type.
ii. FIGO grade.
iii. Depth of myometrial invasion.
iv. LVSI (Substantial or focal).

Molecular test with help of IHC marker study, p53/ MMR/ POLE gene study should be carried out for all endometrial cancer regardless any histological type.

Preoperative staging and investigation along Risk assessment

Preoprative staging may help to establish a recurrence risk group mainly on the basis of myometrial invasion / cervical invasion / Pelvic lymphnode mets, Workup Includes transvaginal ultrasonograpy routine blood test (HMG/KFT/LFT), MRI imaging considered most accurate imaging technique for endometrial carcinoma disease extension due to its excellent soft tissue resolution T2 weighted image of MRI having 98% accuracy for myometrial invasion, CECT abdomen and thorax required to rule out extra pelvic disease, PET Scan may be useful for detecting distant metastasis.

What are Low Risk and High-Risk Criteria for Endometrial Cancer LOW RISK ENDOMERIAL CANCER - having good prognosis are

i. Stage 1A G1/G2 WITH endometriod type with no or only focal LVSI.
ii. Stage 1 and stage 2 with POLE mutant endometrial cancer.

There is no indication of adjuvant treatment for early-stage low risk endometrial carcinomas after adequate surgery, further to note all early stage (stage1 and stage 2) endometrial cancer patients with PLOE mutation should be considered under lowrisk group.

High Risk Endometrial Cancer

i. Any stage and any histological type tumor with p53abn or > 50% of myometrial invasion.
ii. Any stage with serous/ undifferentiated/ carcinosarcoma histology falls under high-risk group.
iii. Stage 3 and stage 4a with no residual tumor regardless of any histology as well as regardless of any molecular types fall under high-risk group.

As per PROTEC-1 and GOG 99 TRAIL early stage 1 and 2 even having high risk after surgery required adjuvant radiotherapy but No chemotherapy required to be given. As per PROTEC-3 and GOG 258 trail high stage (stage 3 and stage 4a ) and high-risk group of patients get benefited when we add chemotherapy after radiotherapy.

Recurrent and Metastatic Endometrial Carcinoma Treatment Approach

Outcome of recurrent / metastatic endometrial cancer remains poor with 5-year overall survival rate only 20%, few important prognostic factors impacting the local control and survival for this group of patients depends upon given below finding.
i. isolated vaginal / pelvic /peritoneal mets provide good survival.
ii. if recurrent tumor size is less or equal up to 2 cm provides good survival.
iii. 3-if recurrent / relapse free survival period longer provides good survival.
iv. if recurrent / relapse tumor histology is endometrioid type, provide good survival.

Radiotherapy Role in Recurrent and Metastatic Endometrial Carcinoma

If patient had history of primary surgery only on recurrence radiotherapy can be given as salvage radiotherapy with EBRT and Vaginal brachytherapy which provides best survival.

Surgery Role in Recurrent and Metastatic Endometrial Carcinoma

Those patients had given prior radiotherapy only salvage surgery can be done particularly those having isolated vaginal stump or small size local recurrence.

Role of Systemic Therapy (Hormone/Chemotherapy/ Immunotherapy) in Recurrent and Metastatic Endometrial Carcinoma Hormone therapy indicated in

i. Low grade carcinoma.
ii. Enodometeroid type carcinoma.
iii. Low volume disease.

Hormone therapy includes various anti estrogenic agents like - Progesterone, Aromatase inhibiters, tamoxifin, fulvistrant among this progesterone used as first line hormone therapy and provides response rate 23.3% and median survival 2.9-month progesterone used as Medroxi progesterone acetate 200mg and Megestral acetate 160mg per orally.

Chemotherapy Role in Recurrent and Metastatic Endometrial Carcinoma

If relapse or recurrent lesion not amenable to surgery or radiotherapy these candidates can be given chemotherapy paclitaxil 175mg/m2 along carboplatin AUC 5-6, six cycle 3weekly basis (GOG - 209 trail) results shown overall respose rate 40% to 50% thus above regimen becomes standard of care, with paclitaxil and corboplatin addition of bevasuzimab failed to provide superior result thus not recommended, Another regimen paclitaxil with doxorubicine provides only 20% response rate thus not considered.

Chemotherapy Role in Endometrial Carcinoma in General Indication are

i. Any stage if p53abn mutation present indication of paclitaxil with carboplatin.
ii. High stage and high-risk chemotherapy indicated.
iii. Recurrent and metastatic endometrial carcinoma.
iv. NOTE - Early stage with high risk factor chemotherapy not indicated.

Endometrial Carcinoma Role of Immunotherapy

Knowing the fact 30% of endometrial carcinoma on IHC study shows MIS/MMRd mutation that leads to consideration of immunotherapy we also knowing the fact MIS/MMRd gene frequently associated with PDLI gene mutation henceforth Anti PDL1 antibodies Pembrolizumab 300mg 3 weekly indicated with paclitaxil carboplatin chemotherapy. Immunotherapy with Antiangiogenic target agents - FDA approves combination of oral multikinase inhibitor LEVATINIB which targets vasculo endothelial growth factors/ fibroblastic growth factor along platelet derived growth factor. Levatinib given in combination of Pembrolizumab indicated in those endometrial cancer patients become resistant to paclitaxil and carboplatin chemotherapy. Levatinib 20mg oral capsule along pembrolizumab 200mg 3 weekly recommended until disease progression side effects of above agents are hypertension / fatigue / muscle pain / diarrhea / skin reactions along reduction of dose or interruption in treatment occurs in 70% cases Single agent immunotherapy indicated once platinum-based chemotherapy failure occurs [18-21].

Conclusion

In the management of endometrial cancer role of pelvic as well as intra vaginal radiotherapy has been well established since long back but after advent of specific molecular markers for endometrial cancer role of chemotherapy and immunotherapy has been encouraging results in terms of overall survival and progression free survival henceforth it has been incorporated as integral part of endometrial cancer management

Conflict of Interest

None.

References

1. Friberg E, Orsini N, Mantzoros CS, Wolk A (2007) Diabetes mellitus and risk of endometrial cancer: a meta-analysis. Diabetologia 50(7): 1365-1374.
2. Lauby-Secretan B, Scoccianti C, Loomis D, Yann G, Franca B, et al. (2016) Body Fatness and Cancer-Viewpoint of the IARC Working Group. N Engl J Med 375(8): 794-798.
3. Rahib L, Smith BD, Aizenberg R, Allison B, Julie M, et al. (2014) Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 74(11): 2913-2921.
4. Bokhman JV (1983) Two pathogenetic types of endometrial carcinoma. Gynecol Oncol 15(1): 10-17.
5. Kandoth C, Schultz N, Andrew D, Elaine R, Yuexin L, et al. (2013) Integrated genomic characterization of endometrial carcinoma. Nature 497(7447): 67-73.
6. Domchek SM, Robson ME (2019) Update on genetic testing in gynecologic cancer. J Clin Oncol 37(27): 2501-2509.
7. Soslow RA, Tornos C, Park KJ, Anais M, Esther O, et al. (2019) Endometrial carcinoma diagnosis: Use of FIGO grading and genomic subcategories in clinical practice: Recommendations of the International Society of Gynecological Pathologists. Int J Gynecol Pathol 38(Suppl 1): S64-S74.
8. Bosse T, Peters EE, Creutzberg CL, Ina MS, Jan J Jobsen, et al. (2015) Substantial lymph-vascular space invasion (LVSI) is a significant risk factor for recurrence in endometrial cancer-A pooled analysis of PORTEC 1 and 2 trials. Eur J Cancer. 51(13): 1742-1750.
9. Peters EEM, Leon-Castillo A, Smit V, Marie B, Estrid H, et al. (2022) Defining substantial lymphovascular space invasion in endometrial cancer. Int J Gynecol Pathol 41(3): 220-226.
10. Peters EEM, Leon-Castillo A, Hogdall E, Marie B, Claus H, et al. (2022) Substantial lymphovascular space invasion is an adverse prognostic factor in high-risk endometrial cancer. Int J Gynecol Pathol 41(3): 227-234.
11. Zeimet AG, Reimer D, Huszar M, Samira Abdel A, Mina F, et al. (2013) L1CAM in early-stage type I endometrial cancer: results of a large multicenter evaluation. J Natl Cancer Inst 105(15): 1142-1150.
12. Bosse T, Nout RA, Stelloo E, Dreef E, Nijman HW, et al. (2014) L1 cell adhesion molecule is a strong predictor for distant recurrence and overall survival in early-stage endometrial cancer: pooled PORTEC trial results. Eur J Cancer 50(15): 2602-2610.
13. Van Gool IC, Stelloo E, Nout RA, Hans W, David N, et al. (2016) Prognostic significance of L1CAM expression and its association with mutant p53 expression in high-risk endometrial cancer. Mod Pathol 29(2): 174-181.
14. Stelloo E, Nout RA, Osse EM, Ina J Jürgenliemk, Jan J, et al. (2016) Improved risk assessment by integrating molecular and clinicopathological factors in early-stage endometrial cancer-combined analysis of the PORTEC cohorts. Clin Cancer Res 22(16): 4215-4224.
15. Gilks CB, Oliva E, Soslow RA (2013) Poor interobserver reproducibility in the diagnosis of high-grade endometrial carcinoma. Am J Surg Pathol 37(6): 874-881.
16. de Boer SM, Wortman BG, Bosse T, Singh N, Hollema H, et al. (2018) Clinical consequences of upfront pathology review in the randomised PORTEC-3 trial for highrisk endometrial cancer. Ann Oncol 29(2): 424-430.
17. Kommoss S, McConechy MK, Kommoss F, S Leung, A Bunz, et al. (2018) Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series. Ann Oncol 29(5): 1180-1188.
18. Talhouk A, McConechy MK, Leung S, Kwon JS, Melnyk N, et al. (2015) A clinically applicable molecular-based classification for endometrial cancers. Br J Cancer 113(2): 299-310.
19. Leon-Castillo A, de Boer SM, Powell ME, Linda R, Helen J, et al. (2020) Molecular classification of the PORTEC-3 trial for high-risk endometrial cancer: impact on prognosis and benefit from adjuvant therapy. J Clin Oncol 38(29): 3388-3397.
20. Vermij L, Smit V, Nout R, Tjalling B (2020) Incorporation of molecular characteristics into endometrial cancer management. Histopathology 76(1): 52-63.
21. Leon-Castillo A, Britton H, McConechy MK, Jessica N, Remi N, et al. (2020) Interpretation of somatic POLE mutations in endometrial carcinoma. J Pathol 250(3): 323-335.