Adjuvant treatment in endometrial cancer: when and what to choose

Endometrial cancer is the most common gynecological malignancy in developed countries. The management is primarily surgical, but adjuvant treatment may be indicated after surgery, according to the risk of recurrence. This review will focus on the prognostic risk groups presented in the 2020 ESGO/ESTRO/ESP guidelines and the ongoing trials based on new molecular markers that will help to get a more personalized cancer medicine.

Endometrial carcinoma; Adjuvant treatment; Molecular markers; Risk factors

[1] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians. 2021; 71: 209–249.

[2] Concin N, Matias-Guiu X, Vergote I, Cibula D, Mirza MR, Mar-nitz S, et al. ESGO/ESTRO/ESP Guidelines for the Management of Patients with Endometrial Carcinoma. International Journal of Gynecological Cancer. 2021; 31: 12–39.

[3] Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecologic Oncology. 1983; 15: 10–17.

[4] Creutzberg CL, van Putten WLJ, Koper PC, Lybeert MLM, Jobsen JJ, Wárlám-Rodenhuis CC, et al. Survival after relapse in patients with endometrial cancer: results from a randomized trial. Gynecologic Oncology. 2003; 89: 201–209.

[5] Fung-Kee-Fung M, Dodge J, Elit L, Lukka H, Chambers A, Oliver T. Follow-up after primary therapy for endometrial cancer: a systematic review. Gynecologic Oncology. 2006; 101: 520–529.

[6] Colombo N, Creutzberg C, Amant F, Bosse T, González-Martín A, Ledermann J, et al. ESMO–ESGO–ESTRO consensus conference on endometrial cancer: Diagnosis, treatment and follow-up. Radiotherapy and Oncology. 2016; 117: 559–581.

[7] Stelloo E, Nout RA, Osse EM, Jürgenliemk-Schulz IJ, Jobsen JJ, Lutgens LC, et al. Improved Risk Assessment by Integrating Molecular and Clinicopathological Factors in Early-stage Endometrial Cancer—Combined Analysis of the PORTEC Co-horts. Clinical Cancer Research. 2016; 22: 4215–4224.

[8] Levine DA. Integrated genomic characterization of endometrial carcinoma. Nature. 2013; 497: 67–73.

[9] Talhouk A, McConechy MK, Leung S, Yang W, Lum A, Senz J, et al. Confirmation of ProMisE: a simple, genomics-based clinical classifier for endometrial cancer. Cancer. 2017; 123: 802–813.

[10] Kommoss S, McConechy MK, Kommoss F, Leung S, Bunz A, Magrill J, et al. Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series. Annals of Oncology. 2018; 29: 1180–1188.

[11] Plotkin A, Kuzeljevic B, De Villa V, Thompson EF, Gilks CB, Clarke BA, et al. Interlaboratory Concordance of ProMisE Molecular Classification of Endometrial Carcinoma Based on Endometrial Biopsy Specimens. International Journal of Gynecological Pathology. 2020; 39: 537–545.

[12] Alexa M, Hasenburg A, Battista MJ. The TCGA Molecular Classification of Endometrial Cancer and Its Possible Impact on Adjuvant Treatment Decisions. Cancers. 2021; 13: 1478.

[13] León-Castillo A, Britton H, McConechy MK, McAlpine JN, Nout R, Kommoss S, et al. Interpretation of somatic POLE mutations in endometrial carcinoma. The Journal of Pathology. 2020; 250: 323–335.

[14] Piulats JM, Guerra E, Gil-Martín M, Roman-Canal B, Gatius S, Sanz-Pamplona R, et al. Molecular approaches for classifying endometrial carcinoma. Gynecologic Oncology. 2017; 145: 200–207.

[15] Church DN, Stelloo E, Nout RA, Valtcheva N, Depreeuw J, ter Haar N, et al. Prognostic Significance of POLE Proofreading Mutations in Endometrial Cancer. JNCI: Journal of the National Cancer Institute. 2014; 107: 402.

[16] McConechy MK, Talhouk A, Leung S, Chiu D, Yang W, Senz J, et al. Endometrial Carcinomas with POLE Exonuclease Domain Mutations have a Favorable Prognosis. Clinical Cancer Research. 2016; 22: 2865–2873.

[17] Church DN, Briggs SE, Palles C, Domingo E, Kearsey SJ, Grimes JM, et al. DNA polymerase epsilon and delta exonuclease domain mutations in endometrial cancer. Human Molecular Genetics. 2013; 22: 2820–2828.

[18] Meng B, Hoang LN, McIntyre JB, Duggan MA, Nelson GS, Lee C, et al. POLE exonuclease domain mutation predicts long progression-free survival in grade 3 endometrioid carcinoma of the endometrium. Gynecologic Oncology. 2014; 134: 15–19.

[19] Raffone A, Travaglino A, Mascolo M, Carbone L, Guida M, Insabato L, et al. TCGA molecular groups of endometrial cancer: Pooled data about prognosis. Gynecologic Oncology. 2019; 155: 374–383.

[20] Meyer LA, Broaddus RR, Lu KH. Endometrial Cancer and Lynch Syndrome: Clinical and Pathologic Considerations. Cancer Control. 2009; 16: 14–22.

[21] Dunlop M. Cancer risk associated with germline DNA mismatch repair gene mutations. Human Molecular Genetics. 1997; 6: 105–110.

[22] Aarnio M, Sankila R, Pukkala E, Salovaara R, Aaltonen LA, de la Chapelle A, et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes. International Journal of Cancer. 1999; 81: 214–218.

[23] SEER Training Modules, Cancer Stat Facts: Uterine Cancer. U. S. National Institutes of Health, National Cancer Institute. Available at: https://seer.cancer.gov/statfacts/html/corp.ht ml (Accessed: 13 December 2021).

[24] Mills AM, Liou S, Ford JM, Berek JS, Pai RK, Longacre TA. Lynch Syndrome Screening should be Considered for all Patients with Newly Diagnosed Endometrial Cancer. American Journal of Surgical Pathology. 2014; 38: 1501–1509.

[25] Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013; 502: 333–339.

[26] Talhouk A, McConechy MK, Leung S, Li-Chang HH, Kwon JS, Melnyk N, et al. A clinically applicable molecular-based classification for endometrial cancers. British Journal of Cancer. 2015; 113: 299–310.

[27] León‐Castillo A, Gilvazquez E, Nout R, Smit VT, McAlpine JN, McConechy M, et al. Clinicopathological and molecular characterisation of ‘multiple‐classifier’ endometrial carcinomas. The Journal of Pathology. 2020; 250: 312–322.

[28] Creutzberg CL, van Putten WL, Koper PC, Lybeert ML, Jobsen JJ, Wárlám-Rodenhuis CC, et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. The Lancet. 2000; 355: 1404–1411.

[29] León-Castillo A, de Boer SM, Powell ME, Mileshkin LR, Mackay HJ, Leary A, et al. Molecular Classification of the PORTEC-3 Trial for High-Risk Endometrial Cancer: Impact on Prognosis and Benefit from Adjuvant Therapy. Journal of Clinical Oncology. 2020; 38: 3388–3397.

[30] Nout R, Smit V, Putter H, Jürgenliemk-Schulz I, Jobsen J, Lutgens L, et al. Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, noninferiority, randomised trial. The Lancet. 2010; 375: 816–823.

[31] Barney BM, Petersen IA, Mariani A, Dowdy SC, Bakkum-Gamez JN, Haddock MG. The Role of Vaginal Brachytherapy in the Treatment of Surgical Stage i Papillary Serous or Clear Cell Endometrial Cancer. International Journal of Radiation Oncology, Biology, Physics. 2013; 85: 109–115.

[32] R.A. S, Bhavsar D, M.N. S, Kunikullaya US, R.K. V, Parikh A, et al. Combined external beam radiotherapy and vaginal brachytherapy versus vaginal brachytherapy in stage i, intermediate- and high-risk cases of endometrium carcinoma. Journal of Contemporary Brachytherapy. 2018; 10: 105–114.

[33] Cham S, Huang Y, Tergas AI, Hou JY, Burke WM, Deutsch I, et al. Utility of radiation therapy for early-stage uterine papillary serous carcinoma. Gynecologic Oncology. 2017; 145: 269–276.

[34] Shinde A, Li R, Amini A, Chen Y, Cristea M, Dellinger T, et al. Improved survival with adjuvant brachytherapy in stage IA endometrial cancer of unfavorable histology. Gynecologic Oncology. 2018; 151: 82–90.

[35] Sorbe B, Horvath G, Andersson H, Boman K, Lundgren C, Pettersson B. External Pelvic and Vaginal Irradiation Versus Vaginal Irradiation alone as Postoperative Therapy in Medium-Risk Endometrial Carcinoma—a Prospective Randomized Study. International Journal of Radiation Oncology, Biology, Physics. 2012; 82: 1249–1255.

[36] Ørtoft G, Hansen ES, Bertelsen K. Omitting Adjuvant Radio-therapy in Endometrial Cancer Increases the Rate of Locoregional Recurrences but has no Effect on Long-Term Survival. International Journal of Gynecological Cancer. 2012; 23: 1429–1437.

[37] Aalders J, Abeler V, Kolstad P, Onsrud M. Postoperative External Irradiation and Prognostic Parameters in Stage I Endometrial Carcinoma: Clinical and histopathologic Study of 540 Patients. Obstetrics & Gynecology. 1980; 56: 419–427.

[38] Randall ME, Filiaci V, McMeekin DS, von Gruenigen V, Huang H, Yashar CM, et al. Phase III Trial: Adjuvant Pelvic Radiation Therapy Versus Vaginal Brachytherapy Plus Paclitaxel/Carboplatin in High-Intermediate and High-Risk Early-Stage Endometrial Cancer. Journal of Clinical Oncology. 2019; 37: 1810–1818.

[39] Maggi R, Lissoni A, Spina F, Melpignano M, Zola P, Favalli G, et al. Adjuvant chemotherapy vs radiotherapy in high-risk endometrial carcinoma: results of a randomised trial. British Journal of Cancer. 2006; 95: 266–271.

[40] Susumu N, Sagae S, Udagawa Y, Niwa K, Kuramoto H, Satoh S, et al. Randomized phase III trial of pelvic radiotherapy versus cisplatin-based combined chemotherapy in patients with intermediate- and high-risk endometrial cancer: a Japanese Gynecologic Oncology Group study. Gynecologic Oncology. 2008; 108: 226–233.

[41] Hogberg T, Signorelli M, de Oliveira CF, Fossati R, Lissoni AA, Sorbe B, et al. Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer–Results from two randomised studies. European Journal of Cancer. 2010; 46: 2422–2431.

[42] de Boer SM, Powell ME, Mileshkin L, Katsaros D, Bessette P, Haie-Meder C, et al. Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial. The Lancet Oncology. 2018; 19: 295–309.

[43] Keys HM, Roberts JA, Brunetto VL, Zaino RJ, Spirtos NM, Bloss JD, et al. A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study. Gynecologic Oncology. 2004; 92: 744–751.

[44] de Boer SM, Powell ME, Mileshkin L, Katsaros D, Bessette P, Haie-Meder C, et al. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. The Lancet Oncology. 2019; 20: 1273–1285.

[45] Matei D, Filiaci V, Randall ME, Mutch D, Steinhoff MM, DiS-ilvestro PA, et al. Adjuvant Chemotherapy plus Radiation for Locally Advanced Endometrial Cancer. New England Journal of Medicine. 2019; 380: 2317–2326.

[46] van den Heerik ASVM, Horeweg N, Nout RA, Lutgens LCHW, van der Steen-Banasik EM, Westerveld GH, et al. PORTEC-4a: international randomized trial of molecular profile-based adjuvant treatment for women with high-intermediate risk endometrial cancer. International Journal of Gynecologic Cancer. 2020; 30: 2002–2007.

[47] Zeimet AG, Reimer D, Huszar M, Winterhoff B, Puistola U, Abdel Azim S, et al. L1CAM in Early-Stage Type i Endometrial Cancer: Results of a Large Multicenter Evaluation. JNCI: Journal of the National Cancer Institute. 2013; 105: 1142–1150.

[48] Corrado G, Laquintana V, Loria R, Carosi M, de Salvo L, Sperduti I, et al. Endometrial cancer prognosis correlates with the expression of L1CAM and miR34a biomarkers. Journal of Experimental & Clinical Cancer Research. 2018; 37: 139.

[49] Fader AN, Roque DM, Siegel E, Buza N, Hui P, Abdelghany O, et al. Randomized Phase II Trial of Carboplatin–Paclitaxel Compared with Carboplatin–Paclitaxel–Trastuzumab in Advanced (Stage III–IV) or Recurrent Uterine Serous Carcinomas that Overexpress her2/Neu (NCT01367002): Updated Overall Survival Analysis. Clinical Cancer Research. 2020; 26: 3928–3935.

[50] Keir M, Francisco L, Sharpe A. PD-1 and its ligands in T-cell immunity. Current Opinion in Immunology. 2007; 19: 309–314.

[51] Post CCB, Westermann AM, Bosse T, Creutzberg CL, Kroep JR. PARP and PD-1/PD-L1 checkpoint inhibition in recurrent or metastatic endometrial cancer. Critical Reviews in Oncology/Hematology. 2020; 152: 102973.

[52] Lee V, Murphy A, Le DT, Diaz LA. Mismatch Repair Deficiency and Response to Immune Checkpoint Blockade. The Oncologist. 2016; 21: 1200–1211.

[53] Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord J, et al. Efficacy of Pembrolizumab in Patients with Noncolorectal High Microsatellite Instability/Mismatch Repair–Deficient Cancer: Results from the Phase II KEYNOTE-158 Study. Journal of Clinical Oncology. 2020; 38: 1–10.

[54] Oaknin A, Tinker AV, Gilbert L, Samouëlian V, Mathews C, Brown J, et al. Clinical Activity and Safety of the Anti–Programmed Death 1 Monoclonal Antibody Dostarlimab for Patients with Recurrent or Advanced Mismatch Repair–Deficient Endometrial Cancer. JAMA Oncology. 2020; 6: 1766.

[55] US National Library of Medicine. Testing the addition of the immunotherapy drug, pembrolizumab, to the usual radiation treatment for newly diagnosed early stage high intermediate risk endometrial cancer. 2021. Available at: https://clinicaltrals.gov/ct 2/show/NCT04214067 (Accessed: 18 November 2021).

[56] de Jonge MM, Auguste A, van Wijk LM, Schouten PC, Meijers M, ter Haar NT, et al. Frequent Homologous Recombination Deficiency in High-grade Endometrial Carcinomas. Clinical Cancer Research. 2019; 25: 1087–1097.