Oncology

Endometrial Cancer

Predicting Endometrial Cancer Recurrence and Response to Adjuvant Therapy

clinical topic updates by Richard T. Penson, MD, MRCP

Overview

Approximately 66,000 women develop endometrial cancer in this country each year, and the incidence is anticipated to rise to more than 80,000 in 2030, making it the third commonest cancer. Recurrence remains a major challenge, and scientific advances have improved risk stratification based on tumor size, stage, grade, immunohistochemical markers, and molecular profile.

“The single biggest recent change with the FIGO 2023 staging system was its integration of the 4 molecular subtypes of endometrial cancer that help predict recurrence: POLE ultramutated, dMMR, TP53 mutated, and nonspecific molecular profile.”

— Richard T. Penson, MD, MRCP

The major risk factors for endometrial cancer recurrence have traditionally been a diameter of at least 2 cm, a higher stage and grade, the presence of lymphovascular space invasion, and a more aggressive histology, such as serous carcinoma or carcinosarcoma. More recently defined characteristics associated with the risk of recurrence related to molecular drivers and immune-related factors are now being integrated into clinical decisions.

The staging of endometrial cancer has changed over time with updates to the International Federation of Gynecology and Obstetrics (FIGO) staging system in 1988, 2009, and 2023. The single biggest recent change with the FIGO 2023 staging system was its integration of the 4 molecular subtypes of endometrial cancer that help predict recurrence: POLE ultramutated, mismatch repair deficient (dMMR), TP53 mutated, and nonspecific molecular profile. POLE ultramutation is associated with a lower risk of recurrence than the other subtypes. The integration of molecular profiling into the staging helps differentiate endometrial cancers with aggressive histology into substages. Although contemporary guidelines recommend POLE testing, most centers cannot do such testing. So, it is possible that World Health Organization (WHO) histologic staging and FIGO staging systems will be revised because of the practical logistics of what is available in terms of next-generation sequencing at different institutions.

Molecular subtyping has transformed treatment for endometrial cancer. This is being translated into improved adjuvant therapy with chemotherapy for patients with TP53 mutations and potential treatment with immunotherapy for patients with dMMR tumors. dMMR is a powerful predictor of benefit from immunotherapy among patients with endometrial cancer, but it is less clear whether PD-L1 expression is also a predictor, although it may be integrated with markers such as TP53 mutation. HER2-targeted treatment has transformed the management of recurrent disease. Hopefully, ADCs will help to further improve patient outcomes in this treatment setting.

References

Addante F, d’Amati A, Santoro A, et al. Mismatch repair deficiency as a predictive and prognostic biomarker in endometrial cancer: a review on immunohistochemistry staining patterns and clinical implications. Int J Mol Sci. 2024;25(2):1056. doi:10.3390/ijms25021056

Berek JS, Matias-Guiu X, Creutzberg C, et al; Endometrial Cancer Staging Subcommittee, FIGO Women’s Cancer Committee. FIGO staging of endometrial cancer: 2023. J Gynecol Oncol. 2023;34(5):e85. doi:10.3802/jgo.2023.34.e85

Cancer Genome Atlas Research Network; Kandoth C, Schultz N, Cherniack AD, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497(7447):67-73. Published correction appears in Nature. 2013;500(7461):242.

Fader AN, Roque DM, Siegel E, 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. Clin Cancer Res. 2020;26(15):3928-3935. doi:10.1158/1078-0432.CCR-20-0953

Jumaah AS, Al-Haddad HS, Salem MM, McAllister KA, Yasseen AA. Mismatch repair deficiency and clinicopathological characteristics in endometrial carcinoma: a systematic review and meta-analysis. J Pathol Transl Med. 2021;55(3):202-211. doi:10.4132/jptm.2021.02.19

Mariani A, Webb MJ, Keeney GL, Lesnick TG, Podratz KC. Surgical stage I endometrial cancer: predictors of distant failure and death. Gynecol Oncol. 2002;87(3):274-280. doi:10.1006/gyno.2002.6836

Mirza MR, Sharma S, Herrstedt J, et al. Dostarlimab + chemotherapy for the treatment of primary advanced or recurrent endometrial cancer (pA/rEC): analysis of progression free survival (PFS) and overall survival (OS) outcomes by molecular classification in the ENGOT-EN6-NSGO/GOG-3031/RUBY trial. Ann Oncol. 2023;34(suppl 2):S507. doi:10.1016/j.annonc.2023.09.1919

Porter RL, Xiong N, Tayob N, et al. Abstract CT008: a phase 2, two-stage study of mirvetuximab soravtansine (IMGN853) in combination with pembrolizumab in patients with microsatellite stable (MSS) recurrent or persistent endometrial cancer. Cancer Res. 2024;84(suppl 7):CT008. doi:10.1158/1538-7445.AM2024-CT008

Walsh CS, Hacker KE, Secord AA, DeLair DF, McCourt C, Urban R. Molecular testing for endometrial cancer: an SGO clinical practice statement. Gynecol Oncol. 2023;168:48-55. doi:10.1016/j.ygyno.2022.10.024

Profile

Richard T. Penson, MD, MRCP

Associate Professor of Medicine
Harvard Medical School
Medical Gynecologic Oncologist
Massachusetts General Hospital
Institutional Review Board Chair
Dana-Farber/Partners Cancer Care
Boston, MA