Can Immunotherapy Replace Radiation in Locally Advanced Endometrial Cancer?

Endometrial cancer represents the fourth most commonly diagnosed cancer in women in the United States and the sixth leading cause of cancer-related death. 1 Siegel RL Miller KD Wagle NS Jemal A Cancer statistics, 2023. CA Cancer J Clin. 2023; 73: 17-48 Crossref PubMed Scopus (601) Google Scholar Despite the recent advances in the management of recurrent and metastatic endometrial cancer, mortality has increased by 1.7% over the past 10 years, 2 Giaquinto AN Broaddus RR Jemal A Siegel RL The changing landscape of gynecologic cancer mortality in the United States. Obstet Gynecol. 2022; 139: 440-442 Crossref PubMed Scopus (22) Google Scholar largely attributable to an increasing overall incidence of endometrial cancer. 1 Siegel RL Miller KD Wagle NS Jemal A Cancer statistics, 2023. CA Cancer J Clin. 2023; 73: 17-48 Crossref PubMed Scopus (601) Google Scholar The management of locally advanced endometrial cancer (LAEC) involves a multimodal approach including surgical resection followed by risk-adapted adjuvant therapy. In addition to traditional risk factors, more recently molecular markers have become incorporated into prognostication and prediction of outcomes in the management of endometrial cancer. Mismatch repair-deficient (dMMR), microsatellite instability (MSI)-high tumors account for approximately 28% of endometrial cancers. 3 Kandoth C Schultz N et al. Cancer Genome Atlas Research NetworkIntegrated genomic characterization of endometrial carcinoma. Nature. 2013; 497: 67-73 Crossref PubMed Scopus (3234) Google Scholar Although MMR deficiency is oncogenic, dMMR-MSI-high has been demonstrated to increase the susceptibility of tumors to immunotherapy through increased mutational burden and neoantigens, which can serve as tumor-specific targets for the immune system. Inhibiting the programmed death-1 (PD-1) signaling pathway releases the “brakes” and modulates the immune response in favor of immune targeting of tumor cells and has been demonstrated in multiple prior reports. 4 Le DT Durham JN Smith KN et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017; 357: 409-413 Crossref PubMed Scopus (4141) Google Scholar ,5 Le DT Uram JN Wang H et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015; 372: 2509-2520 Crossref PubMed Scopus (6548) Google Scholar As a result of available data, The European Society of Gynaecological Oncology (ESGO), the European Society for Radiotherapy and Oncology (ESTRO) and the European Society of Pathology (ESP) published their guideline on the management of endometrial cancer in 2021. 6 Concin N Matias-Guiu X Vergote I et al. ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma. Radiother Oncol. 2021; 154: 327-353 Abstract Full Text Full Text PDF PubMed Google Scholar Molecular markers are integrated into the prognostic risk groups and are used to inform adjuvant treatment decisions. 6 Concin N Matias-Guiu X Vergote I et al. ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma. Radiother Oncol. 2021; 154: 327-353 Abstract Full Text Full Text PDF PubMed Google Scholar The American Society for Radiation Oncology (ASTRO) guideline on adjuvant therapy for endometrial cancer strongly recommends routine molecular testing when adjuvant therapy is considered. 7 Harkenrider MM Abu-Rustum N Albuquerque K et al. Radiation therapy for endometrial cancer: An American Society for Radiation Oncology Clinical Practice Guideline. Pract Radiat Oncol. 2023; 13: 41-65 Abstract Full Text Full Text PDF PubMed Google Scholar