Clinical issues of surgery for uterine endometrial cancer in Japan

Objective The mainstay of treatment for uterine endometrial cancer is surgery, and recurrent-risk cases require multidisciplinary treatment, including surgery, chemotherapy and radiation therapy. Methods The standard surgery for uterine endometrial cancer is hysterectomy and bilateral salpingooophorectomy, with additional retroperitoneal lymph node dissection and omentectomy, depending on the case. The appropriate treatment is determined based on the risk classification, such as the depth of invasion into the myometrium, diagnosis of histological type and grade, and risk assessment of lymph node metastasis. Results Recently, minimally invasive surgery has been widely used not only in low-risk patients but also in intermediate- and high-risk patients. In low-risk patients, the possibility of ovarian preservation is discussed from a healthcare perspective for young women. Determining the need for retroperitoneal lymph node dissection based on sentinel lymph node evaluation may contribute in minimizing the incidence of post-operative lymphedema while ensuring accurate diagnosis of lymph node metastasis. Recently, many studies using sentinel lymph nodes have been reported for patients with uterine endometrial cancer, and the feasibility of sentinel lymph node mapping surgery has been proven. Unfortunately, sentinel lymph node biopsy and sentinel lymph node mapping surgery have not been widely adopted in surgery for uterine cancer in Japan. In addition, the search for biomarkers, such as RNA sequencing using The Cancer Genome Atlas, metabolic profile and lipidomic profile for early detection and prognostic evaluation, has been actively pursued. Conclusions Gynecologic oncologists expect to be able to provide uterine endometrial cancer patients with appropriate treatment that preserves their quality of life without compromising oncologic outcomes in the near future.

Testing methods for surgical treatment of endometrial cancer

Annotation. The urgency of the study is due to an increase in the incidence (more than 50%) of newly diagnosed uterine endometrial cancer, especially among young people. The main method of treatment for stage I-II endometrial cancer remains surgery. The study aimed to identify possible cytological conversion during laparoscopic procedures. The main method of research was a non-randomized, prospective cohort study with subsequent observation of the duration of hospitalization and 30 days after discharge for the period from 2010 to 2019. The duration of hospitalization was estimated, while in the perioperative period and within 30 days after discharge – the presence of postoperative complications. A total of 812 patients with stage I-IV endometrial cancer were analyzed, with a mean age of 52±5 years (25 to 75 years). The first group included patients who underwent laparotomy, the second – laparoscopic surgery. The presence of metastases and recurrences was confirmed by morphological, radiological, echoscopic and clinical methods. Standard methods of descriptive statistics were used for data processing; in particular, the average values were calculated with their standard errors when using the standard Student’s t-test at p<0.05 using Microsoft Excel software packages. Conclusions were made about the volume and type of surgery, taking into account the histological type of tumor, lymphovascular invasion, clinical stage, presence or absence of obesity and other comorbidities that may affect metabolism, life history and the presence of surgery. The obtained data confirm the safety of laparoscopic hysterectomy for women with stage I endometrial cancer. However, there are no data on whether laparoscopy can lead to intra-abdominal dissemination of tumor cells.

186 Distinct immune signatures predicting clinical response to PD-1 blockade therapy in gynecological cancers revealed by high-dimensional immune profiling

BackgroundAlthough immune checkpoint blockade revolutionized cancer therapy, response rates have been mixed in gynecological malignancies. While uterine endometrial cancer with high microsatellite instability (MSIHI) and high tumor mutational burden (TMB) respond robustly to checkpoint blockade, high-grade serous ovarian cancer (HGSOC) with low TMB respond modestly. Currently, there has been no known immune signature or T cell phenotype that predicts clinical response in gynecological tumors.MethodsTo dissect the immune landscape and T cell phenotypes in gynecological cancer patients receiving PD-1 blockade, we used high-dimensional cytometry (flow cytometry and mass cytometry (CyTOF)). We performed longitudinal deep immune profiling of PBMC from patients with recurrent uterine endometrial cancer receiving single-arm nivolumab, and HSGOC patients receiving neoadjuvant nivolumab plus platinum-based chemotherapy prior to debulking surgery.ResultsChemotherapy-resistant MSI-H uterine cancer patients treated with nivolumab had a proliferative T cell response 2–4 weeks post PD-1 blockade, consistent with responses seen in high TMB melanoma and lung cancer. The responding Ki67+ CD8 T cell population was largely CD45RAloCD27hi or CD45RAloCD27lo and highly expressed PD1, CTLA-4, and CD39, consistent with the phenotype of exhausted T cells (TEX). These exhausted-like cells are enriched in responders, whereas early expansion Tregs are enriched in non-responders. Unlike patients with uterine endometrial cancer, patients with TMBlo ovarian cancer did not have a clear proliferative CD8 T cell response after neoadjuvant nivolumab plus chemotherapy treatment, suggesting systemic immune suppression. At baseline, ovarian cancer without recurrence have more terminally differentiated effector-like CD8 T cells, and patients with recurrence have more naive-like cells. Thus, both high and low TMB gynecological tumors have distinct immune landscapes associated with clinical response. Additionally, in MSI-H uterine endometrial cancer patients, the length of time between the prior chemotherapy and the initiation of immunotherapy was negatively correlated with T cell reinvigoration post immunotherapy and clinical response. This suggests the importance of optimize therapeutic timing to maximize the therapeutic efficacy when combining immunotherapy and chemotherapy.ConclusionsCollectively, our immune profiling revealed the distinct immune signatures associated with clinical response to PD-1 blockade in gynecological cancers. Our results also suggest that TMBhi inflamed versus TMBlo cold tumor microenvironment, and timing of chemo/immunotherapy could impact differentiation and functions of T cells.Ethics ApprovalThe study was approved by MSKCC Ethics Board, approval number 17–180 and 17–182.