Sentinel node-positive POLE-mutated endometrial cancer.

BackgroundThe endometrial cancer molecular classification has been integrated into the 2020 World Health Organization (WHO) diagnostic classification and European treatment guidelines, and provides direction towards more effective and less toxic...

Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Molecular subtype stratified response to adjuvant therapy in endometrial cancer (086)

Molecular classification of human endometrial cancer based on gene expression profiles from specialized microarrays

Lymph node status is one of the most important factors in determining prognosis and the need for adjuvant treatment in endometrial cancer (EMCA). Unfortunately, full lymphadenectomy bears significant surgical and postoperative risks. The majority of patients with clinical stage I disease will not have metastatic disease; thus, a full lymphadenectomy only increases morbidity in this population of patients. The use of the sentinel lymph node (SLN) biopsy has emerged as an alternative to complete lymphadenectomy in EMCA. By removing the highest yield lymph nodes, the SLN biopsy has the same diagnostic ability as lymphadenectomy while minimizing morbidity. The sensitivity of sentinel lymph node identification with robotic fluorescence imaging for detecting metastatic endometrial and cervical cancer (FIRES) trial published this year is the largest prospective, multi-institution trial investigating the accuracy of the SLN biopsy for endometrial and cervical cancer. Results of this trial found an excellent sensitivity (97.2%) and false negative rate (3%) with the technique. The conclusions from the FIRES trial and those of a recent meta-analysis are that SLN biopsy has an acceptable diagnostic accuracy in detecting lymphatic metastases, and can replace lymphadenectomy for this diagnostic purpose. There remains controversy surrounding the SLN biopsy in high-risk disease and the use of adjuvant therapy in the setting of low volume disease detected with ultrastaging. Current data suggests that the technique is accurate in high-risk disease and that the increased detection of metastasis helps guide adjuvant therapy such that oncologic outcomes are likely not affected by forgoing a full lymphadenectomy. Further prospective study is needed to investigate the impact of low volume metastatic disease on oncologic outcomes and the need for adjuvant therapy in these patients.

For endometrial cancer (EC), clinical and pathological risk factors are taken to triage patients and estimate their prognosis. Lymph node involvement (pN+), lymphovascular space involvement (LSVI), grading, age of the patients, and Tclassification are internationally accepted parameters for treatment decisions. Studies on adjuvant radiation, chemotherapy, and chemoradiation are discussed against the background of risk stratification and clinical decision-making in early-to-advanced stage endometrial cancer. Recent publications on adjuvant treatment in high-risk disease and its implications for the patients with regard to expected oncologic benefit and treatment-related toxicity are discussed. Surgery is the mainstay of treatment of EC patients. Well-differentiated tumors and early disease (FIGO IA) should be followed up without further treatment. In FIGOI stage without risk factors, VBT remains the standard treatment after surgery. FIGOI, II patients with one or more risk factors (MI ≥ 50%, Grading[G]3, age >60years, LVSI) benefit from external beam radiotherapy (EBRT) in terms of survival. There are no data of acceptable quality demonstrating that chemotherapy is superior to radiation in locally advanced carcinomas. Therefore, even in locally advanced disease (FIGOIII, IV), EBRT remains the standard of care after surgery. EBRT contributes to the very low rate of local relapses and better DFS in these patients and should not be replaced by chemotherapy only. Whether and which subgroups of patients benefit from an additional (concomitant and/or adjuvant) chemotherapy in terms of disease-free survival remains acontroversial issue. The recently published PORTEC-3 trial could not create clear evidence. With ahigh rate of isolated tumors cells and micrometastases in the specimens, the increasing use of unvalidated sentinel concepts in endometrial cancer raises more questions with regard to indications for adjuvant treatment. In the future, integrated genomic characterization of tumors might be helpful for treatment individualization in the adjuvant setting.

PD-(L)1 inhibitors have shown benefit in mismatch repair-deficient (MMRd) endometrial cancer. However, their efficacy in mismatch repair-proficient endometrial cancer (comprising POLE-mutated (POLEmut), p53-abnormal (p53abn), and no-specific-molecular-profile (NSMP) molecular classes) remains unclear. This systematic review and meta-analysis evaluated the efficacy of PD-(L)1 inhibitors, as monotherapy or combined with chemotherapy, across the 4 molecular classes. Systematic searches were conducted across Embase, PubMed, Cochrane, and Web of Science, with manual searches of reference lists and conference websites. A total of 7 reports on 5 clinical trials were identified, with 3 included in the meta-analysis. Overall survival and progression-free survival were assessed. In patients with primary advanced or recurrent MMRd endometrial cancer (n=215), adding a PD-(L)1 inhibitor to platinum-based chemotherapy significantly improved overall (HR 0.36, 95% CI 0.21 to 0.62) and progression-free survival (HR 0.35, 95% CI 0.23 to 0.53). In patients with p53abn endometrial cancer, no significant benefits in overall (HR 0.91, 95% CI 0.26 to 3.22; n=135) or progression-free survival (HR 0.84, 95% CI 0.41 to 1.70; n=326) were observed, but both were affected by significant heterogeneity. In patients with NSMP endometrial cancer, a significant benefit was observed for progression-free survival (HR 0.73, 95% CI 0.57 to 0.95; n=373), but no overall survival benefit (HR 0.93, 95% CI 0.63 to 1.39; n=242). Insufficient data were available for patients with POLEmut endometrial cancer (n=12), with no events reported in 2 of 3 clinical trials comprising the majority of patients (n=11). PD-(L)1 inhibition demonstrated significant efficacy in patients with advanced or recurrent MMRd endometrial cancer. In NSMP endometrial cancer, adding a PD-(L)1 inhibitor to platinum-based chemotherapy showed potential benefit, whereas in p53abn endometrial cancer, such benefit was not found. POLEmut endometrial cancer, although rare in recurrent or metastatic settings, was associated with a favorable prognosis, regardless of treatment. These findings underscore the relevance of the molecular classification of endometrial cancer and highlight the importance of prioritizing molecular analyses in clinical trials to guide personalized PD-(L)1 inhibition strategies.

e17623 Background: Endometrial cancer (EC) is one of the most prevalent gynecologic tumors. Current diagnosis and treatment of EC no longer rely solely on traditional histopathological classification. Nevertheless, molecular classification of EC demonstrated clear prognostic value and may guide clinical decision. Methods: In this study, archived tissue specimens from 240 EC patients from Department of Pathology, Peking University People’s Hospital. Four subtypes [POLE ultramutated (POLE mut), microsatellite instability high (MSI-H), copy number low (CNL), and copy number high (CNH)] were stratified by next-generation sequencing (NGS) panel (Amoy Diagnostics, Xiamen, China) targeting POLE, TP53, BRCA1, and BRCA2 genes and microsatellite instability (MSI) status. Immunohistochemistry (IHC) was applied to detect the expression of P53, MMR and other related proteins. Results: Distribution of the EC subtypes in 240 patients was 13 (5.42%) of POLE mut, 36 (15.00%) of MSI-H, 41 (17.08%) of CNH, and 150 (62.50%) of CNL. Compared to published results of EC subtypes in Caucasian including TCGA, ProMisE as well as TransPORTEC, real-world data on Chinese ECs displayed a significantly larger proportion of CNL. In addition, novel biomarkers such as DUSP1, MCF7 and BUB1, which were independent prognostic marker from our previous research were validated. Also, it was found that BRCA2 appeared to be more prevalent in EC than BRCA1. Further analysis revealed that the overall consistency for NGS-based and IHC-based TP53 abnormalities detection and MSI/MMR status assessment were as high as 87.5% and 100%, respectively. Conclusions: Chinese ECs have unique molecular characteristics. In order to perform accurate molecular typing of Chinese ECs, more molecular indicators that match the characteristics of the Chinese population need to be added to the existing classifiers. NGS-based panel is easy to operate and replicate with high accuracy. Thus, it is a viable alternative to IHC in EC molecular classification.

The Fourth Edition of the Guidelines for Treatment of Uterine Body Neoplasm was published in 2018. These guidelines include 9 chapters: 1. Overview of the guidelines, 2. Initial treatment for endometrial cancer, 3. Postoperative adjuvant therapy for endometrial cancer, 4. Post-treatment surveillance for endometrial cancer, 5. Treatment for advanced or recurrent endometrial cancer, 6. Fertility-sparing therapy, 7. Treatment of uterine carcinosarcoma and uterine sarcoma, 8. Treatment of trophoblastic disease, 9. Document collection; and nine algorithms: 1-3. Initial treatment of endometrial cancer, 4. Postoperative adjuvant treatment for endometrial cancer, 5. Treatment of recurrent endometrial cancer, 6. Fertility-sparing therapy, 7. Treatment for uterine carcinosarcoma, 8. Treatment for uterine sarcoma, 9. Treatment for choriocarcinoma. Each chapter includes overviews and clinical questions, and recommendations, objectives, explanation, and references are provided for each clinical question. This revision has no major changes compared to the 3rd edition, but does have some differences: 1) an explanation of the recommendation decision process and conflict of interest considerations have been added in the overview, 2) nurses, pharmacists and patients participated in creation of the guidelines, in addition to physicians, 3) the approach to evidence collection is listed at the end of the guidelines, and 4) for clinical questions that lack evidence or clinical validation, the opinion of the Guidelines Committee is given as a “Recommendations for tomorrow”.

The molecular classification of endometrial cancer (EC) has proven to have prognostic value and is predictive of response to adjuvant chemotherapy. Here, we investigate its predictive value for response to external beam radiotherapy (EBRT) and vaginal brachytherapy (VBT) in early-stage endometrioid EC (EEC). Data of the randomized PORTEC-1 trial (n = 714) comparing pelvic EBRT with no adjuvant therapy in early-stage intermediate-risk EC and the PORTEC-2 trial (n = 427) comparing VBT with EBRT in early-stage high-intermediate-risk EC were used. Locoregional (including vaginal and pelvic) recurrence-free survival was compared between treatment groups across the four molecular classes using Kaplan-Meier's methodology and log-rank tests. A total of 880 molecularly classified ECs, 484 from PORTEC-1 and 396 from PORTEC-2, were included. The majority were FIGO-2009 stage I EEC (97.2%). The median follow-up was 11.3 years. No locoregional recurrences were observed in EC with a pathogenic mutation of DNA polymerase-ε (POLEmut EC). In mismatch repair-deficient (MMRd) EC, locoregional recurrence-free survival was similar after EBRT (94.2%), VBT (94.2%), and no adjuvant therapy (90.3%; P = .74). In EC with a p53 abnormality (p53abn EC), EBRT (96.9%) had a substantial benefit over VBT (64.3%) and no adjuvant therapy (72.2%; P = .048). In EC with no specific molecular profile (NSMP EC), both EBRT (98.3%) and VBT (96.2%) yielded better locoregional control than no adjuvant therapy (87.7%; P < .0001). The molecular classification of EC predicts response to radiotherapy in stage I EEC and may guide adjuvant treatment decisions. Omitting radiotherapy seems to be safe in POLEmut EC. The benefit of radiotherapy seems to be limited in MMRd EC. EBRT yields a significantly better locoregional recurrence-free survival than VBT or no adjuvant therapy in p53abn EC. VBT is the treatment of choice for NSMP EC as it is as effective as EBRT and significantly better than no adjuvant therapy for locoregional tumor control.

The role of vaginal cuff brachytherapy in endometrial cancer

The majority of endometrial cancer patients are cured by surgical removal of the uterus. Adjuvant treatment is recommended for a subset of patients with tumor characteristics associated with increased risk of recurrence. Historically pathologists have played a central role in defining histopathological factors that together make-up a risk profile which directs the type of adjuvant treatment. This traditional approach suffers from interobserver variability and lacks a biological basis. With the advance of molecular pathology, we have been able to define molecularly distinct endometrial cancer subsets which also carry distinct prognostic information and may form a basis for targeted adjuvant treatment. The RAINBO program exploits this concept by running 4 molecular subclass specific clinical trials. During my talk I will go over the past, the present and the future of adjuvant treatment in endometrial cancer with an emphasis on the role of pathology. Citation Format: Tjalling Bosse. Personalized adjuvant treatment in endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr IA014.

Introduction/BackgroundThe incidence of endometrial cancer is increasing worldwide. While delays in diagnosis reduce survival, case molecular misclassification might be associated with under- and over-treatment. The objective of this study was...

Evaluation of somatic mutations in cervicovaginal samples as a non-invasive method for the detection and molecular classification of endometrial cancer.

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