Search

The Gynecologic Cancer InterGroup (GCIG) Endometrial Cancer Consensus Conference on Clinical Research (ECCC) was held in Incheon, South Korea, Nov 2–3, 2023. The aims were to develop consensus statements for future trials in endometrial cancer to achieve harmonisation on design elements, select important questions, and identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and finalisation of 18 statements within four topic groups, addressing adjuvant treatment in high-risk disease; treatment for metastatic and recurrent disease; trial designs for rare endometrial cancer subgroups and special circumstances; and specific methodology and adaptation for trials in low-resource settings. In addition, eight areas of unmet need were identified. This was the first GCIG Consensus Conference to include patient advocates and an expert on inclusion, diversity, equity, and access to take part in all aspects of the process and output. Four early-career investigators were also selected for participation, ensuring that they represented different GCIG member groups and regions. Unanimous consensus was obtained for 16 of the 18 statements, with 97% concordance for the remaining two. Using the described methodology from previous Ovarian Cancer Consensus Conferences, this conference did not require even one minority statement. The high acceptance rate following active involvement in the preparation, discussion, and refinement of the statements by all representatives confirmed the consensus progress within a global academic setting, and the expectation that the ECCC will lead to greater harmonisation, actualisation, inclusion, and resolution of unmet needs in clinical research for individuals living with and beyond endometrial cancer worldwide. [ABSTRACT FROM AUTHOR]

Introduction: Many advances in the understanding of the pathologic and molecular features of endometrial cancer have occurred since the FIGO staging was last updated in 2009. Substantially more outcome and biological behavior data are now available regarding the several histological types. Molecular and genetic findings have accelerated since the publication of The Cancer Genome Atlas (TCGA) data and provide improved clarity on the diverse biological nature of this collection of endometrial cancers and their differing prognostic outcomes. The goals of the new staging system are to better define these prognostic groups and create substages that indicate more appropriate surgical, radiation, and systemic therapies. Methods: The FIGO Women's Cancer Committee appointed a Subcommittee on Endometrial Cancer Staging in October 2021, represented by the authors. Since then, the committee members have met frequently and reviewed new and established evidence on the treatment, prognosis, and survival of endometrial cancer. Based on these data, opportunities for improvements in the categorization and stratification of these factors were identified in each of the four stages. Data and analyses from the molecular and histological classifications performed and published in the recently developed ESGO/ESTRO/ESP guidelines were used as a template for adding the new subclassifications to the proposed molecular and histological staging system. Results: Based on the existing evidence, the substages were defined as follows: S tage I (IA1): non-aggressive histological type of endometrial carcinoma limited to a polyp or confined to the endometrium; (IA2) non-aggressive histological types of endometrium involving less than 50% of the myometrium with no or focal lymphovascular space invasion (LVSI) as defined by WHO criteria; (IA3) low-grade endometrioid carcinomas limited to the uterus with simultaneous low-grade endometrioid ovarian involvement; (IB) non-aggressive histological types involving 50% or more of the myometrium with no LVSI or focal LVSI; (IC) aggressive histological types, i.e. serous, high-grade endometrioid, clear cell, carcinosarcomas, undifferentiated, mixed, and other unusual types without any myometrial invasion. S tage II (IIA): non-aggressive histological types that infiltrate the cervical stroma; (IIB) nonaggressive histological types that have substantial LVSI; or (IIC) aggressive histological types with any myometrial invasion. S tage III (IIIA): differentiating between adnexal versus uterine serosa infiltration; (IIIB) infiltration of vagina/parametria and pelvic peritoneal metastasis; and (IIIC) refinements for lymph node metastasis to pelvic and para-aortic lymph nodes, including micrometastasis and macrometastasis. S tage IV (IVA): locally advanced disease infiltrating the bladder or rectal mucosa; (IVB) extrapelvic peritoneal metastasis; and (IVC) distant metastasis. The performance of complete molecular classification ( POLEmut, MMRd, NSMP, p53abn) is encouraged in all endometrial cancers. If the molecular subtype is known, this is recorded in the FIGO stage by the addition of "m" for molecular classification, and a subscript indicating the specific molecular subtype. When molecular classification reveals p53abn or POLEmut status in Stages I and II, this results in upstaging or downstaging of the disease (IICmp53abn or IAmPOLEmut). Summary: The updated 2023 staging of endometrial cancer includes the various histological types, tumor patterns, and molecular classification to better reflect the improved understanding of the complex nature of the several types of endometrial carcinoma and their underlying biologic behavior. The changes incorporated in the 2023 staging system should provide a more evidence-based context for treatment recommendations and for the more refined future collection of outcome and survival data. [ABSTRACT FROM AUTHOR]

Evidence on the optimal follow-up schedule after endometrial cancer is lacking. The study aim was to compare satisfaction with care between women who received reduced follow-up care and women who received usual guideline-directed follow-up care for three years after surgery. The ENSURE (ENdometrial cancer SURvivors' follow-up carE) trial was a non-inferiority randomized controlled multicenter trial in 42 hospitals in the Netherlands. The intervention arm received reduced follow-up care (4 visits/3 years), while the control group received usual follow-up care (8–11 visits/3 years). Primary outcome was overall satisfaction with care, PSQIII score, over three years follow-up, with a non-inferiority margin of 6. Mixed linear regression, intention-to-treat and per-protocol analyses (presented below) were used. Among 316 women included, overall satisfaction with care was not lower in the reduced follow-up (mean 82; SD = 15) compared with the usual follow-up group (mean 80; SD = 15) group (B = 1.80(−2.09;5.68)). At 6, 12 and 36 months, more women (93/94/90%) in the reduced follow-up group were satisfied with their follow-up schedule than in the usual follow-up group (79/79/82%; p < 0.001; p < 0.001; p = 0.050). Women with low-risk, early-stage endometrial cancer who received reduced follow-up care were no less satisfied with their care than women receiving usual follow-up care. Compared with usual follow-up, women in the reduced follow-up group had fewer clinical visits and, at the same time, more often reported being satisfied with their follow-up schedule. Findings suggest that reduced follow-up care may be the new standard, but should be tailored to meet additional needs where indicated. • Reduced follow-up does not compromise satisfaction with care or worry. • Patients prefer the schedule of reduced follow-up. • Reduced follow-up care may be the new standard for endometrial cancer. • Follow-up should be tailored to meet individual patient needs in case of worry. • Findings may be relevant for other low-risk cancers. [ABSTRACT FROM AUTHOR]

Endometrial cancer is primarily treated with surgery. Adjuvant treatment strategies for endometrial cancer, such as external beam pelvic radiotherapy, vaginal brachytherapy, chemotherapy, and combined chemotherapy and radiotherapy, have been studied in several randomized trials. Adjuvant treatment is currently based on the presence of clinicopathological risk factors. Low- risk disease is adequately managed with surgery alone. In high- intermediate risk endometrial cancer, adjuvant vaginal brachytherapy is recommended to maximize local control, with only mild side effects and without impact on quality of life. For high- risk endometrial cancer, recent large randomized trials support the use of pelvic radiotherapy, especially in stage I-II endometrial cancer with risk factors. For women with serous cancers and those with stage III disease, chemoradiation increased both recurrence- free and overall survival, while GOG-258 showed similar recurrence- free survival compared with six cycles of chemotherapy alone, but with better pelvic and para- aortic nodal control with combined chemotherapy and radiotherapy. Recent molecular studies, most notably the work from The Cancer Genome Atlas (TCGA) project, have shown that four endometrial cancer molecular classes can be distinguished; POLE ultra- mutated, microsatellite instable hypermutated, copy- number- low, and copy- number- high. Subsequent studies, using surrogate markers to identify groups analogous to TCGA sub- classes, showed that all four endometrial cancer sub- types are found across all stages, histological types, and grades. Moreover, the molecular sub- groups have proved to have a stronger prognostic impact than histo- pathological tumor characteristics. This introduces an new era of molecular classification based diagnostics and treatment approaches. Integration of the molecular factors and new therapeutic targets will lead to molecular- integrated adjuvant treatment including targeted treatments, which are the rationale of new and ongoing trials. This review presents an overview of current adjuvant treatment strategies in endometrial cancer, highlights the development and evaluation of a molecular- integrated risk profile, and briefly discusses ongoing developments in targeted treatment [ABSTRACT FROM AUTHOR]

Aims POLE exonuclease domain mutations identify a subset of endometrial cancer ( EC) patients with an excellent prognosis. The use of this biomarker has been suggested to refine adjuvant treatment decisions, but the necessary sequencing is not widely performed and is relatively expensive. Therefore, we aimed to identify histopathological and immunohistochemical characteristics to aid in the detection of POLE-mutant ECs. Methods and results Fifty-one POLE-mutant endometrioid, 67 POLE-wild-type endometrioid and 15 POLE-wild-type serous ECs were included (total N = 133). An expert gynaecopathologist, blinded to molecular features, evaluated each case (two or more slides) for 16 morphological characteristics. Immunohistochemistry was performed for p53, p16, MLH1, MSH2, MSH6, and PMS2. POLE-mutant ECs were characterised by a prominent immune infiltrate: 80% showed peritumoral lymphocytes and 59% showed tumour-infiltrating lymphocytes, as compared with 43% and 28% of POLE-wild-type endometrioid ECs, and 27% and 13% of their serous counterparts ( P < 0.01, all comparisons). Of POLE-mutant ECs, 33% contained tumour giant cells; this proportion was significantly higher than that in POLE-wild-type endometrioid ECs (10%; P = 0.003), but not significantly different from that in serous ECs (53%). Serous-like features were as often (focally) present in POLE-mutant as in POLE-wild-type endometrioid ECs (6-24%, depending on the feature). The majority of POLE-mutant ECs showed wild-type p53 (86%), negative/focal p16 (82%) and normal mismatch repair protein expression (90%). Conclusions A simple combination of morphological and immunohistochemical characteristics (tumour type, grade, peritumoral lymphocytes, MLH1, and p53 expression) can assist in prescreening for POLE exonuclease domain mutations in EC, increasing the probability of a mutation being detected from 7% to 33%. This facilitates the use of this important prognostic biomarker in routine pathology. [ABSTRACT FROM AUTHOR]

In this dosimetric comparison study it was shown that IMPT with robust planning reduces dose to surrounding organs in cervical and endometrial cancer treatment compared with IMRT. Especially for the para-aortic region, clinically relevant dose reductions were obtained for kidneys, spinal cord and bowel, justifying the use of proton therapy for this indication. [ABSTRACT FROM AUTHOR]

Background Postoperative radiation therapy for stage I endometrial cancer improves locoregional control but is without survival benefit. To facilitate treatment decision support for individual patients, accurate statistical models to predict locoregional relapse (LRR), distant relapse (DR), overall survival (OS), and disease-free survival (DFS) are required. Methods and Materials Clinical trial data from the randomized Post Operative Radiation Therapy for Endometrial Cancer (PORTEC-1; N=714 patients) and PORTEC-2 (N=427 patients) trials and registered group (grade 3 and deep invasion, n=99) were pooled for analysis (N=1240). For most patients (86%) pathology review data were available; otherwise original pathology data were used. Trial variables which were clinically relevant and eligible according to data constraints were age, stage, given treatment (pelvic external beam radiation therapy (EBRT), vaginal brachytherapy (VBT), or no adjuvant treatment, FIGO histological grade, depth of invasion, and lymph-vascular invasion (LVSI). Multivariate analyses were based on Cox proportional hazards regression model. Predictors were selected based on a backward elimination scheme. Model results were expressed by the c-index (0.5-1.0; random to perfect prediction). Two validation sets (n=244 and 291 patients) were used. Results Accuracy of the developed models was good, with training accuracies between 0.71 and 0.78. The nomograms validated well for DR (0.73), DFS (0.69), and OS (0.70), but validation was only fair for LRR (0.59). Ranking of variables as to their predictive power showed that age, tumor grade, and LVSI were highly predictive for all outcomes, and given treatment for LRR and DFS. The nomograms were able to significantly distinguish low- from high-probability patients for these outcomes. Conclusions The nomograms are internally validated and able to accurately predict long-term outcome for endometrial cancer patients with observation, pelvic EBRT, or VBT after surgery. These models facilitate decision support in daily clinical practice and can be used for patient counseling and shared decision making, selecting patients who benefit most from adjuvant treatment, and generating new hypotheses. [ABSTRACT FROM AUTHOR]

The second Gynecologic Cancer InterGroup (GCIG) Endometrial Cancer Clinical Trials Planning Meeting was held on December 1, 2012, and included international multidisciplinary representatives of the 24 member groups. The aims were to review recent advances in molecular pathology of endometrial cancer, focusing on molecular-based therapy, and to identify key hypotheses and issues to be addressed through international collaborative clinical trials.Reviews and summaries of current knowledge were presented followed by parallel working group sessions for surgery, adjuvant and systemic therapy, and translational research. Plenary discussions were held to integrate translational and clinical issues, and a final discussion session to agree on key trial concepts.Proposals to take forward on the following trials were agreed: (1) lymphadenectomy to direct adjuvant treatment in women with high-risk endometrial cancer, including a sentinel node substudy; (2) conservative therapy for low-risk endometrial cancers in morbidly obese women with high surgical risks and for fertility-sparing treatment in premenopausal patients; (3) adjuvant therapy for women with early-stage carcinosarcoma. A proposal was made that a GCIG Early Phase Consortium be developed to serve as an international platform for rapid assessment of biomarkers. [ABSTRACT FROM AUTHOR]

High-risk endometrial cancer (EC), only 15% of all EC cases, mainly affects elderly women, often with significant comorbid diseases. Because patients with high-risk EC are at increased risk of distant metastases and EC death, the use of adjuvant chemotherapy has been investigated in several trials. Trials comparing radiotherapy and chemotherapy have not shown survival difference. A first trial comparing combinations of chemotherapy and radiotherapy with radiotherapy alone suggested a progression-free survival benefit. Toxicity and quality-of-life data are lacking. The role of adjuvant chemotherapy for endometrial carcinoma remains unproven. High-risk EC remains the challenge for further research. [ABSTRACT FROM AUTHOR]

Purpose: Endometrial carcinoma is the most common malignancy of the female genital tract. Recognized prognostic factors include FIGO stage, histologic grade, depth of myometrial invasion, and age. Although determination of these factors may seem clear and reproducible, the histologic grade has recently been the subject of debate. A retrospective analysis of long-term outcome and predictive factors in endometrial carcinoma was conducted, focusing on the prognostic value of tumor grade.Methods and Materials: The study included 253 patients with endometrial carcinoma Stages I to III, who were treated between 1984 and 1993. The histologic slides were reviewed and the prognostic value of stage, age, myometrial invasion (depth and pattern), tumor grade, and histologic subtype was analyzed. The end point was cancer-specific death; the median follow-up time was 11.7 years.Results: The actuarial 5- and 10-year cancer-specific survival rates (CSS) were 85% and 82%, respectively. Five-year vaginal and/or pelvic recurrence and distant relapse rates were 7% and 15%. In multivariate analysis, stage, pattern of myometrial invasion, tumor grade, and age were independent prognostic factors. At pathology review, a shift from Grade 2 to Grade 1 was seen in 112 of the original 144 Grade 2 (78%). There was no difference in CSS between Grade 1 and Grade 2 (94 vs. 90% for original grade and 92 vs. 95% for grade after review), whereas Grade 3 was found to be a significant adverse prognostic factor (p < 0.001).Conclusions: The independent prognostic factors for patients with endometrial cancer were stage, pattern of myometrial invasion, tumor grade, and age. Systematic grading led to a considerable shift from Grade 2 to Grade 1. However, there was no difference in prognostic significance between Grade 1 and 2, whereas Grade 3 was a major adverse prognostic factor. A two-tiered grading system, instead of the currently used three-tiered system seems preferable, because it has a better correlation with clinical outcome and is expected to have less interobserver variability. [Copyright &y& Elsevier]

Simple Summary: HER2 testing in endometrial cancer (EC) has gained renewed interest as a therapeutic target. However, HER2 status has not been investigated in the context of the molecular EC classification. Here, we aimed to determine the clinicopathological features and prognostic significance of the HER2 status in the molecularly classified PORTEC-3 trial population of patients with high-risk EC. HER2 status of 407 high-risk EC was determined by HER2 immunohistochemistry and HER2 dual in situ hybridization. Twenty-four (5.9%) HER2-positive EC of various histological subtypes were identified, including serous (n = 9, 37.5%), endometrioid (n = 6, 25.0%), and clear cell (n = 5, 20.8%). HER2 positivity was highly associated with the p53-abnormal subgroup (p53abn, 23/24 cases; p < 0.0001). The correlation between p53abn and the HER2 status (ρ = 0.438; p < 0.0001) was significantly stronger (p < 0.0001) than between serous histology and the HER2 status (ρ = 0.154; p = 0.002). HER2 status did not have independent prognostic value for survival after correction for the molecular classification. Our study strongly suggests that molecular subclass-directed HER2 testing is superior to histotype-directed testing. HER2 status has not been investigated in the context of the molecular endometrial cancer (EC) classification. Here, we aimed to determine the clinicopathological features and prognostic significance of the HER2 status in the molecularly classified PORTEC-3 trial population of patients with high-risk EC (HREC). HER2 testing was performed on tumor tissues of 407 molecularly classified HREC. HER2 status was determined by HER2 immunohistochemistry (IHC; all cases) and subsequent HER2 dual in situ hybridization for cases with any (in) complete moderate to strong membranous HER2 IHC expression. The Χ2 test and Spearman's Rho correlation coefficient were used to compare clinicopathological and molecular features. The Kaplan–Meier method, log-rank test, and Cox proportional hazards models were used for survival analysis. We identified 24 (5.9%) HER2-positive EC of various histological subtypes including serous (n = 9, 37.5%), endometrioid (n = 6, 25.0%), and clear cell (n = 5, 20.8%). HER2 positivity was highly associated with the p53-abnormal subgroup (p53abn, 23/24 cases; p < 0.0001). The correlation between p53abn and the HER2 status (ρ = 0.438; p < 0.0001) was significantly stronger (p < 0.0001) than between serous histology and the HER2 status (ρ = 0.154; p = 0.002). HER2 status did not have independent prognostic value for survival after correction for the molecular classification. Our study strongly suggests that molecular subclass-directed HER2 testing is superior to histotype-directed testing. This insight will be relevant for future trials targeting HER2. [ABSTRACT FROM AUTHOR]

Embracing the complex and diverse nature of the heterogenous group of malignancies that are included under the umbrella of "endometrial cancer" (EC) to better align prognosis with treatment recommendations, requires a more comprehensive staging system. Our goal at the development of the new FIGO staging was to provide 1) high accuracy in the predictive prognosis for a patient with EC, which is the genuine purpose of a staging system, and 2) identification of distinct treatment relevant subgroups. Since the publication of the 2009 staging system by the International Federation of Gynecology and Obstetrics (FIGO) 14 years ago (1, 2), our understanding of the biology and natural history of EC has undergone a radical transformation. The TGCA results in 2013 (3), and the many validation reports published since then (4–9), have taught us that "EC" is composed of at least four distinct molecularly defined diseases. Strong histopathologic markers reflecting tumor biology such as lymph vascular space invasion (LVSI) were identified. Importantly, anatomical borders were shown to lose their prognostic relevance for EC patients in the presence of dominant tumor biology-markers such as molecular subtypes/LVSI (10, 11). This emphasizes the integration of these novel markers into a prognostic staging system that aims to be relevant to patients. The 2023 FIGO staging system for EC harmonizes and integrates old and new knowledge on anatomic, histopathologic, and molecular features (12). It requires a change in our perception of a staging system, from a traditional purely anatomical borders-based system to an integrated staging system integrating anatomical borders and tumor biology as pivotal prognostic factors for EC patients while providing important information for treatment decision making. Therefore, the 2023 FIGO staging system demonstrates the logical next step in the evolution of the revolution in a patient-centric staging approach. Below, we elucidate the rationale for the FIGO 2023 endometrial cancer staging system. • 2023 FIGO staging system integrates old and new knowledge on anatomic, histopathologic, and (optional) molecular features. • 2023 FIGO is superior to 2009 FIGO in the prediction of survival, confirmed by to do date 5 validation studies. • 2023 FIGO adds prognostic granularity and identifies treatment-relevant subgroups of EC patients. • 2023 FIGO reinforces molecular testing to EC patients leveraging a strong demand for global access. • FIGO 2023 system will spur worldwide adoption of molecular classification so more tailored therapy will be adopted. [ABSTRACT FROM AUTHOR]

The article discusses the new 2023 FIGO staging system for endometrial cancer, which takes into account advancements in scientific knowledge and the heterogeneity of tumors. The system aims to improve prognostic precision and individualize treatment approaches by integrating biomarkers and molecular parameters. Several validation studies have demonstrated the higher prognostic value of the new staging system compared to the previous 2009 system. The article also addresses concerns about upstaging and the impact of molecular classification, as well as the need for global resource availability and cost-effective analysis. Overall, the new staging system is seen as a step forward in improving the care and treatment of women with endometrial cancer. [Extracted from the article]

High-risk endometrial cancer (EC) is an aggressive disease for which new therapeutic options are needed. Aims of this study were to validate the enhanced immune response in highly mutated ECs and to explore immune profiles in other EC subgroups. We evaluated immune infiltration in 116 high-risk ECs from the TransPORTEC consortium, previously classified into four molecular subtypes: (i) ultramutatedPOLEexonuclease domain-mutant ECs (POLE-mutant); (ii) hypermutated microsatellite unstable (MSI); (iii) p53-mutant; and (iv) no specific molecular profile (NSMP). Within The Cancer Genome Atlas (TCGA) EC cohort, significantly higher numbers of predicted neoantigens were demonstrated inPOLE-mutant and MSI tumors compared with NSMP and p53-mutants. This was reflected by enhanced immune expression and infiltration inPOLE-mutant and MSI tumors in both the TCGA cohort (mRNA expression) and the TransPORTEC cohort (immunohistochemistry) with high infiltration of CD8+(90% and 69%), PD-1+(73% and 69%) and PD-L1+immune cells (100% and 71%). Notably, a subset of p53-mutant and NSMP cancers was characterized by signs of an antitumor immune response (43% and 31% of tumors with high infiltration of CD8+cells, respectively), despite a low number of predicted neoantigens. In conclusion, the presence of enhanced immune infiltration, particularly high numbers of PD-1 and PD-L1 positive cells, in highly mutated, neoantigen-richPOLE-mutant and MSI endometrial tumors suggests sensitivity to immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Background: Current risk stratification in endometrial cancer (EC) results in frequent over- and underuse of adjuvant therapy, and may be improved by novel biomarkers. We examined whether POLE proofreading mutations, recently reported in about 7% of ECs, predict prognosis. Methods: We performed targeted POLE sequencing in ECs from the PORTEC-1 and -2 trials (n = 788), and analyzed clinical outcome according to POLE status. We combined these results with those from three additional series (n = 628) by meta-analysis to generate multivariable-adjusted, pooled hazard ratios (HRs) for recurrence-free survival (RFS) and cancer-specific survival (CSS) of POLE-mutant ECs. All statistical tests were two-sided. Results: POLE mutations were detected in 48 of 788 (6.1%) ECs from PORTEC-1 and-2 and were associated with high tumor grade (P < .001). Women with POLE-mutant ECs had fewer recurrences (6.2% vs 14.1%) and EC deaths (2.3% vs 9.7%), though, in the total PORTEC cohort, differences in RFS and CSS were not statistically significant (multivariable-adjusted HR = 0.43, 95% CI = 0.13 to 1.37, P = .15; HR = 0.19, 95% CI = 0.03 to 1.44, P = .11 respectively). However, of 109 grade 3 tumors, 0 of 15 POLE-mutant ECs recurred, compared with 29 of 94 (30.9%) POLE wild-type cancers; reflected in statistically significantly greater RFS (multivariable-adjusted HR = 0.11, 95% CI = 0.001 to 0.84, P = .03). In the additional series, there were no EC-related events in any of 33 POLE-mutant ECs, resulting in a multivariable-adjusted, pooled HR of 0.33 for RFS (95% CI = 0.12 to 0.91, P = .03) and 0.26 for CSS (95% CI = 0.06 to 1.08, P = .06). Conclusion: POLE proofreading mutations predict favorable EC prognosis, independently of other clinicopathological variables, with the greatest effect seen in high-grade tumors. This novel biomarker may help to reduce overtreatment in EC. [ABSTRACT FROM PUBLISHER]

Purpose: To evaluate the very long-term results of the randomized Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC)-1 trial for patients with Stage I endometrial carcinoma (EC), focusing on the role of prognostic factors for treatment selection and the long-term risk of second cancers. Patients and Methods: The PORTEC trial (1990–1997) included 714 patients with Stage IC Grade 1–2 or Stage IB Grade 2–3 EC. After surgery, patients were randomly allocated to external-beam pelvic radiotherapy (EBRT) or no additional treatment (NAT). Analysis was by intention to treat. Results: 426 patients were alive at the date of analysis. The median follow-up time was 13.3 years. The 15-year actuarial locoregional recurrence (LRR) rates were 6% for EBRT vs. 15.5% for NAT (p < 0.0001). The 15-year overall survival was 52% vs. 60% (p = 0.14), and the failure-free survival was 50% vs. 54% (p = 0.94). For patients with high-intermediate risk criteria, the 15-year overall survival was 41% vs. 48% (p = 0.51), and the 15-year EC-related death was 14% vs. 13%. Most LRR in the NAT group were vaginal recurrences (11.0% of 15.5%). The 15-year rates of distant metastases were 9% vs. 7% (p = 0.25). Second primary cancers had been diagnosed over 15 years in 19% of all patients, 22% vs. 16% for EBRT vs. NAT (p = 0.10), with observed vs. expected ratios of 1.6 (EBRT) and 1.2 (NAT) compared with a matched population (p = NS). Multivariate analysis confirmed the prognostic significance of Grade 3 for LRR (hazard ratio [HR] 3.4, p = 0.0003) and for EC death (HR 7.3, p < 0.0001), of age >60 (HR 3.9, p = 0.002 for LRR and 2.7, p = 0.01 for EC death) and myometrial invasion >50% (HR 1.9, p = 0.03 and HR 1.9, p = 0.02). Conclusions: The 15-year outcomes of PORTEC-1 confirm the relevance of HIR criteria for treatment selection, and a trend for long-term risk of second cancers. EBRT should be avoided in patients with low- and intermediate-risk EC. [ABSTRACT FROM AUTHOR]

Endometrial cancer is the most common gynaecological tumour in developed countries, and its incidence is increasing. The most frequently occurring histological subtype is endometrioid adenocarcinoma. Patients are often diagnosed when the disease is still confined to the uterus. Standard treatment consists of primary hysterectomy and bilateral salpingo-oophorectomy, often using minimally invasive approaches (laparoscopic or robotic). Lymph node surgical strategy is contingent on histological factors (subtype, tumour grade, involvement of lymphovascular space), disease stage (including myometrial invasion), patients' characteristics (age and comorbidities), and national and international guidelines. Adjuvant treatment is tailored according to histology and stage. Various classifications are used to assess the risks of recurrence and to determine optimum postoperative management. 5 year overall survival ranges from 74% to 91% in patients without metastatic disease. Trials are ongoing in patients at high risk of recurrence (including chemotherapy, chemoradiation therapy, and molecular targeted therapies) to assess the modalities that best balance optimisation of survival with the lowest adverse effects on quality of life. [ABSTRACT FROM AUTHOR]

Background Lymph-vascular space invasion (LVSI) is an important adverse prognostic factor in endometrial cancer (EC). However, its role in relation to type of recurrence and adjuvant treatment is not well defined, and there is significant interobserver variation. This study aimed to quantify LVSI and correlate this to risk and type of recurrence. Methods In the post operative radiation therapy in endometrial carcinoma (PORTEC)-trials stage I EC patients were randomised to receive external beam radiotherapy (EBRT) versus no additional treatment after surgery (PORTEC-1, n = 714), or to EBRT versus vaginal brachytherapy (PORTEC-2, n = 427). In tumour samples of 926 (81.2%) patients with endometrioid tumours LVSI was quantified using 2-, 3- and 4-tiered scoring systems. Cox proportional hazard models were used for time-to-event analysis. Results Any degree of LVSI was identified in 129 cases (13.9%). Substantial LVSI ( n = 44, 4.8%) using the 3-tiered approach had the strongest impact on the risk of distant metastasis (hazard ratio (HR) 4.5 confidence interval (CI) 2.4–8.5). In multivariate analysis (including: age, depth of myometrial invasion, grade, treatment) substantial LVSI remained the strongest independent prognostic factor for pelvic regional recurrence (HR 6.2 CI 2.4–16), distant metastasis (HR 3.6 CI 1.9–6.8) and overall survival (HR 2.0 CI 1.3–3.1). Only EBRT (HR 0.3 CI 0.1–0.8) reduced the risk of pelvic regional recurrence. Conclusions Substantial LVSI, in contrast to focal or no LVSI, was the strongest independent prognostic factor for pelvic regional recurrence, distant metastasis and overall survival. Therapeutic decisions should be based on the presence of substantial, not ‘any’ LVSI. Adjuvant EBRT and/or chemotherapy should be considered for stage I EC with substantial LVSI. [ABSTRACT FROM AUTHOR]

The clinical role of the molecular endometrial cancer (EC) classification has not been fully explored in patients staged with lymphadenectomy or without adjuvant treatment, conditions that could potentially moderate the prognostic value of the classification. We aimed to evaluate the clinical outcome of the molecular subgroups in patients with high-grade EC staged by lymphadenectomy and those without adjuvant treatment. DNA-sequencing for the detection of pathogenic POLE -exonuclease domain mutations and immunohistochemistry for mismatch repair (MMR) proteins and p53 expression were performed on 412 high-grade EC from the Danish Gynaecological Cancer Database (2005–2012) to classify them as POLE -ultramutated (POLE mut), MMR-deficient (MMRd), p53-mutant (p53abn), or no specific molecular profile (NSMP). Patients with stage IV or residual disease after surgery were excluded. Kaplan-Meier method, log-rank test and Cox proportional hazard models were used for analysis. Molecular analysis was successful in 367 EC; 251 patients had undergone lymphadenectomy. Five-year recurrence rates in this subgroup of patients was 36.7% for women with p53abn EC, 0.0% for POLE mut EC, 13.4% for MMRd EC and 42.9% for NSMP EC (p < 0.001). Similar results were observed among stage IA-IB patients. Among patients without adjuvant treatment (n = 264), none with POLE mut EC (n = 26) had a recurrence. The molecular EC classification has strong prognostic value, independent of clinicopathological factors, also among high-grade EC patients staged by lymphadenectomy and those without adjuvant treatment. The unfavourable prognosis of early-stage p53abn EC is not due to undetected lymph node metastasis, and the indolent behaviour of POLE mut EC is independent of adjuvant treatment. • The molecular endometrial cancer (EC) classification has independent prognostic value among women with high-grade EC. • P53 abnormal EC have a poor clinical outcome, also those staged by lymphadenectomy as stage I. • Patients with POLE- ultramutated EC have an excellent clinical outcome even when not receiving adjuvant treatment. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To investigate if analysis of genetic alterations in the main pathways involved in endometrioid type carcinogenesis (PI3K–AKT, Wnt/β-catenin, P53-activation and MSI) improves the current risk assessment based on clinicopathological factors. Methods: Formalin fixed paraffin embedded (FFPE) primary tumor samples of 65 patients with FIGO-stage I endometrioid type endometrial cancer (EEC) were selected from the randomized PORTEC-2 trial. Tumors were stained by immunohistochemistry for P53, PTEN and β-catenin. Tumor DNA was isolated for sequence analysis of TP53 (exons 4 to 8), hotspot mutation analysis of KRAS (exon 1) and PI3K (exon 9 and 20) and microsatellite-instability (MSI) analysis including MLH1 promotor-methylation status. Univariate and multivariate analyses for disease-free survival (DFS) using Cox regression models were performed. Results: P53 status (HR 6.7, 95%CI 1.75–26.0, p=0.006) and MSI were the strongest single genetic prognostic factors for decreased DFS, while high PI3K–AKT pathway activation showed a trend and β-catenin was not prognostic. The combination of multiple activated pathways was the most powerful prognostic factor for decreased DFS (HR 5.0; 95%CI 1.59–15.6 p=0.006). Multiple pathway activation, found in 8% of patients, was strongly associated with aggressive clinical course. In contrast, 40% of patients had no alterations in the investigated pathways and had a very low risk of disease progression. Conclusions: Activation of multiple oncogenic pathways in EEC was the most powerful prognostic factor for decreased DFS, resulting in an individual risk assessment superior to the current approach based on clinicopathological factors. [Copyright &y& Elsevier]

Endometrial cancer is the most common gynecological malignancy in high- and middle-income countries. Although the overall prognosis is relatively good, high-grade endometrial cancers have a tendency to recur. Recurrence needs to be prevented since the prognosis for recurrent endometrial cancer is dismal. Treatment tailored to tumor biology is the optimal strategy to balance treatment efficacy against toxicity. Since The Cancer Genome Atlas defined four molecular subgroups of endometrial cancers, the molecular factors are increasingly used to define prognosis and treatment. Standard treatment consists of hysterectomy and bilateral salpingo-oophorectomy. Lymphadenectomy (and increasingly sentinel node biopsy) enables identification of lymph node-positive patients who need adjuvant treatment, including radiotherapy and chemotherapy. Adjuvant therapy is used for Stage I-II patients with high-risk factors and Stage III patients; chemotherapy is especially used in non-endometrioid cancers and those in the copy-number high molecular group characterized by TP53 mutation. In advanced disease, a combination of surgery to no residual disease and chemotherapy with or without radiotherapy results in the best outcome. Surgery for recurrent disease is only advocated in patients with a good performance status with a relatively long disease-free interval. [ABSTRACT FROM AUTHOR]

Decision making regarding adjuvant therapy for high-risk endometrial cancer is complex. The aim of this study was to determine patients' and clinicians' minimally desired survival benefit to choose chemoradiotherapy over radiotherapy alone. Moreover, influencing factors and importance of positive and negative treatment effects (i.e. attribute) were investigated. Patients with high-risk endometrial cancer treated with adjuvant pelvic radiotherapy with or without chemotherapy and multidisciplinary gynaecologic oncology clinicians completed a trade-off questionnaire based on PORTEC-3 trial data. In total, 171 patients and 63 clinicians completed the questionnaire. Median minimally desired benefit to make chemoradiotherapy worthwhile was significantly higher for patients versus clinicians (10% vs 5%, p = 0.02). Both patients and clinicians rated survival benefit most important during decision making, followed by long-term symptoms. Older patients (OR 0.92 [95%CI 0.87–0.97]; p = 0.003) with comorbidity (OR 0.34 [95% CI 0.12–0.89]; p = 0.035) had lower preference for chemoradiotherapy, while patients with better numeracy skills (OR 1.2 [95%CI 1.05–1.36], p = 0.011) and chemoradiotherapy history (OR 25.0 [95%CI 8.8–91.7]; p < 0.001) had higher preference for chemoradiotherapy. There is a considerable difference in minimally desired survival benefit of chemoradiotherapy in high-risk endometrial cancer among and between patients and clinicians. Overall, endometrial cancer patients needed higher benefits than clinicians before preferring chemoradiotherapy. • Desired benefit to choose adjuvant chemotherapy was assessed in endometrial cancer. • Desired benefit varied considerably among and between patients and clinicians. • Patients desired higher survival benefit than clinicians to choose chemoradiotherapy. • Survival benefit and long-term symptoms are most important in decision making. • Patient preferences are strongly influenced by treatment history. [ABSTRACT FROM AUTHOR]

Purpose: Accurate target definition is critical for the appropriate application of radiation therapy. In 2008, the Radiation Therapy Oncology Group (RTOG) published an international collaborative atlas to define the clinical target volume (CTV) for intensity modulated pelvic radiation therapy in the postoperative treatment of endometrial and cervical cancer. The current project is an updated consensus of CTV definitions, with removal of all references to bony landmarks and inclusion of the para-aortic and inferior obturator nodal regions.Methods and Materials: An international consensus guideline working group discussed modifications of the current atlas and areas of controversy. A document was prepared to assist in contouring definitions. A sample case abdominopelvic computed tomographic image was made available, on which experts contoured targets. Targets were analyzed for consistency of delineation using an expectation-maximization algorithm for simultaneous truth and performance level estimation with kappa statistics as a measure of agreement between observers.Results: Sixteen participants provided 13 sets of contours. Participants were asked to provide separate contours of the following areas: vaginal cuff, obturator, internal iliac, external iliac, presacral, common iliac, and para-aortic regions. There was substantial agreement for the common iliac region (sensitivity 0.71, specificity 0.981, kappa 0.64), moderate agreement in the external iliac, para-aortic, internal iliac and vaginal cuff regions (sensitivity 0.66, 0.74, 0.62, 0.59; specificity 0.989, 0.966, 0.986, 0.976; kappa 0.60, 0.58, 0.52, 0.47, respectively), and fair agreement in the presacral and obturator regions (sensitivity 0.55, 0.35; specificity 0.986, 0.988; kappa 0.36, 0.21, respectively). A 95% agreement contour was smoothed and a final contour atlas was produced according to consensus.Conclusions: Agreement among the participants was most consistent in the common iliac region and least in the presacral and obturator nodal regions. The consensus volumes formed the basis of the updated NRG/RTOG Oncology postoperative atlas. Continued patterns of recurrence research are encouraged to refine these volumes. [ABSTRACT FROM AUTHOR]

Background and purpose The goals of this study were to determine the rate and risk factors of rectal bleeding (RB) after external beam radiotherapy and vaginal brachytherapy (EBRT + VB), and to compare these data to previously unreported RB rates from PORTEC-2 patients receiving EBRT or VB alone. Materials and methods Retrospective chart review identified 212 endometrial cancer patients receiving adjuvant EBRT + VB between 2006 and 2013. Patient-reported RB data were also obtained from PORTEC-2 patients randomized to EBRT ( n = 166) or VB ( n = 182). The two populations were compared using an RB scale of symptom severity. Results After a median 35 months, 17.9% of EBRT + VB patients ( n = 38) experienced any RB with 1.9% ( n = 4) having bleeding requiring intervention. Age ⩽70 years was the only predictor of RB (OR 2.8; 95% CI 1.1–8.7; p = 0.027). Rates of patient-reported RB after EBRT were similar with 15.0% ( n = 25) having any RB and 0.6% ( n = 1) having “very much” bleeding. On regression analysis, any EBRT (either EBRT alone or EBRT + VB) increased the risk of RB compared to those who received VB alone (OR 3.0; p = 0.0028; 95% CI 1.4–6.7). The rates of more severe RB were low and did not significantly differ between treatments. Conclusions Significant RB is rare after radiation. EBRT has higher rates of rectal bleeding than VB. The addition of VB to EBRT does not significantly alter bleeding rates. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Molecular alterations in endometrial cancer have been shown to be prognostically significant but have not yet been implemented in the current clinical risk assessment. Few studies have investigated the reliability of molecular alterations in pre-operative specimens. Therefore, the objective was to determine whether molecular analysis of pre-operative endometrial cancer samples accurately reflects those alterations in the subsequent hysterectomy specimens. Methods: Paired pre-operative and hysterectomy specimens of 48 patients diagnosed with endometrial carcinoma, 42 endometrioid (EEC) and 6 non-endometrioid (NEEC) carcinomas, were analyzed for immunohistochemical expression of p53, PTEN and β-catenin. Tumor DNA was isolated and analyzed for microsatellite instability (MSI), TP53 mutations and somatic hot spot mutations in 13 genes. Results: In EEC patients, loss of PTEN, nuclear β-catenin and p53-mutant expression was found in 43%, 7% and 12%, respectively. No nuclear β-catenin was found in 5 of 6 NEEC patients, all serous cancers, whereas a p53-mutant expression was present in all serous cases. MSI was found in 19.5%, all EEC. Concordance for PTEN, β-catenin, p53 expression and MSI status was found in 79%, 92%, 79% and 93.5%, respectively. We detected 65 hot spot mutations in 39/48 (81%) tumors. Overall concordance of the GynCarta multigene analysis was 99.8%. Conclusions: The results confirm the reliability of immunohistochemical and DNA-based techniques in the evaluation of molecular alterations in pre-operative endometrial specimens and high concordance rates with the definitive hysterectomy specimens. The resulting molecular signature provides initial pre-operative diagnostic information on the status of oncogenic pathways, which may contribute to individualized treatment strategies. [Copyright &y& Elsevier]

Aim: A validation study was conducted to evaluate the psychometric properties of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Endometrial Cancer Module (EORTC QLQ-EN24). This module was designed to assess disease and treatment specific aspects of the quality of life (QoL) of patients with endometrial cancer. Methods: Two hundred and sixty-eight women with endometrial cancer were recruited in different phases of treatment: after pelvic surgery (Group 1); during adjuvant chemotherapy and/or radiotherapy (Group 2); after completion of treatment (Group 3). Patients completed the EORTC QLQ-C30, the endometrial cancer module and a short debriefing questionnaire. Results: Multi-trait scaling analyses confirmed the hypothesised scale structure of the QLQ-EN24. Internal consistency reliability was good with Cronbach’s alpha coefficients ranging from 0.74 to 0.86 (lymphoedema 0.80, urological symptoms 0.75, gastrointestinal symptoms 0.74, body image problems 0.86 and sexual/vaginal problems 0.86). Convergent and discriminant validity did not show any scaling errors for the subscales. The QLQ-EN24 module discriminated well between clinically different groups of patients. All items exhibited a high completion rate with less than 2% missing values except for the sexuality items (19%). Conclusion: The validation study supports the reliability, the convergent and divergent validity of the EORTC QLQ-EN24. This newly developed QLQ-EN24 module is a useful instrument for the assessment of the QoL in patients treated for endometrial cancer in clinical trials. [Copyright &y& Elsevier]

Purpose: To develop an atlas of the clinical target volume (CTV) definitions for postoperative radiotherapy of endometrial and cervical cancer to be used for planning pelvic intensity-modulated radiotherapy. Methods and Materials: The Radiation Therapy Oncology Group led an international collaberation of cooperative groups in the development of the atlas. The groups included the Radiation Therapy Oncology Group, Gynecologic Oncology Group, National Cancer Institute of Canada, European Society of Therapeutic Radiology and Oncology, and American College of Radiology Imaging Network. The members of the group were asked by questionnaire to define the areas that were to be included in the CTV and to outline theses areas on individual computed tomography images. The initial formulation of the group began in late 2004 and culminated with a formal consensus conference in June 2005. Results: The committee achieved a consensus CTV definition for postoperative therapy for endometrial and cervical cancer. The CTV should include the common, external, and internal iliac lymph node regions. The upper 3.0 cm of the vagina and paravaginal soft tissue lateral to the vagina should also be included. For patients with cervical cancer, or endometrial cancer with cervical stromal invasion, it is also recommended that the CTV include the presacral lymph node region. Conclusion: This report serves as an international template for the definition of the CTV for postoperative intensity-modulated radiotherapy for endometrial and cervical cancer. [Copyright &y& Elsevier]

Purpose: In 2000, the results of the multicenter Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC) trial were published. This trial included 714 Stage I endometrial carcinoma patients randomly assigned to postoperative pelvic radiotherapy (RT) or no further treatment, excluding those with Stage IC, Grade 3, or Stage IB, Grade 1 lesions. Radiotherapy significantly decreased the risk of locoregional recurrence (4% vs. 14%), without affecting overall survival. In this report the long-term outcome and results with central pathology review are presented. Methods and Materials: The slides of 569 patients (80%) could be obtained for pathology review. Median follow-up for patients alive was 97 months. Analysis was done according to the intention-to-treat principle. The primary study endpoints were locoregional recurrence and death. Results: Ten-year locoregional relapse rates were 5% (RT) and 14% (controls; p < 0.0001), and 10-year overall survival was 66% and 73%, respectively (p = 0.09). Endometrial cancer related death rates were 11% (RT) and 9% (controls; p = 0.47). Pathology review showed a substantial shift from Grade 2 to Grade 1, but no significant difference for Grade 3. When cases diagnosed at review as Grade 1 with superficial myometrial invasion were excluded from the analysis, the results remained essentially the same, with 10-year locoregional recurrence rates of 5% (RT) and 17% (controls; p < 0.0001). Conclusions: In view of the significant locoregional control benefit, radiotherapy remains indicated in Stage I endometrial carcinoma patients with high-risk features for locoregional relapse. [Copyright &y& Elsevier]

• Effective treatment options for metastatic/recurrent endometrial cancer are limited. • Hypermutated (POLE/MMRd) tumors are particularly susceptible to PD-1/PD-L1 blockers. • Homologous recombination deficient tumors may be sensitive to PARP inhibitors. • PARP inhibitors and PD-1/PD-L1 checkpoint inhibitors may synergize. • Three ongoing trials are investigating this combination in endometrial cancer. The prognosis of recurrent or metastatic endometrial cancer is poor, with five-year survival of only 10–20 %. First-line therapy consists of either platinum-based chemotherapy or hormonal therapy. No standard subsequent-line therapy has been identified. In recent years, significant progress has been made in the knowledge on underlying molecular biology of endometrial cancer and potential targets for therapy have been identified. Targeted therapies as poly (ADP-ribose) polymerase (PARP) inhibitors and immunotherapy as PD-1/PD-L1 checkpoint inhibitors have the potential to be effective against specific subtypes of endometrial cancer. Preclinical studies have shown that combining these agents may result in a synergistic effect. In this review, we focus on the molecular basis of checkpoint inhibition and targeted therapy as PARP inhibition in endometrial cancer and summarize available clinical data, and ongoing and planned clinical trials that investigate these agents as mono- or combination therapies in endometrial cancer and where relevant, other gynecological cancers. [ABSTRACT FROM AUTHOR]