The author presents a hypothesis that the complex of endocrine and metabolic disturbances arising long before the development of endometrial carcinoma determines the biological peculiarities of the tumor, its clinical course, and the prognosis of the disease. On the basis of a prospective study of 366 patients with endometrial carcinoma, the author postulates that there are two different pathogenetic types of endometrial carcinoma. The first pathogenetic type of the disease arises in women with obesity, hyperlipidemia, and signs of hyperestrogenism: anovulatory uterine bleeding, infertility, late onset of the menopause, and hyperplasia of the stroma of the ovaries and endometrium. The second pathogenetic type of the disease arises in women who have no signs stated above or these signs are not clearly defined. The frequency of the first pathogenetic type in the studied group of women was 65%, whereas the frequency of the second type was 35%. The peculiarities outlined above which are characteristic of the first pathogenetic type of the disease determine the development of highly and moderately differentiated tumors (82.3% G1 and G2), superficial invasion of the myometrium (69.4%), high sensitivity to progestogens (80.2%), and favorable prognosis (85.6% 5-year survival rate). In patients who have the second pathogenetic type of endometrial cancer when endocrine and metabolic disturbances are absent or occult, poorly differentiated tumors arise (62.5% G3), a tendency to deep invasion of tumor into the myometrium is observed (65.7%); high frequency of metastatic spread into the pelvic lymph nodes (27.8%); decrease of sensitivity to progestogens (42.5%); and doubtful prognosis (58.8% 5-year survival rate) are noted.

Endometrial cancers (ECs) with somatic mutations in DNA polymerase epsilon (POLE) are characterized by unfavorable pathological features, which prompt adjuvant treatment. Paradoxically, women with POLE-mutated EC have outstanding clinical outcomes, and this raises concerns of overtreatment. The authors investigated whether favorable outcomes were independent of treatment.A PubMed search for POLE and endometrial was restricted to articles published between March 1, 2012, and March 1, 2018, that provided individual patient data (IPD), adjuvant treatment, and survival. Following the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) reporting guidelines for IPD, the authors used univariate and multivariate one-stage meta-analyses with mixed effects Cox models (random effects for study cohorts) to infer the associations of treatment, traditional prognostic factors, and outcome, which was defined as the time from first diagnosis to any adverse event (progression/recurrence or death from EC).Three hundred fifty-nine women with POLE-mutated EC were identified; 294 (82%) had pathogenic mutations. Worse outcomes were demonstrated in patients with nonpathogenic POLE mutations (hazard ratio, 3.42; 95% confidence interval, 1.47-7.58; log-rank P <.01). Except for stage (P <.01), traditional prognosticators were not associated with progression/recurrence or death from disease. Adverse events were rare (11 progressions/recurrences and 3 disease-specific deaths). Salvage rates in patients who experienced recurrence were high and sustained, with 8 of 11 alive without evidence of disease (range, 5.5-14.2 years). Adjuvant treatment was not associated with outcome.Clinical outcomes for ECs with pathogenic POLE mutations are not associated with most traditional risk parameters, and patients do not appear to benefit from adjuvant therapy. The observed low rates of recurrence/progression and the high and sustained salvage rates raise the possibility of safely de-escalating treatment for these patients.Ten percent of all endometrial cancers have mutations in the DNA repair gene DNA polymerase epsilon (POLE). Women who have endometrial cancers with true POLE mutations experience almost no recurrences or deaths from their cancer even when their tumors appear to have very unfavorable characteristics. Additional therapy (radiation and chemotherapy) does not appear to improve outcomes for women with POLE-mutated endometrial cancer, and this supports the move to less therapy and less associated toxicity. Diligent classification of endometrial cancers by molecular features provides valuable information to inform prognosis and to direct treatment/no treatment.© 2021 American Cancer Society.

Microsatellite unstable (MSI) colorectal cancers (CRCs) are due to DNA mismatch repair (MMR) deficiency and occurs in15% of non-metastatic diseases and 5% in the metastatic setting. Nearly 30% of MSI CRCs occur in a context of constitutional mutation of the MMR system (Lynch syndrome). Others are sporadic cancers linked to a hypermethylation of the MLH-1 promoter. The pathogenic alterations of MMR genes lead to the accumulation of frequent somatic mutational events and these tumours arbour a high antigen burden and are highly infiltrated with cytotoxic T-cell lymphocytes. Microsatellite instability/DNA mismatch repair deficiency (MSI/dMMR) status has prognostic and predictive implications in non-metastatic and metastatic CRCs. The prognostic value of MSI status in non-metastatic CRCs has been studied extensively, yet the data are more limited for its predictive value in terms of adjuvant chemotherapy efficacy. In both cases (metastatic and non-metastatic settings) treatment with immune check-point inhibitors (ICIs) have shown a remarkable effectiveness in the context of MSI/dMMR status. Indeed, recent data from prospective cohorts and randomised trials have shown a dramatical improvement of survival with immunotherapy (programmed death-ligand 1 [PD-(L)1]   cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] blockage) in metastatic or non-metastatic MSI/dMMR CRC. In this review we report and discuss how and for whom to test for the MSI/dMMR phenotype, as well as the prognostic value of this phenotype and the new treatment recommendations options for this unique CRC population. Despite their efficacy, primary and secondary resistance to immune checkpoint inhibitors (ICIs) are observed in more than 50% MSI-H/dMMR CRC patients and in the future how to identify these patients and to overcome resistance will be an important challenge.Copyright © 2022 Elsevier Ltd. All rights reserved.

Recommendations for adjuvant treatment for women with early-stage endometrial carcinoma are based on clinicopathologic features. Comprehensive genomic characterization defined four subgroups: p53-mutant, microsatellite instability (MSI), POLE-mutant, and no specific molecular profile (NSMP). We aimed to confirm the prognostic capacity of these subgroups in large randomized trial populations, investigate potential other prognostic classifiers, and integrate these into an integrated molecular risk assessment guiding adjuvant therapy.Analysis of MSI, hotspot mutations in 14 genes including POLE, protein expression of p53, ARID1a, β-catenin, L1CAM, PTEN, ER, and PR was undertaken on 947 available early-stage endometrioid endometrial carcinomas from the PORTEC-1 and -2 trials, mostly high-intermediate risk (n = 614). Prognostic value was determined using univariable and multivariable Cox proportional hazard models. AUCs of different risk stratification models were compared.Molecular analyses were feasible in >96% of the patients and confirmed the four molecular subgroups: p53-mutant (9%), MSI (26%), POLE-mutant (6%), and NSMP (59%). Integration of prognostic molecular alterations with established clinicopathologic factors resulted in a stronger model with improved risk prognostication. Approximately 15% of high-intermediate risk patients had unfavorable features (substantial lymphovascular space invasion, p53-mutant, and/or >10% L1CAM), 50% favorable features (POLE-mutant, NSMP being microsatellite stable, and CTNNB1 wild-type), and 35% intermediate features (MSI or CTNNB1-mutant).Integrating clinicopathologic and molecular factors improves the risk assessment of patients with early-stage endometrial carcinoma. Assessment of this integrated risk profile is feasible in daily practice, and holds promise to reduce both overtreatment and undertreatment. Clin Cancer Res; 22(16); 4215-24. ©2016 AACR.©2016 American Association for Cancer Research.

A European consensus conference on endometrial carcinoma was held in 2014 to produce multi-disciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide.© IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.

We have previously developed and confirmed a pragmatic molecular classifier for endometrial cancers; ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer). Inspired by the Cancer Genome Atlas, ProMisE identifies four prognostically distinct molecular subtypes and can be applied to diagnostic specimens (biopsy/curettings) enabling earlier informed decision-making. We have strictly adhered to the Institute of Medicine (IOM) guidelines for the development of genomic biomarkers, and herein present the final validation step of a locked-down classifier before clinical application.We assessed a retrospective cohort of women from the Tübingen University Women's Hospital treated for endometrial carcinoma between 2003 and 2013. Primary outcomes of overall, disease-specific, and progression-free survival were evaluated for clinical, pathological, and molecular features.Complete clinical and molecular data were evaluable from 452 women. Patient age ranged from 29 to 93 (median 65) years, and 87.8% cases were endometrioid histotype. Grade distribution included 282 (62.4%) G1, 75 (16.6%) G2, and 95 (21.0%) G3 tumors. 276 (61.1%) patients had stage IA disease, with the remaining stage IB [89 (19.7%)], stage II [26 (5.8%)], and stage III/IV [61 (13.5%)]. ProMisE molecular classification yielded 127 (28.1%) MMR-D, 42 (9.3%) POLE, 55 (12.2%) p53abn, and 228 (50.4%) p53wt. ProMisE was a prognostic marker for progression-free (P = 0.001) and disease-specific (P = 0.03) survival even after adjusting for known risk factors. Concordance between diagnostic and surgical specimens was highly favorable; accuracy 0.91, κ 0.88.We have developed, confirmed, and now validated a pragmatic molecular classification tool (ProMisE) that provides consistent categorization of tumors and identifies four distinct prognostic molecular subtypes. ProMisE can be applied to diagnostic samples and thus could be used to inform surgical procedure(s) and/or need for adjuvant therapy. Based on the IOM guidelines this classifier is now ready for clinical evaluation through prospective clinical trials.

Vaginal brachytherapy is currently recommended as adjuvant treatment in patients with high-intermediate risk endometrial cancer to maximize local control and has only mild side effects and no or limited impact on quality of life. However, there is still considerable overtreatment and also some undertreatment, which may be reduced by tailoring adjuvant treatment to the patients' risk of recurrence based on molecular tumor characteristics.To compare the rates of vaginal recurrence in women with high-intermediate risk endometrial cancer, treated after surgery with molecular-integrated risk profile-based recommendations for either observation, vaginal brachytherapy or external pelvic beam radiotherapy or with standard adjuvant vaginal brachytherapy STUDY HYPOTHESIS: Adjuvant treatment based on a molecular-integrated risk profile provides similar local control and recurrence-free survival as current standard adjuvant brachytherapy in patients with high-intermediate risk endometrial cancer, while sparing many patients the morbidity of adjuvant treatment and reducing healthcare costs.A multicenter, international phase III randomized trial (2:1) of molecular-integrated risk profile-based adjuvant treatment (experimental arm) or adjuvant vaginal brachytherapy (standard arm).Women aged 18 years and over with a histological diagnosis of high-intermediate risk endometrioid endometrial cancer after total abdominal or laparoscopic hysterectomy and bilateral salpingo-oophorectomy. High-intermediate risk factors are defined as: (i) International Federation of Gynecology and Obstetrics stage IA (with invasion) and grade 3; (ii) stage IB grade 1 or 2 with age ≥60 and/or lymph-vascular space invasion; (iii) stage IB, grade 3 without lymph-vascular space invasion; or (iv) stage II (microscopic and grade 1).The primary endpoint is vaginal recurrence. Secondary endpoints are recurrence-free and overall survival; pelvic and distant recurrence; 5-year vaginal control (including treatment for relapse); adverse events and patient-reported symptoms and quality of life; and endometrial cancer-related healthcare costs.500 eligible and evaluable patients.Estimated date for completing accrual will be late 2021. Estimated date for presentation of (first) results is expected in 2023.The trial is registered at clinicaltrials.gov (NCT03469674) and ISRCTN (11659025).© IGCS and ESGO 2020. Re-use permitted under CC BY. Published by BMJ.

Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti‒programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.

Due to previously reported trastuzumab safety concerns and the scant data available in endometrial cancer patients, we sought to assess the safety, tolerability and toxicity profile of trastuzumab in patients with advanced/recurrent uterine serous carcinoma (USC) that overexpress HER2/neu in our multicenter randomized phase II trial.Patients were randomized 1:1 to receive carboplatin/paclitaxel (C/P) for 6 cycles ± trastuzumab (T) with the experimental arm continuing to receive single agent trastuzumab maintenance treatment until disease progression/toxicity. Progression-free-survival was the primary endpoint; overall-survival and toxicity were secondary endpoints. Adverse events (AEs) were compared between treatment arms.There were 28 patients in the C/P arm and 32 patients in the experimental (C/P + T) arm. Fifty-eight patients (97%) experienced 977 treatment-related AEs of which 875 (89.6%) were low-grade (grade 1-2) and 102 (10.4%) were high-grade (grade 3-5). The mean ± standard deviation of AEs per patient was 15.5 ± 16.3 in the C/P arm and 17.0 ± 16.0 in the C/P + T arm. Gastrointestinal AEs were the most common in both arms (n = 155, 15.7%) of which 94.2% were low-grade (n = 146). Importantly, no significant difference between treatment arms was detected in any system-organ class of AE including cardiac AE. Five (17%) of 29 patients who received prolonged trastuzumab maintenance therapy had no sign of cumulative toxicity after an average (range) of 5.1 (4.2-6.3) years.Trastuzumab appears to be safe and has a manageable toxicity profile both when used in combination with chemotherapy and when used for single agent maintenance in patients with HER2/neu positive USC. This safety profile is reassuring given the proven efficacy of trastuzumab in advanced/recurrent HER2/neu positive USC.Copyright © 2021 Elsevier Inc. All rights reserved.

Homologous recombination-deficient (HRD) tumours, including those harbouring mutations in the BRCA genes, are hypersensitive to treatment with inhibitors of poly(ADP-ribose) polymerase (PARPis). Despite high response rates, most HRD cancers ultimately develop resistance to PARPi treatment through reversion mutations or genetic/epigenetic alterations to DNA repair pathways. Counteracting these resistance pathways, thereby increasing the potency of PARPi therapy, represents a potential strategy to improve the treatment of HRD cancers. In this review, we discuss recent insights derived from genetic screens that have identified a number of novel genes that can be targeted to improve PARPi treatment of HRD cancers and may provide a means to overcome PARPi resistance.Copyright © 2021 Elsevier Inc. All rights reserved.

We performed genomic, epigenomic, transcriptomic, and proteomic characterizations of uterine carcinosarcomas (UCSs). Cohort samples had extensive copy-number alterations and highly recurrent somatic mutations. Frequent mutations were found in TP53, PTEN, PIK3CA, PPP2R1A, FBXW7, and KRAS, similar to endometrioid and serous uterine carcinomas. Transcriptome sequencing identified a strong epithelial-to-mesenchymal transition (EMT) gene signature in a subset of cases that was attributable to epigenetic alterations at microRNA promoters. The range of EMT scores in UCS was the largest among all tumor types studied via The Cancer Genome Atlas. UCSs shared proteomic features with gynecologic carcinomas and sarcomas with intermediate EMT features. Multiple somatic mutations and copy-number alterations in genes that are therapeutic targets were identified.Copyright © 2017 Elsevier Inc. All rights reserved.

Successfully combining targeted agents with chemotherapy is an important future goal for cancer therapy. However, an improvement in patient outcomes requires an enhanced understanding of the tumor biomarkers that predict for drug sensitivity. NRG Oncology/Gynecologic Oncology Group (GOG) Study GOG-86P was one of the first attempts to combine targeted agents (bevacizumab or temsirolimus) with chemotherapy in patients with advanced endometrial cancer. Herein we performed exploratory analyses to examine the relationship between mutations in TP53, the most commonly mutated gene in cancer, with outcomes on GOG-86P.TP53 mutational status was determined and correlated with progression-free survival (PFS) and overall survival (OS) on GOG-86P.Mutations in TP53 were associated with improved PFS and OS for patients that received bevacizumab as compared to temsirolimus (PFS: HR 0.48, 95% CI 0.31, 0.75; OS: HR: 0.61, 95% CI 0.38, 0.98). By contrast, there was no statistically significant difference in PFS or OS between arms for cases with WT TP53.This exploratory study suggests that combining chemotherapy with bevacizumab, but not temsirolimus, may enhance PFS and OS for patients whose tumors harbor mutant p53. These data set the stage for larger clinical studies evaluating the potential of TP53 mutational status as a biomarker to guide choice of treatment for endometrial cancer patients. Clintrials.gov: NCT00977574.Copyright © 2021. Published by Elsevier Inc.