A phase III randomized clinical trial comparing sentinel node biopsy with no retroperitoneal node dissection in apparent early-stage endometrial cancer - ENDO-3: ANZGOG trial 1911/2020.

BACKGROUND: Sentinel node biopsy is a surgical technique to explore lymph nodes for surgical staging of endometrial cancer, which has replaced full retroperitoneal lymph node dissection. However, the effectiveness of sentinel node biopsy, its value to patients, and potential harms compared with no-node dissection have never been shown in a randomized trial. PRIMARY OBJECTIVES: Stage 1 will test recovery from surgery. Stage 2 will compare disease-free survival at 4.5 years between patients randomized to sentinel node biopsy versus no retroperitoneal node dissection. STUDY HYPOTHESIS: The primary hypothesis for stage 1 is that treatment with sentinel node biopsy will not cause detriment to patient outcomes (lymphedema, morbidity, loss of quality of life) and will not increase treatment-related morbidity or health services costs compared with patients treated without a retroperitoneal node dissection at 12 months after surgery. The primary hypothesis for stage 2 is that disease-free survival at 4.5 years after surgery in patients without retroperitoneal node dissection is not inferior to those receiving sentinel node biopsy. TRIAL DESIGN: This phase III, open-label, two-arm, multistage, randomized non-inferiority trial (ENDO-3) will determine the value of sentinel node biopsy for surgical management of endometrial cancer. Patients with endometrial cancer are randomized to receive: (1) laparoscopic/robotic hysterectomy, bilateral salpingo-oophorectomy with sentinel node biopsy or (2) laparoscopic/robotic hysterectomy, bilateral salpingo-oophorectomy without retroperitoneal node dissection. In stage 1, 444 patients will be enrolled to demonstrate feasibility and quality of life. If this is demonstrated, we will enroll another 316 patients in stage 2. MAJOR INCLUSION AND EXCLUSION CRITERIA: Inclusion criteria include women aged 18 years or older with histologically confirmed endometrial cancer; clinical stage 1, who meet the criteria for laparoscopic or robotic total hysterectomy and bilateral salpingo-oophorectomy. Patients with uterine mesenchymal tumors are excluded. PRIMARY ENDPOINTS: The endpoint for stage 1 is surgical recovery, with the proportion of patients returning to usual daily activities at 3 months post-surgery as measured with the EQ-5D. Stage 2 is disease-free survival at 4.5 years. SAMPLE SIZE: 760 participants (both stages). ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Stage 1 commenced in January 2021 and is planned to be completed in December 2024 when 444 participants have completed 12 months' follow-up. Stage 2 will enroll a further 316 participants for a total of 760 patients. TRIAL REGISTRATION: NCT04073706.

Fertility-sparing treatment in early endometrial cancer: current state and future strategies.

Endometrial cancer (EC) is the fifth most common cancer in women worldwide. Global estimates show rising incidence rates in both developed and developing countries. Most women are diagnosed postmenopausal, but 14-25% of patients are premenopausal and 5% are under 40 years of age. Established risk factors include age and hyperestrogenic status associated with nulliparity, obesity, and metabolic syndrome. Standard treatment for EC, which involves total hysterectomy and bilateral salpingo-oophorectomy, has excellent survival outcomes, particularly for low-grade endometrioid tumors. However, it leads to permanent loss of fertility among women who wish to preserve their reproductive potential. With current trends of reproductive-age women delaying childbearing, rising EC incidence rates, and a growing epidemic of obesity, particularly in developed countries, research on conservative non-surgical treatment approaches remains a top priority. Fertility-sparing treatment predominantly involves the use of oral progestins and levonorgestrel-releasing intrauterine devices, which have been shown to be feasible and safe in women with early stage EC and minimal or no myometrial invasion. However, data on the efficacy and safety of conservative management strategies are primarily based on retrospective studies. Randomized clinical trials in younger women and high-risk obese patients are currently underway. Here, we have presented a comprehensive review of the current literature on conservative, fertility-sparing approaches, defining the optimal candidates and evaluating tumor characteristics, reproductive and oncologic outcomes, and ongoing clinical trials. We have also summarized current guidelines and recommendations based on the published literature.

Improving response to progestin treatment of low-grade endometrial cancer.

OBJECTIVES: This review examines how response rates to progestin treatment of low-grade endometrial cancer can be improved. In addition to providing a brief overview of the pathogenesis of low-grade endometrial cancer, we discuss limitations in the current classification of endometrial cancer and how stratification may be refined using molecular markers to reproducibly identify 'low-risk' cancers which may represent the best candidates for progestin therapy. We also discuss constraints in current approaches to progestin treatment of low-grade endometrial cancer and perform a systematic review of predictive biomarkers. METHODS: PubMed, ClinicalTrials.gov, and Cochrane Library were searched for studies reporting pre-treatment biomarkers associated with outcome in women with low-grade endometrial cancer or endometrial hyperplasia with an intact uterus who received progestin treatment. Studies of fewer than 50 women were excluded. The study protocol was registered in PROSPERO (ID 152374). A descriptive synthesis of pre-treatment predictive biomarkers reported in the included studies was conducted. RESULTS: Of 1908 records reviewed, 19 studies were included. Clinical features such as age or body mass index cannot predict progestin response. Lesions defined as 'low-risk' by FIGO criteria (stage 1A, grade 1) can respond well; however, the reproducibility and prognostic ability of the current histopathological classification system is suboptimal. Molecular markers can be reproducibly assessed, have been validated as prognostic biomarkers, and may inform patient selection for progestin treatment. DNA polymerase epsilon (POLE)-ultramutated tumors and a subset of p53 wild-type or DNA mismatch repair (MMR)-deficient tumors with 'low-risk' features (eg, progesterone and estrogen receptor-positive) may have improved response rates, though this needs to be validated. DISCUSSION: Molecular markers can identify cases which may be candidates for progestin treatment. More work is needed to validate these biomarkers and potentially identify new ones. Predictive biomarkers are anticipated to inform future research into progestin treatment of low-grade endometrial cancer and ultimately improve patient outcomes.

G9a-mediated repression of CDH10 in hypoxia enhances breast tumour cell motility and associates with poor survival outcome.

Rationale: Epigenetic mechanisms are fundamental processes that can modulate gene expression, allowing cellular adaptation to environmental conditions. Hypoxia is an important factor known to initiate the metastatic cascade in cancer, activating cell motility and invasion by silencing cell adhesion genes. G9a is a histone methyltransferase previously shown to accumulate in hypoxic conditions. While its oncogenic activity has been previously reported, not much is known about the role G9a plays in the hypoxia-mediated metastatic cascade. Methods: The role of G9a in cell motility in hypoxic condition was determined by inhibiting G9a either by short-hairpin mediated knock down or pharmacologically using a small molecule inhibitor. Through gene expression profiling, we identified CDH10 to be an important G9a target that regulates breast cancer cell motility. Lung metastasis assay in mice was used to determine the physiological significance of G9a. Results: We demonstrate that, while hypoxia enhances breast cancer migratory capacity, blocking G9a severely reduces cellular motility under both normoxic and hypoxic conditions and prevents the hypoxia-mediated induction of cellular movement. Moreover, inhibition of G9a histone methyltransferase activity in mice using a specific small molecule inhibitor significantly reduced growth and colonisation of breast cancer cells in the lung. We identify the type-II cadherin CDH10 as being a novel hypoxia-dependent gene, directly repressed by G9a through histone methylation. CDH10 overexpression significantly reduces cellular movements in breast cancer cell lines and prevents the hypoxia-mediated increase in cell motility. In addition, we show that CDH10 expression is prognostic in breast cancer and that it is inversely correlated to EHMT2 (G9a) transcript levels in many tumor-types, including breast cancer. Conclusion: We propose that G9a promotes cellular motility during hypoxic stress through the silencing of the cell adhesion molecule CDH10 and we describe CDH10 as a novel prognostic biomarker for breast cancer.

Mitogen-Activated Protein Kinase (MAPK) and Obesity-Related Cancer.

Obesity is a major public health concern worldwide. The increased risk of certain types of cancer is now an established deleterious consequence of obesity, although the molecular mechanisms of this are not completely understood. In this review, we aim to explore the links between MAPK signalling and obesity-related cancer. We focus mostly on p38 and JNK MAPK, as the role of ERK remains unclear. These links are seen through the implication of MAPK in obesity-related immune paralysis as well as through effects on the endoplasmic reticulum stress response and activation of aromatase. By way of example, we highlight areas of interest and possibilities for future research in endometrioid endometrial cancer and hepatocellular carcinoma associated with non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and MAPK.

Molecular basis of distinct oestrogen responses in endometrial and breast cancer.

Up to 80% of endometrial and breast cancers express oestrogen receptor alpha (ERα). Unlike breast cancer, anti-oestrogen therapy has had limited success in endometrial cancer, raising the possibility that oestrogen has different effects in both cancers. We investigated the role of oestrogen in endometrial and breast cancers using data from The Cancer Genome Atlas (TCGA) in conjunction with cell line studies. Using phosphorylation of ERα (ERα-pSer118) as a marker of transcriptional activation of ERα in TCGA datasets, we found that genes associated with ERα-pSer118 were predominantly unique between tumour types and have distinct regulators. We present data on the alternative and novel roles played by SMAD3, CREB-pSer133 and particularly XBP1 in oestrogen signalling in endometrial and breast cancer.

Jak2V617F and Dnmt3a loss cooperate to induce myelofibrosis through activated enhancer-driven inflammation.

Myeloproliferative neoplasms (MPNs) are a group of blood cancers that arise following the sequential acquisition of genetic lesions in hematopoietic stem and progenitor cells (HSPCs). We identify mutational cooperation between Jak2V617F expression and Dnmt3a loss that drives progression from early-stage polycythemia vera to advanced myelofibrosis. Using in vivo, clustered regularly interspaced short palindromic repeats (CRISPR) with CRISPR-associated protein 9 (Cas9) disruption of Dnmt3a in Jak2V617F knockin HSPC, we show that Dnmt3a loss blocks the accumulation of erythroid elements and causes fibrotic infiltration within the bone marrow and spleen. Transcriptional analysis and integration with human data sets identified a core DNMT3A-driven gene-expression program shared across multiple models and contexts of Dnmt3a loss. Aberrant self-renewal and inflammatory signaling were seen in Dnmt3a-/- Jak2V617F HSPC, driven by increased chromatin accessibility at enhancer elements. These findings identify oncogenic cooperativity between Jak2V617F-driven MPN and Dnmt3a loss, leading to activation of HSPC enhancer-driven inflammatory signaling.

Surgical safety and personal costs in morbidly obese, multimorbid patients diagnosed with early-stage endometrial cancer having a hysterectomy.

BACKGROUND: Many women who develop endometrial cancer (EC) or endometrial hyperplasia with atypia are obese and therefore at high risk of surgical complications. Recently clinical trials have been initiated offering non-surgical treatment to these women, but not all may agree to participate in such trials. This paper aims to describe the patient characteristics, and surgical outcomes of women with suspected early stage endometrial cancer and body mass index (BMI) of 30 or greater, who declined enrolment in the feMMe trial, which offers non-surgical hormonal treatment, hormonal plus metformin or hormonal plus weight loss as primary treatment. METHODS: Consecutive case series from a tertiary gynaecological oncology unit. Over the course of the first 2 years of the feMMe trial, 27 patients met the initial eligibility screening, but declined enrolment in the feMMe trial and opted for upfront surgery. The main surgical outcome measures were type of surgical approach, need for conversion from laparoscopic to open approach, length of stay in hospital and adverse events. RESULTS: Patients' median age was 63 years (range 40 to 86); median BMI was 37.3 kg/m2 (range 30.7 to 54.7); median medical co-morbidities were six (range 3-10). Of the 26/27 surgeries planned to be undertaken laparoscopically, 2/26 patients had to be converted (7 %). Overall, the average hospital stay was 4.5 days, and 11/27 (41 %) of the patients developed one or more adverse events grade 2+ rated according to the Common Toxicity Criteria Version 3. CONCLUSIONS: Adverse surgical outcomes are common in multi-morbid, obese or morbidly obese patients diagnosed with early stage EC or endometrial hyperplasia with atypia and who have a hysterectomy.

Epigenetic regulation in cancer progression.

Cancer is a disease arising from both genetic and epigenetic modifications of DNA that contribute to changes in gene expression in the cell. Genetic modifications include loss or amplification of DNA, loss of heterozygosity (LOH) as well as gene mutations. Epigenetic changes in cancer are generally thought to be brought about by alterations in DNA and histone modifications that lead to the silencing of tumour suppressor genes and the activation of oncogenic genes. Other consequences that result from epigenetic changes, such as inappropriate expression or repression of some genes in the wrong cellular context, can also result in the alteration of control and physiological systems such that a normal cell becomes tumorigenic. Excessive levels of the enzymes that act as epigenetic modifiers have been reported as markers of aggressive breast cancer and are associated with metastatic progression. It is likely that this is a common contributor to the recurrence and spread of the disease. The emphasis on genetic changes, for example in genome-wide association studies and increasingly in whole genome sequencing analyses of tumours, has resulted in the importance of epigenetic changes having less attention until recently. Epigenetic alterations at both the DNA and histone level are increasingly being recognised as playing a role in tumourigenesis. Recent studies have found that distinct subgroups of poor-prognosis tumours lack genetic alterations but are epigenetically deregulated, pointing to the important role that epigenetic modifications and/or their modifiers may play in cancer. In this review, we highlight the multitude of epigenetic changes that can occur and will discuss how deregulation of epigenetic modifiers contributes to cancer progression. We also discuss the off-target effects that epigenetic modifiers may have, notably the effects that histone modifiers have on non-histone proteins that can modulate protein expression and activity, as well as the role of hypoxia in epigenetic regulation.