Publications by authors named "Richard Edmondson"

57 Publications

Factors determining ultra-short-term survival and the commencement of active treatment in high-grade serous ovarian cancer: a case comparison study.

BMC Cancer 2021 Apr 8;21(1):378. Epub 2021 Apr 8.

Division of Cancer Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, St Mary's Hospital, Research Floor, Oxford Road, Manchester, M13 9WL, UK.

Background: Despite improvements in median survival some patients with advanced ovarian cancer die within 100 days of diagnosis; the reasons for which remain poorly understood. Here we investigate if ultra short-term survival can be explained by patient characteristics or treatment pathways.

Methods: A nested case comparison study was used to examine differences between patients with high grade serous ovarian/fallopian tube cancer who died within 100 days (n = 28) compared to a comparison group of patients matched for histology and including any survival greater than 100 days (n = 134).

Results: Cases and comparison patients had similar ages, BMI, ACE-27, deprivation indices, and distribution of disease on CT. There were no significant delays in time to diagnosis or treatment (p = 0.68) between the groups. However, cases had lower serum albumin, haemoglobin and higher platelet counts than matched comparison patients (p < 0.0001) and a worse performance score (P = 0.006).

Conclusion: Patients who die rapidly after a diagnosis of ovarian cancer are only slightly older and have similar pre treatment frailty compared to patients whose survival approaches the median. However they do appear to undergo greater physiological compromise as a result of their disease.
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http://dx.doi.org/10.1186/s12885-021-08019-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034099PMC
April 2021

A Prospective Study to Identify Rates of SARS-CoV-2 Virus in the Peritoneum and Lower Genital Tract of Patients Having Surgery: An Observational Study.

J Minim Invasive Gynecol 2021 Feb 11. Epub 2021 Feb 11.

Department of Obstetrics and Gynaecology, Manchester University NHS Foundation Trust (Ms. Jones, Mr. Faluyi, Ms. Hamilton, Mr. Ma and Dr. Edmondson); Division of Cancer Sciences, Faculty of Biology, Medicine and Health, Saint Mary's Hospital, University of Manchester (Dr. Edmondson), Manchester, United Kingdom.. Electronic address:

Study Objective: The risks to surgeons of carrying out aerosol-generating procedures during the coronavirus disease 2019 (COVID-19) pandemic are unknown. To start to define these risks, in a systematic manner, we investigated the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus in the abdominal fluid and lower genital tract of patients undergoing surgery.

Design: Prospective cross-sectional observational study.

Setting: Single, large United Kingdom hospital.

Patients: Total of 113 patients undergoing abdominal surgery or instrumentation of the lower genital tract.

Interventions: We took COVID-19 swabs from the peritoneal cavity and from the vagina from all eligible patients. Results were stratified by preoperative COVID-19 status.

Measurements And Main Results: In patients who were presumed COVID-19 negative at the time of surgery, SARS-CoV-2 virus RNA was detected in 0 of 102 peritoneal samples and 0 of 98 vaginal samples. Both cohorts included 4 patients who were antibody positive but nasopharyngeal swab test negative at the time of surgery. Peritoneal and vaginal swabs were also negative in 1 patient who had a positive nasopharyngeal swab immediately before surgery.

Conclusion: The presence of SARS-CoV-2 RNA in the abdominal fluid or lower genital tract of presumed negative patients is nil or extremely low. These data will inform surgeons of the risks of restarting laparoscopic surgery at a time when COVID-19 is endemic in the population.
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http://dx.doi.org/10.1016/j.jmig.2021.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877891PMC
February 2021

Uptake and efficacy of bilateral risk reducing surgery in unaffected female and carriers.

J Med Genet 2021 Feb 10. Epub 2021 Feb 10.

Manchester Centre for Genomic Medicine, Central Manchester NHS Foundation Trust, Manchester, UK

Background: Women testing positive for pathogenic variants have high lifetime risks of breast cancer (BC) and ovarian cancer. The effectiveness of risk reducing surgery (RRS) has been demonstrated in numerous previous studies. We evaluated long-term uptake, timing and effectiveness of risk reducing mastectomy (RRM) and bilateral salpingo-oophorectomy (RRSO) in healthy carriers.

Methods: Women were prospectively followed up from positive genetic test (GT) result to censor date. χ² testing compared categorical variables; Cox regression model estimated HRs and 95% CI for BC/ovarian cancer cases associated with RRS, and impact on all-cause mortality; Kaplan-Meier curves estimated cumulative RRS uptake. The annual cancer incidence was estimated by women-years at risk.

Results: In total, 887 women were included in this analysis. Mean follow-up was 6.26 years (range=0.01-24.3; total=4685.4 women-years). RRS was performed in 512 women, 73 before GT. Overall RRM uptake was 57.9% and RRSO uptake was 78.6%. The median time from GT to RRM was 18.4 months, and from GT to RRSO-10.0 months. Annual BC incidence in the study population was 1.28%. Relative BC risk reduction (RRM versus non-RRM) was 94%. Risk reduction of ovarian cancer (RRSO versus non-RRSO) was 100%.

Conclusion: Over a 24-year period, we observed an increasing number of women opting for RRS. We showed that the timing of RRS remains suboptimal, especially in women undergoing RRSO. Both RRM and RRSO showed a significant effect on relevant cancer risk reduction. However, there was no statistically significant RRSO protective effect on BC.
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http://dx.doi.org/10.1136/jmedgenet-2020-107356DOI Listing
February 2021

British Gynaecological Cancer Society/British Association of Gynaecological Pathology consensus for germline and tumor testing for 1/2 variants in ovarian cancer in the United Kingdom.

Int J Gynecol Cancer 2021 Feb 19;31(2):272-278. Epub 2021 Jan 19.

Birmingham Women's and Children's NHS Trust, Birmingham, UK.

The British Gynecological Cancer Society and the British Association of Gynecological Pathologists established a multidisciplinary consensus group comprising experts in surgical gynecological oncology, medical oncology, genetics, and laboratory science, and clinical nurse specialists to identify the optimal pathways to germline and tumor testing in patients with ovarian cancer in routine clinical practice. In particular, the group explored models of consent, quality standards identified at pathology laboratories, and experience and data from pioneering cancer centers. The group liaised with representatives from ovarian cancer charities to also identify patient perspectives that would be important to implementation. Recommendations from these consensus group deliberations are presented in this manuscript.
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http://dx.doi.org/10.1136/ijgc-2020-002112DOI Listing
February 2021

Engineering microrobots for targeted cancer therapies from a medical perspective.

Nat Commun 2020 11 5;11(1):5618. Epub 2020 Nov 5.

Institute for Integrative Nanosciences, Leibniz IFW Dresden, Helmholtzstraße 20, 01069, Dresden, Germany.

Systemic chemotherapy remains the backbone of many cancer treatments. Due to its untargeted nature and the severe side effects it can cause, numerous nanomedicine approaches have been developed to overcome these issues. However, targeted delivery of therapeutics remains challenging. Engineering microrobots is increasingly receiving attention in this regard. Their functionalities, particularly their motility, allow microrobots to penetrate tissues and reach cancers more efficiently. Here, we highlight how different microrobots, ranging from tailor-made motile bacteria and tiny bubble-propelled microengines to hybrid spermbots, can be engineered to integrate sophisticated features optimised for precision-targeting of a wide range of cancers. Towards this, we highlight the importance of integrating clinicians, the public and cancer patients early on in the development of these novel technologies.
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http://dx.doi.org/10.1038/s41467-020-19322-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645678PMC
November 2020

Specialist oncological surgery for removal of the ovaries and fallopian tubes in BRCA1 and BRCA2 pathogenic variant carriers may reduce primary peritoneal cancer risk to very low levels.

Int J Cancer 2021 Mar 11;148(5):1155-1163. Epub 2020 Nov 11.

Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.

Risk-reducing bilateral salpingo-oophorectomy (RRBSO) is highly effective for the prevention of high-grade serous ovarian cancer (HGSOC) in BRCA1/2 pathogenic variant carriers (PVCs), but does not completely eliminate future risk of primary peritoneal cancer (PPC). The requirement to completely remove fallopian tubes at RRBSO and carefully exclude occult cancer/serous tubal intraepithelial carcinoma (STIC) lesions may not have been appreciated historically. We calculated rates of HGSOC and PPC in confirmed BRCA1/2 PVCs registered on the regional database in those who did (cases) and did not (controls) undergo RRBSO after genetic testing. Expected annual rates of ovarian/peritoneal cancer were 1% for BRCA1 ≥ 35 years and 0.5% for BRCA2 ≥ 45 years. Follow-up before 35/45 years was "risk free" and lead time excluded RRBSO <35 years and <45 years for BRCA1 and BRCA2, respectively. Women were followed from personal mutation report (controls) or RRBSO (cases) to death, ovarian/peritoneal cancer or last follow-up, whichever was sooner. In total, 891 cases (BRCA1 = 468, BRCA2 = 423) and 1302 controls had follow-up ≥35 years (BRCA1 = 736) and ≥45 years (BRCA2 = 566), respectively, over a total of 7261.1 risk eligible years (mean = 8.15 years). Twenty-one occult ovarian cancers were found at RRBSO (2.4%), 16 at stage 1. Post RRBSO, 56.97 ovarian/peritoneal cancers were expected but only 3 were observed (HR = 0.053; 95% CI = 0.013-0.14), with combined Kaplan-Meier analysis HR = 0.029 (95% CI = 0.009-0.100, P < .001). Risk reduction was greater in specialist (HR = 0.03; 95% CI = 0.001-0.13) compared to non-specialist centres (HR = 0.11; 95% CI = 0.02-0.37) (P = .07). In controls, 23.35 ovarian/peritoneal cancers were expected with 32 observed (HR = 1.37; 95% CI = 0.95-1.91). RRBSO <35/<45 years reduces the risk of ovarian/peritoneal cancer by 95% in BRCA1/2 PVCs and may be greater in specialist centres.
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http://dx.doi.org/10.1002/ijc.33378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839461PMC
March 2021

Human spermbots for patient-representative 3D ovarian cancer cell treatment.

Nanoscale 2020 Oct;12(39):20467-20481

Institute for Integrative Nanosciences, Leibniz IFW Dresden, Helmholtzstraße 20, 01069 Dresden, Germany. and Research Centre for Materials, Architectures and Integration of Nanomembranes (MAIN), Rosenbergstraße 6, TU Chemnitz, 09126 Chemnitz, Germany and Material Systems for Nanoelectronics, TU Chemnitz, Reichenhainer Straße 70, 09126 Chemnitz, Germany and School of Science, TU Dresden, 01062 Dresden, Germany.

Cellular micromotors are attractive for locally delivering high concentrations of drug, and targeting hard-to-reach disease sites such as cervical cancer and early ovarian cancer lesions by non-invasive means. Spermatozoa are highly efficient micromotors perfectly adapted to traveling up the female reproductive system. Indeed, bovine sperm-based micromotors have shown potential to carry drugs toward gynecological cancers. However, due to major differences in the molecular make-up of bovine and human sperm, a key translational bottleneck for bringing this technology closer to the clinic is to transfer this concept to human material. Here, we successfully load human sperm with Doxorubicin (DOX) and perform treatment of 3D cervical cancer and patient-representative ovarian cancer cell cultures, resulting in strong anticancer cell effects. Additionally, we define the subcellular localization of the chemotherapeutic drug within human sperm, using high-resolution optical microscopy. We also assess drug effects on sperm motility and viability over time, employing sperm samples from healthy donors as well as assisted reproduction patients. Finally, we demonstrate guidance and release of human drug-loaded sperm onto cancer tissues using magnetic microcaps, and show the sperm microcap loaded with a second anticancer drug, camptothecin (CPT), which unlike DOX is not suitable for directly loading into sperm due to its hydrophobic nature. This co-drug delivery approach opens up novel targeted combinatorial drug therapies for future applications.
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http://dx.doi.org/10.1039/d0nr04488aDOI Listing
October 2020

PROgesterone Therapy for Endometrial Cancer Prevention in Obese Women (PROTEC) Trial: A Feasibility Study.

Cancer Prev Res (Phila) 2020 Sep 30. Epub 2020 Sep 30.

Division of Gynaecology, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom.

Obesity is the major etiologic driver for endometrial cancer. The levonorgestrel intrauterine system (LNG-IUS) reduces the risk of endometrial cancer and its precursor, atypical hyperplasia. We assessed feasibility and uptake of the LNG-IUS for primary prevention of endometrial cancer in high-risk women and its impact on endometrial tissue biomarkers. Women with class-III obesity [body mass index (BMI) > 40 kg/m] and histologically normal endometrium were invited to participate in a clinical trial of the LNG-IUS for endometrial protection. Recruitment, successful LNG-IUS insertion, and adherence to trial procedures were recorded. We measured impact of the LNG-IUS on circulating biomarkers of endometrial cancer risk, endometrial proliferation (Ki-67, pAKT, PTEN), endometrial hormone receptor status [estrogen receptor and progesterone receptor (PR)], mental wellbeing, and menstrual function. At 6 months, women chose to keep their LNG-IUS or have it removed. In total, 103 women were approached, 54 were offered a participant information sheet, 35 agreed to participate, and 25 received a LNG-IUS. Their median age and BMI were 54 years [interquartile range (IQR) 52-57] and 47 kg/m (IQR 44-51), respectively. Three women (3/35, 9%) were ineligible due to atypical hyperplasia/endometrial cancer on their baseline biopsy. The LNG-IUS was well tolerated and had a positive overall effect on bleeding patterns and mental wellbeing. The LNG-IUS was associated with endometrial morphologic change, reduced Ki-67, and PR expression, but circulating biomarkers of endometrial cancer risk were unchanged. All but one woman (96%) kept her LNG-IUS. The LNG-IUS appears to be acceptable to some women with class-III obesity for primary prevention of endometrial cancer, which could provide a strategy for a prevention trial. PREVENTION RELEVANCE: Novel strategies are urgently needed to prevent the rise in endometrial cancer diagnoses predicted by escalating obesity rates. Here, we show that women with class III obesity are willing to engage in risk reduction with a levonorgestrel intrauterine system, which could provide a strategy for an endometrial cancer prevention trial.
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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0248DOI Listing
September 2020

Molecular Classification of the PORTEC-3 Trial for High-Risk Endometrial Cancer: Impact on Prognosis and Benefit From Adjuvant Therapy.

J Clin Oncol 2020 10 4;38(29):3388-3397. Epub 2020 Aug 4.

Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.

Purpose: The randomized Adjuvant Chemoradiotherapy Versus Radiotherapy Alone in Women With High-Risk Endometrial Cancer (PORTEC-3) trial investigated the benefit of combined adjuvant chemotherapy and radiotherapy (CTRT) versus radiotherapy alone (RT) for women with high-risk endometrial cancer (EC). Because The Cancer Genome Atlas defined an EC molecular classification with strong prognostic value, we investigated prognosis and impact of chemotherapy for each molecular subgroup using tissue samples from PORTEC-3 trial participants.

Methods: Paraffin-embedded tissues of 423 consenting patients were collected. Immunohistochemistry for p53 and mismatch repair (MMR) proteins, and DNA sequencing for exonuclease domain were done to classify tumors as p53 abnormal (p53abn), ultramutated (mut), MMR-deficient (MMRd), or no specific molecular profile (NSMP). The primary end point was recurrence-free survival (RFS). Kaplan-Meier method, log-rank test, and Cox model were used for analysis.

Results: Molecular analysis was successful in 410 high-risk EC (97%), identifying the 4 subgroups: p53abn EC (n = 93; 23%), mut (n = 51; 12%), MMRd (n = 137; 33%), and NSMP (n = 129; 32%). Five-year RFS was 48% for patients with p53abn EC, 98% for mut EC, 72% for MMRd EC, and 74% for NSMP EC ( < .001). The 5-year RFS with CTRT versus RT for p53abn EC was 59% versus 36% ( = .019); 100% versus 97% for patients with mut EC ( = .637); 68% versus 76% ( = .428) for MMRd EC; and 80% versus 68% ( = .243) for NSMP EC.

Conclusion: Molecular classification has strong prognostic value in high-risk EC, with significantly improved RFS with adjuvant CTRT for p53abn tumors, regardless of histologic type. Patients with mut EC had an excellent RFS in both trial arms. EC molecular classification should be incorporated in the risk stratification of these patients as well as in future trials to target specific subgroups of patients.
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http://dx.doi.org/10.1200/JCO.20.00549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527156PMC
October 2020

BRCA1 and BRCA2 pathogenic variant carriers and endometrial cancer risk: A cohort study.

Eur J Cancer 2020 09 19;136:169-175. Epub 2020 Jul 19.

Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK; Division of Evolution and Genomic Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. Electronic address:

Background: An association between BRCA pathogenic variants and an increased endometrial cancer risk, specifically serous-like endometrial cancer, has been postulated but remains unproven, particularly for BRCA2 carriers. Mechanistic evidence is lacking, and any link may be related to tamoxifen exposure or testing bias. Hysterectomy during risk-reducing bilateral salpingo-oophorectomy is, therefore, of uncertain benefit. Data from a large, prospective cohort will be informative.

Methods: Data on UK BRCA pathogenic variant carriers were interrogated for endometrial cancer diagnoses. Standardised incidence ratios (SIRs) were calculated in four distinct cohorts using national endometrial cancer rates; either from 1/1/1980 or age 20, prospectively from date of personal pathogenic variant report, date of family pathogenic variant report or date of risk-reducing salpingo-oophorectomy. Somatic BRCA sequencing of 15 serous endometrial cancers was performed to detect pathogenic variants.

Results: Fourteen cases of endometrial cancer were identified in 2609 women (1350 BRCA1 and 1259 BRCA2), of which two were prospectively diagnosed. No significant increase in either overall or serous-like endometrial cancer risk was identified in any of the cohorts examined (SIR = 1.70, 95% confidence interval = 0.74-3.33; no cases of serous endometrial cancer diagnosed). Results were unaffected by the BRCA gene affected, previous breast cancer or tamoxifen use. No BRCA pathogenic variants were detected in any of the serous endometrial cancers tested.

Conclusions: Women with a BRCA pathogenic variant do not appear to have a significant increased risk of all-type or serous-like endometrial cancer compared with the general population. These data provide some reassurance that hysterectomy is unlikely to be of significant benefit if performed solely as a preventive measure.
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http://dx.doi.org/10.1016/j.ejca.2020.05.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441309PMC
September 2020

Mainstreaming germline BRCA1/2 testing in non-mucinous epithelial ovarian cancer in the North West of England.

Eur J Hum Genet 2020 11 10;28(11):1541-1547. Epub 2020 Jul 10.

St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, UK.

Poly(ADP-ribose) polymerase (PARP) inhibitors improve survival in BRCA-mutant high-grade serous ovarian carcinoma. As a result, germline and somatic BRCA1/2 testing has become standard practice in women diagnosed with ovarian cancer. We outline changes in testing and detection rates of germline BRCA1/2 pathogenic variants (PVs) in cases of non-mucinous epithelial ovarian cancer diagnosed during three eras, spanning 12 years, within the North West of England, and compare the uptake of cascade testing in families identified by oncology-led mainstreaming versus regional genetics clinics. Eras included: Period 1 (20% risk threshold for testing): between January 2007 and May 2013; Period 2 (10% risk threshold for testing): between June 2013 and October 2017 and; Period 3 (mainstream testing): between November 2017 and November 2019. A total of 1081 women underwent germline BRCA1/2 testing between January 2007 and November 2019 and 222 (20.5%) were found to have a PV. The monthly testing rate increased by 3.3-fold and 2.5-fold between Periods 1-2 and Periods 2-3, respectively. A similar incidence of germline BRCA1/2 PVs were detected in Period 2 (17.2%) and Period 3 (18.5%). Uptake of cascade testing from first-degree relatives was significantly lower in those women undergoing mainstream testing compared with those tested in regional genetics clinics (31.6% versus 47.3%, P = 0.038). Mainstream testing allows timely detection of germline BRCA1/2 status to select patients for PARP inhibitors, but shortfalls in the uptake of cascade testing in first-degree relatives requires optimisation to broaden benefits within families.
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http://dx.doi.org/10.1038/s41431-020-0692-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575602PMC
November 2020

First-Line Management of Advanced High-Grade Serous Ovarian Cancer.

Curr Oncol Rep 2020 06 4;22(6):64. Epub 2020 Jun 4.

Department of Medical Oncology, Christie NHS Foundation Trust, Wilmslow Road, Withington, Manchester, M20 4BX, UK.

Purpose Of Review: Epithelial ovarian cancer is a disease that encompasses a number of histologically and molecularly distinct entities; the most prevalent subtype being high-grade serous (HGS) carcinoma. Standard first-line treatment of advanced HGS carcinoma includes cytoreductive surgery plus intravenous paclitaxel/platinum-based chemotherapy. Despite excellent responses to initial treatment, the majority of patients develop recurrent disease within 3 years. The introduction of the vascular endothelial growth factor (VEGF) inhibitor, bevacizumab, and poly(ADP-ribose) polymerase (PARP) inhibitors into first-line management has changed the outlook for this lethal disease. In this review, we summarise the most recent clinical trials that determine current primary therapy of advanced HGS carcinoma and the ongoing trials that aim to change management in the future.

Recent Findings: Recent phase III clinical trials have shown that delayed primary surgery after completing neo-adjuvant chemotherapy is non-inferior to immediate primary surgery, but could provide a survival benefit in FIGO (International Federation of Gynecology and Obstetrics) stage IV disease. The use of weekly intravenous chemotherapy regimens has not been proven to be more effective than standard 3-weekly regimens in Western patient populations, and the use of intraperitoneal chemotherapy remains controversial in the first-line setting. In contrast, newer systemic anti-cancer therapies targeting angiogenesis and/or HR-deficient tumours have been successfully incorporated into front-line therapeutic regimens to treat HGS carcinoma. Recent results from randomised trials investigating the use of PARP inhibitors as monotherapy and in combination with the anti-angiogenic agent, bevacizumab, have demonstrated highly impressive efficacy when combined with traditional first-line multi-modality therapy. Management of HGS carcinoma is evolving, but further work is still required to optimise and integrate tumour and plasma biomarkers to exploit the potential of these highly efficacious targeted agents.
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http://dx.doi.org/10.1007/s11912-020-00933-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270049PMC
June 2020

A living biobank of ovarian cancer ex vivo models reveals profound mitotic heterogeneity.

Nat Commun 2020 02 13;11(1):822. Epub 2020 Feb 13.

Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Cancer Research Centre, Wilmslow Road, Manchester, M20 4GJ, UK.

High-grade serous ovarian carcinoma is characterised by TP53 mutation and extensive chromosome instability (CIN). Because our understanding of CIN mechanisms is based largely on analysing established cell lines, we developed a workflow for generating ex vivo cultures from patient biopsies to provide models that support interrogation of CIN mechanisms in cells not extensively cultured in vitro. Here, we describe a "living biobank" of ovarian cancer models with extensive replicative capacity, derived from both ascites and solid biopsies. Fifteen models are characterised by p53 profiling, exome sequencing and transcriptomics, and karyotyped using single-cell whole-genome sequencing. Time-lapse microscopy reveals catastrophic and highly heterogeneous mitoses, suggesting that analysis of established cell lines probably underestimates mitotic dysfunction in advanced human cancers. Drug profiling reveals cisplatin sensitivities consistent with patient responses, demonstrating that this workflow has potential to generate personalized avatars with advantages over current pre-clinical models and the potential to guide clinical decision making.
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http://dx.doi.org/10.1038/s41467-020-14551-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018727PMC
February 2020

Decision-Making in Gynaecological Oncology Multidisciplinary Team Meetings: A Cross-Sectional, Observational Study of Ovarian Cancer Cases.

Oncol Res Treat 2020 19;43(3):70-77. Epub 2019 Nov 19.

Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St Mary's Hospital, Manchester, United Kingdom,

Introduction: Multidisciplinary team (MDT) meetings are widely used across the UK to provide expert decisions and improve cancer outcomes. However, little is known about the underlying mechanisms of MDT decision-making. We investigated how decisions are made regarding the management of advanced ovarian cancer in gynaecological oncology MDT meetings.

Methods: A cross-sectional observational study was performed, focussing on 41/ 223 MDT case discussions across six hospitals. The validated MDT-MODe tool was adapted to increase relevance to gynaecological oncology. Case information and contributions from seven disciplines were rated on a five-point Likert scale. Spearman's correlation investigated relationships between factors and an exploratory factor analysis examined the underlying structure of MDT discussion.

Results: Forty-one MDT decisions were made for patients with FIGO Stage III/IV ovarian cancer. MDT case discussions were structured by four factors: "Clinical Presentation," "Patient Factors," "Chair's Direction" and "Input from Other Specialties." Nurses were often quiet but facilitated discussion of patient factors. Junior doctors were not involved in MDT decision-making.

Conclusions: The decision-making process in MDT meetings is driven by four underlying factors, the most significant of which represents patient history, tumour markers, images and radiologist input. Patient factors were underrepresented, and nurses should be empowered to overcome this.
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http://dx.doi.org/10.1159/000504260DOI Listing
July 2020

Phase 2 study of anastrozole in recurrent estrogen (ER)/progesterone (PR) positive endometrial cancer: The PARAGON trial - ANZGOG 0903.

Gynecol Oncol 2019 07 23;154(1):29-37. Epub 2019 May 23.

Royal Hospital for Women, Prince of Wales Hospital and Prince of Wales Clinical School, University of New South Wales, Sydney, Australia.

Background: The clinical benefit rate with aromatase inhibitors and the impact of treatment on quality of life (QOL) in endometrial cancer is unclear. We report the results of a phase 2 trial of anastrozole in endometrial cancer.

Methods: Investigator initiated single-arm, open label trial of anastrozole, 1 mg/d in patients with ER and/or PR positive hormonal therapy naive metastatic endometrial cancer. Patients were treated until progressive disease (PD) or unacceptable toxicity. The primary end-point was clinical benefit (response + stable disease) at 3 months. Secondary endpoints include progression-free survival (PFS), quality of life (QOL) and toxicity.

Results: Clinical benefit rate in 82 evaluable patients at 3 months was 44% (95% CI: 34-55%) with a best response by RECIST of partial response in 6 pts. (7%; 95% CI: 3-15%). The median PFS was 3.2 months (95% CI: 2.8-5.4). Median duration of clinical benefit was 5.6 months (95% CI: 3.0-13.7). Treatment was well tolerated. Patients who had clinical benefit at 3 months reported clinically significant improvements in several QOL domains compared to those with PD; this was evident by 2 months including improvements in: emotional functioning (39 vs 6%: p = 0.002), cognitive functioning (45 vs 19%: p = 0.021), fatigue (47 vs 19%: p = 0.015) and global health status (42 vs 9%: p = 0.003).

Conclusion: Although the objective response rate to anastrozole was relatively low, clinical benefit was observed in 44% of patients with ER/PR positive metastatic endometrial cancer and associated with an improvement in QOL.
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http://dx.doi.org/10.1016/j.ygyno.2019.05.007DOI Listing
July 2019

Epithelial ovarian cancer risk: A review of the current genetic landscape.

Clin Genet 2020 01 29;97(1):54-63. Epub 2019 May 29.

Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.

Ovarian cancer is the fourth most common cause of cancer-related death in women in the developed world, and one of the most heritable cancers. One of the most significant risk factors for epithelial ovarian cancer (EOC) is a family history of breast and/or ovarian cancer. Combined risk factors can be used in models to stratify risk of EOC, and aid in decisions regarding risk-reduction strategies. Germline pathogenic variants in EOC susceptibility genes including those involved in homologous recombination and mismatch repair pathways are present in approximately 22% to 25% of EOC. These genes are associated with an estimated lifetime risk of EOC of 13% to 60% for BRCA1 variants and 10% to 25% for BRCA2 variants, with lower risks associated with remaining genes. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) thought to explain an additional 6.4% of the familial risk of ovarian cancer, with 34 susceptibility loci identified to date. However, an unknown proportion of the genetic component of EOC risk remains unexplained. This review comprises an overview of individual genes and SNPs suspected to contribute to risk of EOC, and discusses use of a polygenic risk score to predict individual cancer risk more accurately.
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http://dx.doi.org/10.1111/cge.13566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017781PMC
January 2020

Prevalence of germline pathogenic variants in sequential epithelial ovarian cancer cases.

J Med Genet 2019 05 25;56(5):301-307. Epub 2019 Jan 25.

Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, UK.

Introduction: Poly(ADP-ribose) polymerase inhibitors significantly improve progression-free survival in platinum-sensitive high-grade serous and endometrioid ovarian carcinoma, with greatest benefits observed in women with a pathogenic / variant. Consequently, the demand for germline testing in ovarian cancer has increased substantially, leading to the screening of unselected populations of patients. We aimed to determine the prevalence of pathogenic germline variants in women diagnosed with epithelial ovarian cancer, categorised according to the established risk factors for hereditary breast and ovarian cancer syndrome and the Manchester BRCA Score, to inform risk stratification.

Methods: A cohort of sequential epithelial ovarian cancer cases recruited between June 2013 and September 2018 underwent germline testing by next-generation sequencing and multiplex ligation-dependent probe amplification.

Results: Five hundred and fifty-seven patients were screened. Of these, 18% had inherited a pathogenic / variant. The prevalence of pathogenic variants was >10% in women diagnosed with ovarian cancer earlier than 60 years of age (21%) and those diagnosed later than 60 years of age with a family history of breast and/or ovarian cancer (17%) or a medical history of breast cancer (34%). The prevalence of pathogenic variants was also >10% in women with a Manchester BRCA Score of ≥15 points (14%).

Discussion: Our study suggests that age at diagnosis, family history of breast and/or ovarian cancer, medical history of breast cancer or a Manchester BRCA Score of ≥15 points are associated with a >10% prevalence of germline pathogenic / variants in epithelial ovarian cancer.
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http://dx.doi.org/10.1136/jmedgenet-2018-105792DOI Listing
May 2019

Impact of surgical site infection (SSI) following gynaecological cancer surgery in the UK: a trainee-led multicentre audit and service evaluation.

BMJ Open 2019 01 24;9(1):e024853. Epub 2019 Jan 24.

Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

Objectives: Surgical site infection (SSI) complicates 5% of all surgical procedures in the UK and is a major cause of postoperative morbidity and a substantial drain on healthcare resources. Little is known about the incidence of SSI and its consequences in women undergoing surgery for gynaecological cancer. Our aim was to perform the first national audit of SSI following gynaecological cancer surgery through the establishment of a UK-wide trainee-led research network.

Design And Setting: In a prospective audit, we collected data from all women undergoing laparotomy for suspected gynaecological cancer at 12 specialist oncology centres in the UK during an 8-week period in 2015. Clinicopathological data were collected, and wound complications and their sequelae were recorded during the 30 days following surgery.

Results: In total, 339 women underwent laparotomy for suspected gynaecological cancer during the study period. A clinical diagnosis of SSI was made in 54 (16%) women. 33% (18/54) of women with SSI had prolonged hospital stays, and 11/37 (29%) had their adjuvant treatment delayed or cancelled. Multivariate analysis found body mass index (BMI) was the strongest risk factor for SSI (OR 1.08[95% CI 1.03 to 1.14] per 1 kg/m increase in BMI [p=0.001]). Wound drains (OR 2.92[95% CI 1.41 to 6.04], p=0.004) and staple closure (OR 3.13[95% CI 1.50 to 6.56], p=0.002) were also associated with increased risk of SSI.

Conclusions: SSI is common in women undergoing surgery for gynaecological cancer leading to delays in discharge and adjuvant treatment. Resultant delays in adjuvant treatment may impact cancer-specific survival rates. Modifiable factors, such as choice of wound closure material, offer opportunities for reducing SSI and reducing morbidity in these women. There is a clear need for new trials in SSI prevention in this patient group; our trainee-led initiative provides a platform for their successful completion.
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http://dx.doi.org/10.1136/bmjopen-2018-024853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347877PMC
January 2019

Copy number signatures and mutational processes in ovarian carcinoma.

Nat Genet 2018 09 13;50(9):1262-1270. Epub 2018 Aug 13.

Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.

The genomic complexity of profound copy number aberrations has prevented effective molecular stratification of ovarian cancers. Here, to decode this complexity, we derived copy number signatures from shallow whole-genome sequencing of 117 high-grade serous ovarian cancer (HGSOC) cases, which were validated on 527 independent cases. We show that HGSOC comprises a continuum of genomes shaped by multiple mutational processes that result in known patterns of genomic aberration. Copy number signature exposures at diagnosis predict both overall survival and the probability of platinum-resistant relapse. Measurement of signature exposures provides a rational framework to choose combination treatments that target multiple mutational processes.
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http://dx.doi.org/10.1038/s41588-018-0179-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130818PMC
September 2018

Ex vivo expanded tumour-infiltrating lymphocytes from ovarian cancer patients release anti-tumour cytokines in response to autologous primary ovarian cancer cells.

Cancer Immunol Immunother 2018 Oct 23;67(10):1519-1531. Epub 2018 Jul 23.

Gynaecological Oncology, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.

Epithelial ovarian cancer (EOC) is the leading cause of gynaecological cancer-related death in Europe. Although most patients achieve an initial complete response with first-line treatment, recurrence occurs in more than 80% of cases. Thus, there is a clear unmet need for novel second-line treatments. EOC is frequently infiltrated with T lymphocytes, the presence of which has been shown to be associated with improved clinical outcomes. Adoptive T-cell therapy (ACT) using ex vivo-expanded tumour-infiltrating lymphocytes (TILs) has shown remarkable efficacy in other immunogenic tumours, and may represent a promising therapeutic strategy for EOC. In this preclinical study, we investigated the efficacy of using anti-CD3/anti-CD28 magnetic beads and IL-2 to expand TILs from freshly resected ovarian tumours. TILs were expanded for up to 3 weeks, and then subjected to a rapid-expansion protocol (REP) using irradiated feeder cells. Tumours were collected from 45 patients with EOC and TILs were successfully expanded from 89.7% of biopsies. Expanded CD4 and CD8 subsets demonstrated features associated with memory phenotypes, and had significantly higher expression of key activation and functional markers than unexpanded TILs. Expanded TILs produced anti-tumour cytokines when co-cultured with autologous tumour cells, inferring tumour cytotoxicity. Our findings demonstrate that it is possible to re-activate and expand tumour-reactive T cells from ovarian tumours. This presents a promising immunotherapy that could be used sequentially or in combination with current therapeutic strategies.
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http://dx.doi.org/10.1007/s00262-018-2211-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182400PMC
October 2018

Refinement of high-risk endometrial cancer classification using DNA damage response biomarkers: a TransPORTEC initiative.

Mod Pathol 2018 12 28;31(12):1851-1861. Epub 2018 Jun 28.

Gustave Roussy, Gynecology Unit, U981 INSERM, Villejuif, France.

The TransPORTEC consortium previouslclassified high-risk endometrial cancer including poor-risk histologies such as clear cells, into four molecular subtypes "POLE mutated," "microsatellite unstable," "TP53 mutated," and "no specific molecular profile." We evaluated whether DNA damage response biomarkers could further refine this high-risk tumors classification, in particular the heterogeneous "no specific molecular profile" and "TP53 mutated" subsets recently qualified as poor prognosis in high-risk endometrial cancer. DNA damage response biomarkers including proteins involved in DNA damage (δ-H2AX), homologous recombination (RAD51), regulators of error-prone Non Homologous End-Joining (DNA-pk, FANCD2), and PARP-1 were evaluated in 116 high-risk tumors by immunohistochemistry. CD8 and PD-1 expression by immunochemistry and mutation analyses were performed previously. Survival outcome were calculated using Kaplan-Meier and Log-rank test. None of the DNA damage response biomarkers alone were prognostic. However markers were informative within molecular subsets. Among the "no specific molecular profile" subset, δ-H2AX+ was significantly predictive of poor disease free survival (Hazard Ratio = 2.56; p = 0.026), and among "TP53 mutated," a DNA-pk+/FANCD2- profile (favouring error-prone Non Homologous End-Joining) predicted worst disease free survival (Hazard Ratio = 4.95; p = 0.009) resulting in five distinct prognostic subgroups from best to worst prognosis: group1 "POLE mutated/Microsatellite unstable" > group2 "no specific molecular profile with no DNA damage" > group3 "TP53 mutated/Non Homologous End-Joining negative" > group4 "no specific molecular profile with high DNA damage" > group5 "TP53 mutated/Non Homologous End-Joining positive"; p = 0.0002). Actionable targets were also different among subsets. Group3 had significantly higher infiltration of PD-1+ immune cells (p = 0.003), segregating with group1. Group2 had frequent PI3K pathway mutations and ER positivity. While group5, with the worst prognosis, had high DNA damage and PARP-1 expression providing a rationale for PARP inhibition. Our findings have refined the TransPORTEC prognostic classification of high-risk endometrial cancer into five distinct subgroups by integrating DNA damage response biomarkers and identified molecular subtype-specific therapeutic strategies.
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http://dx.doi.org/10.1038/s41379-018-0055-1DOI Listing
December 2018

DNA damage repair in ovarian cancer: unlocking the heterogeneity.

J Ovarian Res 2018 Jun 20;11(1):50. Epub 2018 Jun 20.

Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St Mary's Hospital, Manchester, UK.

Treatment for advanced ovarian cancer is rarely curative; three quarters of patients with advanced disease relapse and ultimately die with resistant disease. Improving patient outcomes will require the introduction of new treatments and better patient selection. Abrogations in the DNA damage response (DDR) may allow such stratifications.A defective DNA-damage response (DDR) is a defining hallmark of high grade serous ovarian cancer (HGSOC). Indeed, current evidence indicates that all HGSOCs harbour a defect in at least one major DDR pathway. However, defective DDR is not mediated through a single mechanism but rather results from a variety of (epi)genetic lesions affecting one or more of the five major DNA repair pathways. Understanding the relationship between these pathways and how these are abrogated will be necessary in order to facilitate appropriate selection of both existing and novel agents.Here we review the current understanding of the DDR with regard to ovarian, and particularly high grade serous, cancer, with reference to existing and emerging treatments as appropriate.
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http://dx.doi.org/10.1186/s13048-018-0424-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6011341PMC
June 2018

PARP inhibitors in platinum-sensitive high-grade serous ovarian cancer.

Cancer Chemother Pharmacol 2018 04 20;81(4):647-658. Epub 2018 Feb 20.

Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.

Purpose: Poly(ADP-ribose) polymerase inhibitors (PARPi) have changed the management of high-grade serous ovarian cancer (HGSOC). The rationale for the development of PARPi was based on the concept of synthetic lethality, in which a cell can survive a deficiency of one gene/gene product, but may die if there is a deficiency in a combination of genes/gene products. In women with BRCA1/2 deficiency within their ovarian cancer tissue, inhibition of PARP imposes an intolerable burden of DNA damage repair deficiency and may induce cell death.

Methods: Clinical trials have evaluated PARPi as single-agent therapeutics and as maintenance treatment following platinum-based chemotherapy for HGSOC. Clinical data suggest the most impressive anti-tumour activity occurs in women with platinum-sensitive ovarian cancer and germline or somatic BRCA1/2 mutations (g/sBRCAmt).

Results: In the maintenance setting, randomised trials have shown that PARPi compared to placebo reduce the hazard ratio for the development of progressive disease to 0.2-0.27 for patients with a g/sBRCAmt; to 0.34-0.38 for patients with putative evidence of DNA damage repair deficiency; and to 0.35-0.45 in an unselected population with HGSOC. Furthermore, phase 1/2 trials have reported single-agent anti-tumour response rates in gBRCAmt of approximately 50% in platinum-sensitive and 25% in platinum-resistant disease.

Conclusion: Here, we discuss the evidence for the use of PARPi as single-agent therapeutics and maintenance treatment in HGSOC and evaluate the genetic assays used in clinical trials so far. We discuss the emerging role of platinum sensitivity as a broad eligibility criteria for the use of PARPi.
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http://dx.doi.org/10.1007/s00280-018-3532-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854713PMC
April 2018

Interventions for weight reduction in obesity to improve survival in women with endometrial cancer.

Cochrane Database Syst Rev 2018 02 1;2:CD012513. Epub 2018 Feb 1.

Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, 5th Floor - Research, St Mary's Hospital, Manchester, UK, M13 9WL.

Background: Diagnoses of endometrial cancer are increasing secondary to the rising prevalence of obesity. Obesity plays an important role in promoting the development of endometrial cancer, by inducing a state of unopposed oestrogen excess, insulin resistance and inflammation. It also affects treatment, increasing the risk of surgical complications and the complexity of radiotherapy planning, and may additionally impact on subsequent survival. Weight-loss interventions have been associated with improvements in breast and colorectal cancer-specific survival as well as a reduction in the risk of cardiovascular disease, a frequent cause of death in endometrial cancer survivors.

Objectives: To determine the impact of weight-loss interventions, in addition to standard management of endometrial cancer, on overall survival and the frequency of adverse events.Secondary objectives include an assessment of weight-loss interventions on endometrial cancer-specific survival, weight loss achieved, cardiovascular event frequency and quality of life both overall and stratified according to patient body mass index (BMI), where possible.

Search Methods: This review searched Cochrane Central Register of Controlled Trials, MEDLINE, Embase and reference lists of articles, trial registries, and international gynaecological oncology conference abstracts from inception to January 2018.

Selection Criteria: Randomised controlled trials (RCTs) of interventions to facilitate weight loss in overweight or obese women undergoing treatment for, or previously treated for, endometrial cancer were selected.

Data Collection And Analysis: Two review authors independently selected studies, assessed trial quality, and extracted data with disagreements resolved by a third review author. Study authors were contacted to obtain missing data, including details of any adverse events.

Main Results: We included three RCTs in the review, randomising a total of 161 overweight and obese women with endometrial cancer. All studies compared combined behavioural and lifestyle interventions to facilitate weight loss through dietary modification and increased physical activity. The included RCTs were of low or very low quality, due to high risk of bias by failing to blind participants, personnel and outcome assessors, and significant loss to follow-up (attrition rate up to 29%).Combined behaviour and lifestyle interventions were not associated with improved overall survival (risk ratio (RR mortality), 0.23 95% confidence interval (CI) 0.01 to 4.55, P = 0.34, one RCT, 37 participants; very low-certainty evidence) compared with usual care at 24 months. There was no evidence that such interventions were associated with improvements in cancer-specific survival or cardiovascular event frequency as no cancer-related deaths, myocardial infarctions or strokes were reported in the included studies. None of the included RCTs reported data for the outcome of recurrence-free survival. Combined behaviour and lifestyle interventions were not associated with significant weight loss at either six months (mean difference (MD) -1.88 kg, 95% CI -5.98 to 2.21 kg, P = 0.37, three RCTs, 131 participants, I= 0%; low-certainty evidenc e)or 12 months (MD -8.98 kg, 95% CI -19.88 to 1.92 kg, P = 0.11, two RCTs, 91 participants, I= 0%; very low-certainty evidence) when compared with usual care. Combined behaviour and lifestyle interventions were not associated with increased quality of life, when measured using either the SF-12 Physical Health questionnaire or FACT-G at six months (FACT-G MD 2.51, 95% CI -5.61 to 10.64, P = 0.54, two RCTs, 95 participants, I= 83%; very low-certainty evidence), or by FACT-G alone at 12 months (MD 2.77, 95% CI -0.65 to 6.20, P = 0.11, two RCTs, 89 participants, I= 0%; very low-certainty evidence) when compared with usual care. No serious adverse events, for example hospitalisation or deaths, were reported in included trials. Lifestyle and behavioural interventions were associated with a higher risk of musculoskeletal symptoms (RR 19.03, 95% CI 1.17, 310.52, P = 0.04, two RCTs, 91 participants; low-certainty evidence).

Authors' Conclusions: There is currently insufficient high-quality evidence to determine the effect of combined lifestyle and behavioural interventions on survival, quality of life, or significant weight loss in women with a history of endometrial cancer compared to those receiving usual care. The limited evidence suggests that there is little or no serious or life-threatening adverse effects due to these interventions, although musculoskeletal problems were increased, presumably due to increased activity levels. Our conclusion is based on low- and very low-quality evidence from a small number of trials and very few patients. We therefore have very little confidence in the evidence: the true effect of weight-loss interventions in obese women with endometrial cancer is currently not known.Further methodologically-rigorous, adequately-powered RCTs are required with follow-up of 5 to 10 years duration. These should focus on the effects of varying dietary modification regimens, pharmacological treatments associated with weight loss and bariatric surgery on survival, quality of life, weight loss and adverse events.
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http://dx.doi.org/10.1002/14651858.CD012513.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6491136PMC
February 2018

Preclinical Assessment of CAR T-Cell Therapy Targeting the Tumor Antigen 5T4 in Ovarian Cancer.

J Immunother 2018 Apr;41(3):130-140

Oxford BioMedica (UK) Limited, Windrush Court, Transport Way, Oxford, UK.

Chimeric antigen receptor (CAR) T cells represent a novel targeted approach to overcome both quantitative and qualitative shortfalls of the host immune system relating to the detection and subsequent destruction of tumors. The identification of antigens expressed specifically on the surface of tumor cells is a critical first step in the ability to utilize CAR T cells for the treatment of cancer. The 5T4 is a tumor-associated antigen which is expressed on the cell surface of most solid tumors including ovarian cancer. Matched blood and tumor samples were collected from 12 patients with ovarian cancer; all tumors were positive for 5T4 expression by immunohistochemistry. Patient T cells were effectively transduced with 2 different anti-5T4 CAR constructs which differed in their affinity for the target antigen. Co-culture of CAR T cells with matched autologous tumor disaggregates resulted in antigen-specific secretion of IFN-gamma. Furthermore, assessment of the efficacy of anti-5T4 CAR T cells in a mouse model resulted in therapeutic benefit against established ovarian tumors. These results demonstrate proof of principle that 5T4 is an attractive target for immune intervention in ovarian cancer and that patient T cells engineered to express a 5T4-specific CAR can recognize and respond physiologically to autologous tumor cells.
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http://dx.doi.org/10.1097/CJI.0000000000000203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895166PMC
April 2018

The unrecognized burden of cardiovascular risk factors in women newly diagnosed with endometrial cancer: A prospective case control study.

Gynecol Oncol 2018 01 24;148(1):154-160. Epub 2017 Nov 24.

Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St Mary's Hospital, Manchester M13 9WL, United Kingdom; Department of Obstetrics and Gynaecology, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, United Kingdom. Electronic address:

Background: Cardiovascular disease is a major cause of death in endometrial cancer survivors. The aim of this study was to determine whether women newly diagnosed with endometrial cancer have a higher prevalence of cardiovascular risk factors than the general population.

Methods: The prevalence of adequately treated and unrecognized/inadequately treated cardiovascular risk factors and the corresponding 10-year cardiovascular risk by QRISK2 score was measured in 150 consecutive women undergoing primary treatment for endometrioid endometrial cancer in the North West of England, and 746 age and ethnicity-matched control women from the Health Survey for England 2014.

Results: Women with endometrial cancer had higher proportions of obesity (BMI≥30 60.7% vs. 32.4%, p<0.0001) and a preponderance of unrecognized and inadequately treated cardiovascular risk factors. Compared with controls, endometrial cancer cases had a higher prevalence of incident hyperglycemia (57.2%vs.11.5%, p<0.0001), total: HDL cholesterol ratio>4.5 (26.7%vs.13.7%, p<0.0001), and were more likely to have three or more cardiovascular risk factors (22%vs.6%, p<0.0001). This equates to a higher 10-year cardiovascular risk (median QRISK2 score 12.6% vs. 8.8%, p<0.0001). Optimization of risk factors would have a greater impact on absolute cardiovascular disease risk for cases than controls (QRISK2 score reduction 1.8% vs. 0.7%).

Conclusions: Women undergoing primary treatment for endometrial cancer have a higher prevalence of cardiovascular risk factors than women without the disease. Early identification and treatment of these risk factors could improve outcomes for endometrial cancer survivors.
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http://dx.doi.org/10.1016/j.ygyno.2017.11.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562057PMC
January 2018

Combination treatment with rucaparib (Rubraca) and MDM2 inhibitors, Nutlin-3 and RG7388, has synergistic and dose reduction potential in ovarian cancer.

Oncotarget 2017 Sep 15;8(41):69779-69796. Epub 2017 Jul 15.

Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne NE2 4HH, United Kingdom.

Ovarian cancer is the seventh most common cancer worldwide for females and the most lethal of all gynecological malignancies. The treatment of ovarian cancer remains a challenge in spite of advances in debulking surgery and changes in both chemotherapy schedules and routes of administration. Cancer treatment has recently been improving with the introduction of targeted therapies to achieve greater specificity and less cytotoxicity. Both PARP inhibitors and MDM2-p53 binding antagonists are targeted therapeutic agents entered into clinical trials. This preclinical study evaluated the effect of Nutlin-3/RG7388 and rucaparib as single agents and in combination together in a panel of ovarian cancer cell lines. Median-drug-effect analysis showed Nutlin-3/RG7388 combination with rucaparib was additive to, or synergistic in a cell type-dependent manner. Mechanism studies showed rucaparib alone had no effect on p53 stabilization or activity. Although treatment with Nutlin-3 or RG7388 induced stabilization of p53 and upregulation of p21 and MDM2, the addition of rucaparib did not enhance the p53 activation seen with the MDM2 inhibitors alone. These results demonstrate that the synergistic effect on growth inhibition observed in the combination between rucaparib and Nutlin-3/RG7388 is not the result of increased p53 molecular pathway activation. Nevertheless, combined treatment of Nutlin-3/RG7388 with rucaparib increased cell cycle arrest and apoptosis, which was marked for A2780 and IGROV-1. These data indicate that combination treatment with MDM2 inhibitors and rucaparib has synergistic and dose reduction potential for the treatment of ovarian cancer, dependent on cell type.
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http://dx.doi.org/10.18632/oncotarget.19266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642516PMC
September 2017

Functional characterisation of a novel ovarian cancer cell line, NUOC-1.

Oncotarget 2017 Apr;8(16):26832-26844

Division of Molecular and Clinical Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St Mary's Hospital, Manchester, UK.

Background: Cell lines provide a powerful model to study cancer and here we describe a new spontaneously immortalised epithelial ovarian cancer cell line (NUOC-1) derived from the ascites collected at a time of primary debulking surgery for a mixed endometrioid / clear cell / High Grade Serous (HGS) histology.

Results: This spontaneously immortalised cell line was found to maintain morphology and epithelial markers throughout long-term culture. NUOC-1 cells grow as an adherent monolayer with a doubling time of 58 hours. The cells are TP53 wildtype, positive for PTEN, HER2 and HER3 expression but negative for oestrogen, progesterone and androgen receptor expression. NUOC-1 cells are competent in homologous recombination and non-homologous end joining, but base excision repair defective. Karyotype analysis demonstrated a complex tetraploid karyotype. SNP array analysis of parent and derived subpopulations (NUOC-1-A1 and NUOC-1-A2) cells demonstrated heterogeneous cell populations with numerous copy number alterations and a pro-amplification phenotype. The characteristics of this new cell line lends it to be an excellent model for investigation of a number of the identified targets.

Materials And Methods: The cell line has been characterised for growth, drug sensitivity, expression of common ovarian markers and mutations, clonogenic potential and ability to form xenografts in SCID mice. Copy number changes and clonal evolution were assessed by SNP arrays.
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http://dx.doi.org/10.18632/oncotarget.15821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432300PMC
April 2017

BGCS uterine cancer guidelines: Recommendations for practice.

Eur J Obstet Gynecol Reprod Biol 2017 Jun 13;213:71-97. Epub 2017 Apr 13.

British Gynaecological Cancer Society, C/O Williams Denton CYF, Bangor LL57 4FE, United Kingdom.

The British Gynaecological Cancer Society has issued the first Endometrial (Uterine) Cancer guidelines as recommendation for practice for the UK.
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http://dx.doi.org/10.1016/j.ejogrb.2017.04.015DOI Listing
June 2017

Ki-67 in endometrial cancer: scoring optimization and prognostic relevance for window studies.

Mod Pathol 2017 03 2;30(3):459-468. Epub 2016 Dec 2.

Division of Molecular and Clinical Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St Mary's Hospital, Manchester, UK.

Ki-67, a marker of cellular proliferation, is increasingly being used in pre-surgical window studies in endometrial cancer as a primary outcome measure. Unlike in breast cancer, however, there are no guidelines standardizing its measurement and its clinical relevance as a response biomarker is undetermined. It is, therefore, imperative that Ki-67 scoring protocols are optimized and its association with patient survival rigorously evaluated, in order to be able to clinically interpret the results of these studies. Using the International Ki-67 in Breast Cancer Working Group guidelines as a basis, whole slide, hot spot and invasive edge scoring protocols were evaluated using endometrial biopsies and hysterectomy specimens from 179 women. Whole sections and tissue microarrays, manual and semi-automated scoring using Definiens Developer software were additionally compared. Ki-67 scores were related to clinicopathological variables and cancer-specific survival in uni- and multivariate analysis. Against criteria of time efficiency, intra- and inter-observer variability and consistency, semi-automated hot spot scoring was the preferred method. Ki-67 scores positively correlated with grade, stage and depth of myometrial invasion (P-values all <0.03). By univariate analysis, higher Ki-67 scores were associated with a significant reduction in cancer-specific survival (P≤0.05); however, this effect was substantially attenuated in the multivariate model. In conclusion, hot spot scoring of whole sections using Definiens is an optimal method to quantify Ki-67 in endometrial cancer window study specimens. Measured this way, it is a clinically relevant marker, though further work is required to determine whether reductions in Ki-67 in neoadjuvant intervention studies translate into improved patient outcome.
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http://dx.doi.org/10.1038/modpathol.2016.203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5337118PMC
March 2017